EP3250167A1 - Traitement prophylactique par laser à micro-impulsions infraliminaire pour maladies évolutives chroniques de la rétine - Google Patents

Traitement prophylactique par laser à micro-impulsions infraliminaire pour maladies évolutives chroniques de la rétine

Info

Publication number
EP3250167A1
EP3250167A1 EP15880626.5A EP15880626A EP3250167A1 EP 3250167 A1 EP3250167 A1 EP 3250167A1 EP 15880626 A EP15880626 A EP 15880626A EP 3250167 A1 EP3250167 A1 EP 3250167A1
Authority
EP
European Patent Office
Prior art keywords
retinal
laser light
laser
treatment
retina
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP15880626.5A
Other languages
German (de)
English (en)
Other versions
EP3250167A4 (fr
Inventor
Jeffrey K. LUTTRULL
Benjamin W. L. Margolis
David B. Chang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ojai Retinal Technology LLC
Original Assignee
Ojai Retinal Technology LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/607,959 external-priority patent/US9168174B2/en
Priority claimed from US14/921,890 external-priority patent/US9381116B2/en
Application filed by Ojai Retinal Technology LLC filed Critical Ojai Retinal Technology LLC
Publication of EP3250167A1 publication Critical patent/EP3250167A1/fr
Publication of EP3250167A4 publication Critical patent/EP3250167A4/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A61F9/00821—Methods or devices for eye surgery using laser for coagulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A61F2009/00861—Methods or devices for eye surgery using laser adapted for treatment at a particular location
    • A61F2009/00863—Retina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/008—Methods or devices for eye surgery using laser
    • A61F2009/00897—Scanning mechanisms or algorithms

Definitions

  • the present invention generally relates to phototherapy or
  • the present invention is directed to a process for treating an eye to stop or delay the onset of symptoms of retinal diseases in a patient using harmless, subthreshold phototherapy or photostimulation of the retina.
  • Diabetic macular edema is the most common cause of legal blindness in this patient group. Diabetes mellitus, the cause of diabetic retinopathy, and thus diabetic macular edema, is increasing in incidence and prevalence worldwide, becoming epidemic not only in the developed world, but in the developing world as well. Diabetic retinopathy may begin to appear in persons with Type I (insulin-dependent) diabetes within three to five years of disease onset.
  • Type I insulin-dependent
  • diabetic retinopathy increases with duration of disease. By ten years, 1 4%-25% of patients will have diabetic macular edema. By twenty years, nearly 1 00% will have some degree of diabetic retinopathy. Untreated, patients with clinically significant diabetic macular edema have a 32% three-year risk of potentially disabling moderate visual loss.
  • Photocoagulation has been found to be an effective means of producing retinal scars, and has become the technical standard for macular photocoagulation for diabetic macu lar edema. Due to the clinical effectiveness of retinal laser photocoagulation, the long-held view in medicine was that the beneficial effects of treatment were due to the retinal damage created by photocoagulation.
  • a "threshold" lesion is one that is barely visible
  • a "subthreshold” lesion is one that is not visible at treatment time
  • "suprathreshold” laser therapy is retinal photocoagulation performed to a readily visible endpoint.
  • Traditional retinal photocoagulation treatment requires a visible endpoint either to produce a "threshold” lesion or a “suprathreshold” lesion so as to be readily visible and tracked.
  • tissue damage and scarring are necessary in order to create the benefits of the procedure.
  • the gray to white retinal burns testify to the thermal retinal destruction inherent in conventional threshold and suprathreshold photocoagulation.
  • FIG. 1 a diagrammatic view of an eye, generally referred to by the reference number 1 0, is shown.
  • the laser light is passed through the patient's cornea 1 2, pupil 1 4, and lens 1 6 and directed onto the retina 1 8.
  • the retina 1 8 is a thin tissue layer which captures light and transforms it into the electrical signals for the brain. It has many blood vessels, such as those referred to by reference number 20, to nourish it.
  • Various retinal diseases and disorders, and particularly vascular retinal diseases such as diabetic retinopathy, are treated using conventional thermal retinal photocoagulation, as discussed above.
  • the fovea/macula region referred to by the reference number 22 in FIG.
  • the fovea is at the center of the macu la, where the concentration of the cells needed for central vision is the highest. Although it is this area where diseases such as age-related macular degeneration are so damaging, this is the area where conventional
  • photocoagulation phototherapy cannot be used as damaging the cells in the foveal area can significantly damage the patient's vision. Thus, with current convention photocoagulation therapies, the foveal region is avoided.
  • FIGS. 2A-2 F are graphic representations of the effective surface area of various modes of retinal laser treatment for retinal vascular disease.
  • the gray background represents the retina 30 which is unaffected by the laser treatment.
  • the black areas 32 are areas of the retina which are destroyed by conventional laser techniques.
  • the lighter gray or white areas 34 represent the areas of the retina affected by the laser, but not destroyed.
  • FIG. 2A illustrates the therapeutic effect of conventional argon laser retinal photocoagulation.
  • the therapeutic effects attributed to laser-induced thermal retinal destruction include reduced metabolic demand, debulking of diseased retina, increased intraocular oxygen tension and ultra production of vasoactive cytokines, including vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • thermal tissue damage may be the sole sou rce of the many potential complications of conventional photocoagulation which may lead to immediate and late visual loss.
  • complications include inadvertent foveal burns, pre- and sub-retinal fibrosis, choroidal neovascularization, and progressive expansion of laser scars.
  • Inflammation resulting from the tissue destruction may cause or exacerbate macular edema, induced precipitous contraction of fibrovascular proliferation with retinal detachment and vitreous hemorrhage, and cause uveitis, serous choroidal detachment, angle closure or hypotony.
  • retinal photocoagulation treatment typically using a visible laser light
  • retinal photocoagulation treatment is the current standard of care for proliferative diabetic retinopathy, as well as other retinopathy and retinal diseases, including diabetic macular edema and retinal venous occlusive diseases which also respond well to retinal photocoagulation treatment.
  • retinal photocoagulation is the current standard of care for many retinal diseases, including diabetic retinopathy.
  • Point-by-point treatment of a large number of locations tends to be a lengthy procedure, which frequently results in physician fatigue and patient discomfort.
  • the present invention is directed to a process for treating an eye to stop or delay the onset or symptoms of retinal diseases in a patient.
  • the process generally comprises the steps of determining that an eye has a risk for a retinal disease before detectable retinal imaging abnormalities.
  • a laser light beam is generated that creates sublethal, true subthreshold photocoagulation in retinal tissue that provides preventative and protective treatment of the retinal tissue of the eye.
  • the treated retina may comprise the fovea, foveola, retinal pigment epithelium, choroid, choroidal neovascular membrane, subretinal fluid, macula, macu lar edema, parafovea, and /or perifovea.
  • the laser light beam may be exposed to substantially the entire retina and fovea.
  • Determining that an eye of the patient has a risk for a retinal disease before detectable retinal imaging abnormalities may include the step of ascertaining that the patient is at risk for a chronic progressive retinopathy, including diabetes, a risk for age-related macular degeneration or retinitis pigmentosa, or results of a retinal examination or retinal test of the patient is abnormal.
  • a test may be conducted to establish that the patient has a risk for a retinal disease.
  • the test may comprise a retinal physiology test or a genetic test.
  • the laser light beam may be generated as a subthreshold sublethal micropulse laser light beam having a wavelength greater than 532nm and a duty cycle of less than 1 0%. In one embodiment, the generated laser light beam has a duty cycle of approximately 5% or less. The generated laser light beam may have a wavelength between 550nm and 1 300nm. In one embodiment, the generated laser light beam has a wavelength of approximately 81 Onm. The generated laser light beam may have an intensity of between 1 00- 590 watts per square centimeter at a treatment spot on the retina. The generated laser light beam has a pulse length of less than 500 milliseconds.
  • the laser light beam may be manipulated into a geometric object or pattern of simultaneously generated and spaced apart treatment laser light spots with each spot having the intensity cited in paragraph 22.
  • manipulated laser light beam may comprise the step of creating a
  • the moving step may include the step of incrementally moving the laser light beam geometric object or pattern a sufficient distance from where the laser light beam geometric object or pattern was previously applied to the retina to preclude thermal tissue damage.
  • the retina may be retreated periodically.
  • the retreating of the retina may be according to a set schedule. Additionally, or alternatively, visual and/or retinal function or condition of the patient is monitored to determine when the retina of the patient is to be retreated.
  • FIG. 24 Other features and advantages of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention.
  • FIGURE 1 is a cross-sectional diagrammatic view of a human eye
  • FIGURES 2A-2 D are graphic representations of an effective su rface area of various modes of retinal laser treatment performed in accordance with the prior art
  • FIGURES 3A and 3 B are graphic representations of effective surface areas of retinal laser treatment, in accordance with the present invention.
  • FIGURE 4 is a diagrammatic view illustrating a system used to generate a laser light beam and treat an eye, in accordance with the present invention
  • FIGURE 5 is a diagrammatic view of optics used to generate a laser light geometric pattern, in accordance with the present invention.
  • FIGURE 6 is a diagrammatic view illustrating an alternate
  • FIGURE 7 is a diagrammatic view illustrating yet another embodiment of a system used to generate laser light beams to treat an eye in accordance with the present invention.
  • FIGURE 8 is a top plan view of an optical scanning mechanism, used in accordance with the present invention.
  • FIGURE 9 is a partially exploded view of the optical scanning mechanism of FIG. 8, illustrating various component parts thereof.
  • FIGURE 1 0 is a diagrammatic view illustrating the offsetting of a geometric pattern of laser spots over multiple exposures so as to substantially cover an area of the eye being treated, in accordance with the present
  • the present invention is directed to a therapeutic process for treating an eye to stop or delay the onset or symptoms of retinal diseases, including chronic progressive retinal diseases, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD).
  • retinal diseases including chronic progressive retinal diseases, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD).
  • DR diabetic retinopathy
  • AMD age-related macular degeneration
  • RPE retinal pigment epithelium
  • a subthreshold, sublethal micropulse laser light beam which has a wavelength greater than 532nm and a duty cycle of less than 1 0% at a predetermined intensity or power and a predetermined pulse length or exposure time creates desirable retinal photocoagulation, shown by the reference number 28 in FIGS. 3A and 3B, without any visible burn areas or tissue destruction.
  • a laser light beam having a wavelength of between 550nm- l 300nm, and in a particularly preferred embodiment 81 Onm, having a duty cycle of approximately 5% or less and a predetermined intensity or power (such as between 1 00-590 watts per square centimeter for each treatment spot at the retina) and a predetermined pulse length or exposure time (such as 500 milliseconds or less) creates a sublethal, "true subthreshold" retinal photocoagulation in which all areas of the retinal pigment epithelium exposed to the laser irradiation are preserved and available to contribute therapeutically.
  • the inventors have found that raising the retinal tissue at least up to a therapeutic level but below a cellular or tissue lethal level recreates the benefit of the halo effect (referred to by the reference number 26 in FIGS. 2A-2C) without destroying, burning or otherwise damaging the retinal tissue.
  • This is referred to herein as subthreshold diode micropulse laser treatment (SDM).
  • FIGURE 3A represents a low-density treatment of the sublethal, "true subthreshold” SDM or low-intensity laser, such as a micropulsed laser, spots applied to retinal tissue 1 8 to create sublethal, subthreshold retinal photostimu lation, shown by the reference number 28, without any visible burn areas.
  • SDM does not produce laser-induced retinal damage
  • DME diabetic macular edema
  • PDR proliferative diabetic retinopathy
  • BRVO branch retinal vein occlusion
  • CSR chorioretinopathy
  • the present invention can be performed in a high- density manner, as illustrated in FIG. 3 B so as to essentially cover the entire treatment area, and even the entire retina, including the fovea.
  • Traditional and conventional laser photocoagulation treatment is unable to treat the entire retina, including the fovea, as the inherent burns and damage caused by the treatment can impair the vision of the patient or even cause blindness.
  • SDM does not cause tissue damage and has no known adverse treatment effect.
  • SDM has been reported to be an effective treatment in a number of retinal disorders, including DME, proliferative diabetic retinopathy (PDR), macular edema due to branch retinal vein occlusion (BRVO), and central serous chorioretinopathy (CSR).
  • PDR proliferative diabetic retinopathy
  • BRVO branch retinal vein occlusion
  • CSR central serous chorioretinopathy
  • the safety of SDM is such that it may be used transfoveally in eyes with 20/20 visual acuity to reduce the risk of visual loss due to early fovea-involving DME. It is believed that SDM works by targeting, preserving, and normalizing - moving toward normal - function of the RPE.
  • HSPs heat shock proteins
  • DR diabetic retinopathy
  • electrophysiology visual acuity, contrast visual acu ity and improved macular sensitivity measured by microperimetry, as well as long-term effects, such as reduction of DME and involution of retinal neovascularization.
  • SDM near infrared laser effects
  • SDM treatment of patients suffering from age-related macular degeneration can slow the progress or even stop the progression of AMD.
  • Most of the patients have seen significant improvement in dynamic functional logMAR visual acuity and contrast visual acuity after the SDM treatment, with some experiencing better vision. It is believed that SDM works by targeting, preserving, and "normalizing” (moving toward normal) function of the retinal pigment epithelium (RPE).
  • RPE retinal pigment epithelium
  • SDM has also been shown to stop or reverse the manifestations of the diabetic retinopathy disease state without treatment-associated damage or adverse effects, despite the persistence of systemic diabetes mellitus. On this basis it is hypothesized that SDM might work by inducing a return to more normal cell function and cytokine expression in diabetes-affected RPE cells, analogous to hitting the "reset" button of an electronic device to restore the factory default settings.
  • SDM treatment may directly affect cytokine expression and heat shock protein (HSP) activation in the targeted tissue, particularly the retinal pigment epithelium (RPE) layer.
  • HSP heat shock protein
  • RPE retinal pigment epithelium
  • Panretinal and panmacular SDM has been noted by the inventors to reduce the rate of progression of many retinal diseases, including severe non-proliferative and proliferative diabetic retinopathy, AMD, DME, etc.
  • the reset theory also suggests that SDM may have application to many different types of RPE-mediated retinal disorders.
  • panmacular SDM can significantly improve retinal function and health, retinal sensitivity, and dynamic logMAR visual acuity and contrast visual acuity in dry age-related macular degeneration, retinitis pigmentosa, cone-rod retinal degenerations, and Stargardt's disease where no other treatment has previously been found to do so.
  • SDM chronic, progressive retinal diseases.
  • tissue and/or organ structural damage and vision loss are late disease manifestations, treatment instituted at this point must be intensive, often prolonged and expensive, and frequently fails to improve visual acuity and rarely restores normal vision.
  • SDM can also be used to treat an eye to stop or delay the onset or symptoms of retinal diseases prophylactically or as a preventative treatment for such retinal diseases. Any treatment that improves retinal function, and thus health, should also reduce disease severity, progression, untoward events and visual loss.
  • a patient and more particularly an eye of the patient, has a risk for a retinal disease. This may be before retinal imaging abnormalities are detectable. Such a determination may be accomplished by ascertaining if the patient is at risk for a chronic progressive retinopathy, including diabetes, a risk for age-related macu lar degeneration or retinitis pigmentosa. Alternatively, or additionally, results of a retinal examination or retinal test of the patient may be abnormal. A specific test, such as a retinal physiology test or a genetic test, may be conducted to establish that the patient has a risk for a retinal disease.
  • An SDM laser light beam that is sublethal and creates true subthreshold photocoagulation and retinal tissue, is generated and at least a portion of the retinal tissue is exposed to the generated laser light beam without damaging the exposed retinal or foveal tissue, so as to provide preventative and protective treatment of the retinal tissue of the eye.
  • the treated retina may comprise the fovea, foveola, retinal pigment epithelium, choroid, choroidal neovascular membrane, subretinal fluid, macula, macular edema, parafovea, and/or perifovea.
  • the laser light beam may be exposed to only a portion of the retina, or substantially the entire retina and fovea.
  • the retina is periodically retreated. This may be done according to a set schedule or when it is determined that the retina of the patient is to be retreated, such as by periodically monitoring visual and /or retinal function or condition of the patient.
  • FIG. 4 a schematic diagram is shown of a system for realizing the process of the present invention.
  • the system generally referred to by the reference number 30, includes a laser console 32, such as for example the 81 Onm near infrared micropulsed diode laser in the preferred embodiment.
  • the laser generates a laser light beam which is passed through optics, such as an optical lens or mask, or a plurality of optical lenses and/or masks 34 as needed.
  • the laser projector optics 34 pass the shaped light beam to a coaxial wide-field non-contact digital optical viewing
  • the box labeled 36 can represent both the laser beam projector as well as a viewing system /camera, which might in reality comprise two different components in use.
  • the viewing system /camera 36 provides feedback to a display monitor 40, which may also include the necessary computerized hardware, data input and controls, etc. for manipulating the laser 32 , the optics 34, and /or the projection/viewing components 36.
  • the laser light beam 42 is passed through a collimator lens 44 and then through a mask 46.
  • the mask 46 comprises a diffraction grating.
  • the mask/diffraction grating 46 produces a geometric object, or more typically a geometric pattern of simultaneously produced multiple laser spots or other geometric objects. This is represented by the mu ltiple laser light beams labeled with reference number 48.
  • the multiple laser spots may be generated by a plurality of fiber optic wires. Either method of generating laser spots allows for the creation of a very large nu mber of laser spots simultaneously over a very wide treatment field, such as consisting of the entire retina.
  • a very high number of laser spots perhaps numbering in the hundreds even thousands or more could cover the entire ocular fundus and entire retina, including the macula and fovea, retinal blood vessels and optic nerve.
  • the intent of the process in the present invention is to better ensure complete and total coverage and treatment, sparing none of the retina by the laser so as to improve vision.
  • the wavelength of the laser employed for example using a diffraction grating
  • the individual spots produced by such diffraction gratings are all of a similar optical geometry to the input beam, with minimal power variation for each spot.
  • the result is a plurality of laser spots with adequate irradiance to produce harmless yet effective treatment application, simultaneously over a large target area.
  • the present invention also contemplates the use of other geometric objects and patterns generated by other diffractive optical elements.
  • the laser light passing through the mask 46 diffracts, producing a periodic pattern a distance away from the mask 46, shown by the laser beams labeled 48 in FIG. 5.
  • the single laser beam 42 has thus been formed into hundreds or even thousands of individual laser beams 48 so as to create the desired pattern of spots or other geometric objects.
  • These laser beams 48 may be passed through additional lenses, collimators, etc. 50 and 52 in order to convey the laser beams and form the desired pattern on the patient's retina. Such additional lenses, collimators, etc. 50 and 52 can further transform and redirect the laser beams 48 as needed.
  • Arbitrary patterns can be constructed by controlling the shape, spacing and pattern of the optical mask 46.
  • the pattern and exposure spots can be created and modified arbitrarily as desired according to application requirements by experts in the field of optical engineering. Photolithographic techniques, especially those developed in the field of semiconductor
  • manufacturing can be used to create the simultaneous geometric pattern of spots or other objects.
  • FIG. 6 illustrates diagrammatically a system which couples multiple light sources into the pattern-generating optical subassembly described above.
  • this system 30' is similar to the system 30 described in FIG. 4 above.
  • the primary differences between the alternate system 30' and the earlier described system 30 is the inclusion of a plurality of laser consoles 32, the outputs of which are each fed into a fiber coupler 54.
  • the fiber coupler produces a single output that is passed into the laser projector optics 34 as described in the earlier system.
  • the coupling of the plurality of laser consoles 32 into a single optical fiber is achieved with a fiber coupler 54 as is known in the art.
  • Other known mechanisms for combining multiple light sources are available and may be used to replace the fiber coupler described herein.
  • the diffractive element must function differently than described earlier depending upon the wavelength of light passing through, which results in a slightly varying pattern.
  • the variation is linear with the wavelength of the light source being diffracted.
  • the difference in the diffraction angles is small enough that the different, overlapping patterns may be directed along the same optical path through the steering mechanism 36 to the retina 38 for treatment. The slight difference in the diffraction angles will affect how the steering pattern achieves coverage of the retina.
  • a sequential offsetting to achieve complete coverage will be different for each wavelength.
  • This sequential offsetting can be accomplished in two modes. In the first mode, all wavelengths of light are applied simultaneously without identical coverage. An offsetting steering pattern to achieve complete coverage for one of the multiple wavelengths is used. Thus, while the light of the selected wavelength achieves complete coverage of the retina, the application of the other wavelengths achieves either incomplete or overlapping coverage of the retina.
  • the second mode sequentially applies each light source of a varying wavelength with the proper steering pattern to achieve complete coverage of the retina for that particular wavelength. This mode excludes the possibility of simultaneous treatment using multiple wavelengths, but allows the optical method to achieve identical coverage for each wavelength. This avoids either incomplete or overlapping coverage for any of the optical wavelengths.
  • FIG. 7 illustrates diagrammatically yet another alternate
  • This system 30" is configured generally the same as the system 30 depicted in FIG. 4. The main difference resides in the inclusion of multiple pattern-generating subassembly channels tu ned to a specific wavelength of the light source.
  • Multiple laser consoles 32 are arranged in parallel with each one leading directly into its own laser projector optics 34.
  • the laser projector optics of each channel 58a, 58b, 58c comprise a collimator 44, mask or diffraction grating 48 and recollimators 50, 52 as described in connection with FIG. 5 above - the entire set of optics tuned for the specific wavelength generated by the corresponding laser console 32.
  • the output from each set of optics 34 is then directed to a beam splitter 56 for combination with the other wavelengths. It is known by those skilled in the art that a beam splitter used in reverse can be used to combine multiple beams of light into a single output.
  • the system 30" may use as many channels 58a, 58b, 58c, etc. and beam splitters 56a, 56b, 56c, etc. as there are wavelengths of light being used in the treatment.
  • each channel begins with a light source 32 , which could be from an optical fiber as in other embodiments of the pattern- generating subassembly.
  • This light source 32 is directed to the optical assembly 34 for collimation, diffraction, recollimation and directed into the beam splitter which combines the channel with the main output.
  • the system of the present invention incorporates a guidance system to ensure complete and total retinal treatment with retinal photostimu lation.
  • the treatment method of the present invention is harmless, the entire retina, including the fovea and even optical nerve, can be treated.
  • protection against accidental visual loss by accidental patient movement is not a concern. Instead, patient movement would mainly affect the guidance in tracking of the application of the laser light to ensure adequate coverage.
  • Fixation/tracking/registration systems consisting of a fixation target, tracking mechanism, and linked to system operation are common in many ophthalmic diagnostic systems and can be incorporated into the present invention.
  • the geometric pattern of simultaneous laser spots is sequentially offset so as to achieve confluent and complete treatment of the retinal surface.
  • a segment of the retina can be treated in accordance with the present invention, more ideally the entire retina will be treated with one treatment. This is done in a time-saving manner by placing hundreds to thousands of spots over the entire ocular fundus at once.
  • This pattern of simultaneous spots is scanned, shifted, or redirected as an entire array sequentially, so as to cover the entire retina.
  • FIGS. 8 and 9 illustrate an optical scanning mechanism 60 in the form of a MEMS mirror, having a base 62 with electronically actuated controllers 64 and 66 which serve to tilt and pan the mirror 68 as electricity is applied and removed thereto. Applying electricity to the controller 64 and 66 causes the mirror 68 to move, and thus the simultaneous pattern of laser spots or other geometric objects reflected thereon to move accordingly on the retina of the patient.
  • the optical scanning mechanism may also be a small beam diameter scanning galvo mirror system, or similar system, such as that distributed by Thorlabs. Such a system is capable of scanning the lasers in the desired offsetting pattern.
  • FIG. 1 a diagrammatic representation of the process of sequentially offsetting laser spots is shown.
  • a geometric pattern of laser spots is shown in an initial exposure 1 , the geometric pattern is offset and the retina is exposed again in exposure 2, wherein the current exposure is shown by the circles and the prior exposure(s) shown and represented by the solid dots.
  • the spacing of the laser spots prevents overheating and damage to the tissue. This is repeated over multiple exposures until the entire treatment area, or even the entire retina, has been exposed to the SDM laser treatment. In this manner a low-density treatment, as illustrated in FIG. 3A, can become a high-density treatment, as illustrated in FIG. 3B.
  • the optics and number of laser spots generated and the distance between laser spots could be such that an entire treatment area, or even the entire retina, could be exposed simultaneously with only a single exposure.
  • the invention described herein is generally safe for panretinal and/or trans-foveal treatment. However, it is possible that a user, i.e., surgeon, preparing to limit treatment to a particular area of the retina where disease markers are located or to prevent treatment in a particular area with darker pigmentation, such as from scar tissue.
  • MPE maximum permissible exposure
  • the therapeutic range - the interval of doing nothing at all and the 50% of some likelihood of producing a threshold burn - for low-duty cycle micropulsed laser irradiation is 1 0 times wider than for continuous wave laser irradiation with the same energy. It has been determined that safe and effective sublethal, true subthreshold
  • photocoagulation using a micropulsed diode laser is between 1 8 times and 55 times MPE, with a preferred laser exposure, for example, to retinal tissue at 47 times MPE for a near-infrared 81 Onm diode laser. At this level, it has been observed that there is therapeutic effectiveness with no discernible retinal damage whatsoever.
  • the intensity or power of a laser between 1 00 watts to 590 watts, and preferably 350 watts, per square centimeter at a retinal treatment spot is effective yet safe.
  • a particularly preferred intensity or power of the laser light is approximately one watt per laser spot for an 81 Onm micropulsed diode laser.
  • the micropulsed laser light beam of an 81 Onm diode laser should have an exposure envelope duration of 500 milliseconds or less, and preferably approximately 300 milliseconds. Of course, if micropulsed diode lasers become more powerful, the exposure duration should be lessened accordingly.
  • Duty cycle the frequency of the train of micropulses, or the length of the thermal relaxation time in between consecutive pulses. It has been found that the use of a 1 0% duty cycle or higher adjusted to deliver micropulsed laser at similar irradiance at similar MPE levels significantly increase the risk of lethal cell injury, particularly in darker fundi. However, duty cycles less than 1 0%, and preferably approximately 5% duty cycle (or less, such as 2.5%) demonstrate adequate thermal rise and treatment at the level of the MPE cell to stimu late a biologic response, but remain below the level expected to produce lethal cell injury, even in darkly pigmented fundi. If the duty cycle is less than 5%, the exposure envelope duration in some instances can exceed 500 milliseconds.
  • small would generally apply to spots less than 1 mm in diameter. However, the smaller the spot, the more ideal the heat dissipation and uniform energy application becomes. Thus, at the power intensity and exposu re duration described above, small spots, such as along the size of the wavelength of the laser, or small geometric lines or other objects are preferred so as to maximize even heat distribution and heat dissipation to avoid tissue damage.
  • a "low- intensity/high-density" phototherapy treatment for example as illustrated in FIG. 3B for treatment of the entire retina, including sensitive areas such as the macula and even the fovea without creating visual loss or other damage.
  • using conventional phototherapies was impossible on the entire retina, particularly the fovea, as it would create vision loss due to the tissue damage in sensitive areas at the retina.
  • An analysis of the effectiveness and safety of the discussed SDM treatment has been performed with approximations to the exact equations for the laser absorption, heat diffusion, and Arrhenius reaction rates describing the process. Comparisons have also been made with the same approximate equations for alternate approaches (CW and Pascal and nano-second CW laser exposures). The following indicates that for typical operating parameters, SDM is both safe and effective, whereas the alternate techniques can be either ineffective or not safe.
  • the laser wavelength is 81 Onm, while in the
  • the wavelength is 532 nm.
  • the absorption coefficient for 532 nm is approximately 4 times that for 81 0 nm.
  • retinal function testing pre-therapeutically. Such tests may include pattern electroretinography (PERG), microperimetry, and threshold micro-visual acuity testing, which are all existing technologies.
  • PEG pattern electroretinography
  • microperimetry microperimetry
  • threshold micro-visual acuity testing which are all existing technologies.
  • Such post-treatment, pre- therapeutic retinal function testing allows for conformation of treatment administration and effect. It also allows one to prospectively follow patients to determine the need for retreatment, indicated by worsening results of retinal function testing.
  • retinal fu nction testing By combining retinal fu nction testing with true-subthreshold treatment allows for a treatment modality able to demonstrate a desired immediate treatment effect absent detectable retinal damage.
  • the retinal function testing also allows for the prevention of disease progression by detecting early on a need for re-treatment prophylactically.
  • Cu rrent retinal treatment measures are anatomic, meaning that they are "late"-term indicators - abnormal only in advanced and end-stage diseases. Using retinal function indicators that may improve in apparently normal eyes prior to the development of anatomic changes can help document treatment benefits in the absence of anatomic derangement. The retinal function testing can be used to signal the need for re-treatment prior to the development of anatomic disease. The ability to prevent clinical /anatomic disease, vision loss, and the need for more intensive and expensive treatments can be rationally minimized.
  • the process and methodology of the present invention has been the subject of an initial experimental trial study.
  • the invention was offered as a prophylaxis/retinal protection for high-risk AMD and inherited degenerations (IRD). Testing was performed within one week prior to SDM treatment and within one month after treatment.
  • PERG pattern electroretinography
  • AMP automated microperimetry
  • CVA central vision analyzer
  • PERG was performed using standard protocols of a commercially available system (Diopsys ® Nova-ERG, Diopsys Corp., Pine Brook, New Jersey) according to International Society for Clinical Electrophysiology of Vision standards. Both eyes were tested simultaneously and recorded individually, undilated, and refracted for a 60 cm testing distance. For all visual stimuli, a lu minance pattern occupying a 25 ° visual field is presented with a luminance reversal rate of 1 5 Hz.
  • a PERG "Concentric Ring” (CR) visual stimulus optimized for analyzing peripheral retinal sensitivity was employed, presenting with a circle of one luminance and an outer ring with the contrasting lu minance.
  • the concentric ring stimulus used two sub-classes of stimuli with an inner circle occupying a visual field of 1 6 ° and 24 ° , respectively.
  • the concentric ring stimuli used a mean luminance of 1 1 7.6 cd /m 2 with a contrast of 1 00%.
  • Magnetic D is the frequency response of the time-domain averaged signal in microvolts ( ⁇ ). Macular and/or ganglion cell dysfunction cause signal latencies resulting in magnitude and phase variability that reduce MagD by phase cancelation.
  • Magnitude ( ⁇ ) [Mag( V)] measures the frequency response of the total signal in microvolts ( ⁇ ). Mag ( ⁇ ) reflects the signal strength and electrode impedance of the individual test sessions, as well as a gross measure of ganglion fu nction.
  • the MagD( V)/Mag( V) ratio thus provides a measure of patient response normalized to that particular test's electrical quality. The closer MagD( V)/Mag( V) to unity, the more normal macular function.
  • CVA (Visoptics, Mechanicsberg, PA) is an FDA approved measure of visual acuity. A thresholding algorithm is used to dynamically determine logMAR central visual acuity for 6 different levels of contrast, ranging from 99% to 35%, using an interactive computer interface.
  • a thresholding algorithm is used to dynamically determine logMAR central visual acuity for 6 different levels of contrast, ranging from 99% to 35%, using an interactive computer interface.
  • topical proparacaine was applied to the cornea.
  • a Mainster macular contact lens (Ocular Instruments, Mentor, Ohio, magnification factor 1 .05x) was placed on the cornea with the aid of viscoelastic.
  • the entire posterior retina circumscribed by the major vascular arcades was "painted" with l 800-3000 confluent spot applications of SDM ("panmacular" treatment).
  • the laser parameters used were 81 0nm wavelength, 200um aerial spot size, 5% duty cycle; and 1 .6 watt power and 0.075 second duration
  • SD .Variable Mean (SD) Median (IQR) p-value
  • Table 3 shows the comparisons of interest for the PERG Contrast Sensitivity Test dataset. Each row shows the difference (post- minus pre- treatment) in M(d)/M(uv) ratio, M(d) measure, or M(uv) measure, at the two contrast options.
  • linear mixed models predicting the measure using an indicator for time as a covariate, also adjusting for left or right eye, and including a random patient intercept, were performed.
  • the p-values are those associated with the time (pre- versus post-) regression coefficient. A significant p-value indicates that the mean difference is significantly different from zero.
  • Table 4 shows the comparisons of interest for the PERG Concentric Ring Test dataset. Each row shows the difference (first post-treatment minus pre-treatment) in M(d)/M(uv) ratio, M(d) measure, or M(uv) measure, at the 24 and 1 6 degrees.
  • linear mixed models predicting the measure were performed, using an indicator for time as a covariate, also adjusting for left or right eye, and including a random patient intercept.
  • the p-values are those associated with the time (pre- versus post-) regression coefficient. A significant p-value indicates that the mean difference is significantly different from zero.
  • the table shows that all comparisons are not statistically significant. This method accounts for inter-eye correlation.
  • IQR Variable Mean Median
  • IQR p- Mean Median
  • IQR p- Mean Median
  • Table 5 shows the comparisons of interest for the RP dataset. Each row shows the difference (post- minus pre-treatment) in M(d)/M(uv) ratio or
  • M(d) measure at the two degree options. Shown are the statistics for all eyes, treated eyes, and untreated eyes. Statistical significance was tested using
  • Table 6 shows the comparisons of interest for the AMP dataset. Each row shows the difference (follow up- minus pre-operation) in reduced and average threshold as well as PI and P2.
  • a linear mixed models predicting the measure, using an indicator for time (pre-op versus follow-up) as a covariate, also adjusting for left or right eye, and including a random patient intercept was performed.
  • the p-values are those associated with the time (pre-op versus follow-up) regression coefficient. A significant p-value indicates that the mean difference is significantly different from zero. Only average threshold is significantly different pre-op versus follow-up.
  • Table 7 shows the difference (post- minus pre-treatment) for each contrast level.
  • linear mixed models predicting the visual acuity, using an indicator for time as a covariate, also adjusting for left or right eye, and including a random patient intercept were used.
  • the table shows significant improvement at all contrast levels. This method accounts for inter-eye correlation.
  • Linear regression analyses revealed significant negative correlations for all testing measures in both AMD and IRD, indicating that the worse the preoperative measure, the greater the likelihood of postoperative improvement.
  • panretinal SDM was found to reduce the rate of progression of severe non-proliferative to proliferative diabetic retinopathy from the expected 50% per year to just 8.5%.

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Abstract

La présente invention concerne une méthode de traitement d'un œil afin d'arrêter ou de retarder l'apparition ou d'atténuer les symptômes de maladies de la rétine consistant à déterminer que l'œil présente un risque de développer une maladie de la rétine avant l'apparition d'anomalies détectables dans l'imagerie de la rétine. Un faisceau de lumière laser généré permet de fournir un traitement préventif et de protection des tissus de la rétine de l'œil. Au moins une partie des tissus de la rétine est exposée au faisceau de lumière laser sans léser les tissus. La rétine peut être traitée de nouveau selon un programme défini ou de manière périodique en fonction de la détermination selon laquelle la rétine du patient doit être traitée de nouveau par la surveillance d'une fonction ou d'un état visuel et/ou de la rétine.
EP15880626.5A 2015-01-28 2015-11-16 Traitement prophylactique par laser à micro-impulsions infraliminaire pour maladies évolutives chroniques de la rétine Pending EP3250167A4 (fr)

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US14/607,959 US9168174B2 (en) 2012-05-25 2015-01-28 Process for restoring responsiveness to medication in tissue of living organisms
US14/921,890 US9381116B2 (en) 2012-05-25 2015-10-23 Subthreshold micropulse laser prophylactic treatment for chronic progressive retinal diseases
PCT/US2015/060836 WO2016122750A1 (fr) 2015-01-28 2015-11-16 Traitement prophylactique par laser à micro-impulsions infraliminaire pour maladies évolutives chroniques de la rétine

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RU2647803C1 (ru) * 2017-03-29 2018-03-19 Федеральное государственное автономное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации Способ хирургического лечения рубцовой стадии субретинальной неоваскулярной мембраны
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