Method and apparatus for real-time detection, control and recording of sub-clinical therapeutic laser lesions during ocular laser photocoagulation Patent Application (2025)

U.S. patent application number 09/844445 was filed with the patent office on 2001-11-29 for method and apparatus for real-time detection, control and recording of sub-clinical therapeutic laser lesions during ocular laser photocoagulation. Invention is credited to Dorin, Giorgio, Lanzetta, Paolo.

Method and apparatus for real-time detection, control and recordingof sub-clinical therapeutic laser lesions during ocular laserphotocoagulation

Abstract

An optical system is provided for use with a target site andincludes a laser source producing an output beam and a reflector. Abeam splitter is positioned to receive the output beam and splitsthe output beam into a first beam incident on the reflector and asecond beam incident on at least one point of the target site. Thereflector is adjustably positioned and movable along the referenceoptical path moveable along the reference optical path to change alength of the reference optical path.

 WILSON SONSINI GOODRICH & ROSATI 650 PAGE MILL ROAD PALO ALTO CA 943041050

Related U.S. Patent Documents

Claims

1. An optical system for use with a target site, comprising: alaser source producing an output beam; a reflector; a beam splitterpositioned to receive the output beam and split the output beaminto a first beam incident on the reflector and a second beamincident on at least one point of the target site, the splitterbeing positioned to define a target site optical path from thesplitter to the target site and a reference optical path from thesplitter to the reflector; the splitter producing a combined beamfrom at least a portion of a reflected first beam received from thereflector that interacts with at least a portion of a reflectedsecond beam received from the target site; a detector coupled tothe splitter and producing a signal representative of alongitudinal reflectivity profile of the target site; and afeedback coupled to the detector and the laser source to provide ana feedback signal to the laser source that controls an energyoutput of the laser source.

2. The system of claim 1, wherein at least a portion of thesplitter is a reflectometry device.

3. The system of claim 1, wherein at least a portion of thedetector is a reflectometry device.

4. The system of claim 1, wherein the splitter and detectorinterferometrically reconstruct the reflected second beam receivedfrom the target site.

5. The system of claim 1, wherein reflected first beam experiencestime delays which interact interferometrically with differentreflection phases of the reflected second beam at the splitter anddetector.

6. The system of claim 1, wherein the splitter and detector createa sequence of longitudinal reflectivity profiles at a highrepetition rate.

7. The system of claim 6, wherein the detector continuouslyanalyzes the longitudinal reflectivity profiles.

8. The system of claim 6, wherein changes in the longitudinalreflectivity profiles above a threshold result in an adjustment inthe amount of power delivered from the laser source.

9. The system of claim 7, wherein the longitudinal reflectivityprofiles provide information about changes in layers of the targetsite at and below a surface of the target site.

10. The system of claim 7, wherein the continues analysis of thelongitudinal reflectivity profiles provides a real time detectionof changes in the target site.

11. The system of claim 7, wherein the continues analysis of thelongitudinal reflectivity profiles provides a real time detectionof changes in different layers of the target site.

12. The system of claim 6, wherein the longitudinal reflectivityprofiles are represented as a plurality of graphed peaks.

13. The system of claim 12, wherein the detector detects changes ina height, width and area of one or more of the graphed peaks.

14. The system of claim 1, wherein the splitter and detectorprovide real time detection of changes in the target site inresponse to interaction of the first beam at the target site.

15. The system of claim 1, wherein the splitter and detectorprovide real time detection and quantification of changes in thetarget site in response to interaction of the first beam at thetarget site.

16. The system of claim 1, wherein the splitter and detectorprovide real time detection, quantification and discrimination ofchanges in the target site in response to interaction of the firstbeam at the target site.

17. The system of claim 1, wherein the reflector is adjustablypositioned at the reference optical path.

18. The system of claim 17, wherein the reflector is moveable alongthe reference optical path.

19. The system of claim 17, wherein the reflector is adjustablypositioned to change a length of the reference optical path.

20. The system of claim 19, wherein the at least a portion of thereflected first beam experiences time delays which interactinterferometrically with different reflection phases of the targetsite.

21. The system of claim 19, wherein the at least the portion of thereflected first beam experiences time delays which interactinterferometrically with different reflection phases of the atleast the portion of the reflected second beam received from thetarget site.

22. A method of detecting changes in a target site in response tointeraction with a target beam of light, comprising: splitting anoutput beam from a laser source into a first beam and a secondbeam; directing the first beam to a reflector which reflects areflected first beam; directing the second beam to a target site,at least a portion of the second beam creating a change in thetarget site and at least a portion being reflected from the targetsite as a reflected second beam; combining the first and secondreflected beams; interferometrically interacting the first andsecond reflected beams; and adjusting the output beam in responseto the interferometric interaction of the first and secondreflected beams.

23. The method of claim 22, wherein the first beam experiences timedelays which interact interferometrically with different reflectionphases of the reflected second beam.

24. The method of claim 22, further comprising: creating a sequenceof longitudinal reflectivity profiles of the target site inresponse to interferometrically interacting the first and secondreflected beams.

25. The method of claim 24, further comprising: analyzing thelongitudinal reflectivity profiles.

26. The method of claim 25, wherein power delivered from the lasersource is adjusted in response to changes in the longitudinalreflectivity profiles above a threshold.

27. The method of claim 25, wherein the longitudinal reflectivityprofiles provide information about changes in the target siteresulting from interaction of the target site with the secondbeam.

28. The method of claim 25, wherein analysis of the longitudinalreflectivity profiles provides a real time detection of changes inthe target site resulting from interaction of the target site withthe second beam.

29. The system of claim 25, wherein the analysis of thelongitudinal reflectivity profiles provides a real time detectionof changes in different layers of the target site.

30. The system of claim 25, wherein the analysis of thelongitudinal reflectivity profiles provides real time detection andquantification of changes in the target site in response tointeraction of the first beam at the target site.

31. The system of claim 25, wherein the analysis of thelongitudinal reflectivity profiles provides real time detection,quantification and discrimination of changes in the target site inresponse to interaction of the first beam at the target site.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part and claims thebenefit of U.S. provisional application Ser. No. 60/200,709, filedApr. 27, 2000.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to an apparatus and method fordetecting changes in a target site in response to interaction witha target beam of light, and more particularly to an apparatus andmethod for detecting real time changes in a target site in responseto interaction with a target beam of coherent light.

[0004] 2. Description of Related Art

[0005] Pathologies of the Eye:

[0006] There are several pathologies of the eye that cause someform of visual impairment up to and including blindness.Pathologies currently treated with lasers include glaucoma andretinal disorders. Glaucoma disorders treatable with laser includeopen angle glaucoma, angle closure glaucoma andneovascular-refractory glaucoma. Retinal disorders treatable withlaser include diabetic retinopathy, macular edema, central serousretinopathy and age-related macular degeneration (AMD), etc.Diabetic retinopathy represents the major cause of severe visionloss (SVL) for people up to 65 years of age, while AMD representsthe major cause of SVL in people between 65 and 80 years of age.More than 32,000 Americans are blinded from diabetic retinopathyalone, with an estimated 300,000 diabetics at risk of becomingblind. The incidence of AMD in the USA is currently estimated at 2million new cases per year, of which 1.8 million are with the "dry"form and 200,000 are with the "wet" form, also defined as choroidalneovascularization (CNV). CNV causes subretinal hemorrhage,exudates and fibrosis any of that can lead to SVL and legalblindness. A widely used form of laser treatment for retinaldisorders is called laser photocoagulation (P.C.).

[0007] Current Modalities of Laser P.C.:

[0008] Laser P.C. has become the standard treatment for a number ofretinal disorders such as diabetic retinopathy, macular edema,central serous retinopathy, retinal vein occlusion and CNV.

[0009] Laser P.C. is a photo-thermal process, in which heat isproduced by the absorption of laser energy by targeted tissues, forthe purpose of inducing a thermal "therapeutic damage", whichcauses biological reactions and ultimately, the beneficial effects.Conventional retinal P.C. relies on some visible "blanching" of theretina as the treatment endpoint and can be defined asOphthalmoscopically Visible Endpoint Photocoagulation or OVEP.Since the retina is substantially transparent to most wavelengthsused in laser P.C., its "blanching" is not caused directly by thelaser. Visible "blanching" is the sign that the normal transparencyof the retina has been thermally damaged by the conduction of heatgenerated underneath, at super-threshold level, in laser absorbingchromophores (i.e. melanin) contained in the retinal pigmentepithelium (RPE) and in choroidal melanocytes.

[0010] The endpoint of visible retinal "blanching" is a practicalway to assess the laser treatment, but it also constitutes adisadvantageous and unnecessary retinal damage, which in turnresults in a number of undesirable adverse complications includingsome vision loss, decreased contrast sensitivity and reduced visualfields in a substantial number of patients. A discussion of thethermal damage resulting in the eye from laser P.C. treatment willnow be presented to better illustrate the current OVEP methods, theeffects, and the possible ways for limiting or avoiding the currentdrawbacks.

[0011] Retina "blanching" is the result of the spread by conductionof a thermal elevation created around laser absorbing chromophoresunderneath the retina. The thermal elevation can be controlled bylaser: (i) irradiance (power density), (ii) exposure time and (iii)wavelength. High thermal elevations are normally created withcurrent OVEP clinical protocols that are aimed to produce visibleendpoints ranging from intense retinal whitening (full thicknessretinal burn) to barely visible retinal changes. Although themechanisms underpinning the efficacy of laser P.C. are still poorlyunderstood, laser P.C. has been proven therapeutically effectiveand constitutes the standard-of-care in preventing SVL in variousocular disorders. However, because of the drawback of iatrogenicvisual impairment due to thermal damage to the neurosensory retina,conventional OVEP laser treatment is presently considered andadministered only late in the course of the disease, when hasbecome "clinically significant" and the benefit-to-risk ratiojustifies the associated negative effects.

[0012] Recent clinical studies have suggested that patients withcertain types of diabetes, "dry" AMD and "wet" AMD could benefitfrom a much earlier treatment. As an example, Laser P.C. is nowexperimentally administered to patients diagnosed with "dry" AMDpresenting with high-risk drusen, as a prophylactic treatment toprevent or delay the progression toward the "wet" form and theconsequent SVL. Obviously, more aggressive therapeutic approacheswith earlier treatments would easily gain acceptance and be adoptedby the ophthalmic community if new user friendly and less damaginglaser devices could be available to allow the easy administrationof minimally invasive treatment protocols, which would become thenew standard-of-care.

[0013] New hypotheses on the mechanism of action of laser P.C.postulate that full thickness retinal damage may not be needed toobtain beneficial effects and that any ophthalmoscopically visibleretina "blanching" is only a convenient treatment end-point,redundant for the therapeutic effectiveness.

[0014] Current laser devices and treatment protocols do not allowto selectively address laser absorbing structures only (primarilymelanin containing cells, such as RPE cells and choroidalmelanocytes) and to confine the thermal elevation to avoidunnecessary thermal injury to the neurosensory retina. Thus, thereis a need for a new laser device and treatment protocols, which canallow more selective targeting and confinement of the laser thermaleffects, to avoid or minimize the thermal damage to the overlyingneurosensory retina. The present invention provides the solution tothis problem by providing a method and apparatus that allows thephysician to perform treatments with the minimal therapeutic damage(MTD) confined around the RPE cells and without appreciable damageto the neurosensory retina. This can be defined as NonOphthalmoscopically Visible Endpoint Photocoagulation or NOVEPtreatment, to differentiate from the conventional OVEPtreatment.

[0015] Preliminary studies on animals with a near IR 810 nmMicroPulse diode laser beam demonstrated the ability toconsistently create therapeutic lesions confined around the RPEcells (as studied by light microscopy) without causing apparentdamage to the overlying retina. The laser impacts were not visibleby slit lamp bio-microscopy at the time of laser delivery.

[0016] Recent clinical studies have reported that sub-clinical(invisible) laser lesions created with a NOVEP treatment with the810 nm MicroPulse diode laser are therapeutically as effective asthe conventional OVEP treatment in resolving a variety of retinaldisorders. This suggests that the damages to the neurosensoryretina created with conventional OVEP treatment are indeedredundant and should be avoided. Unfortunately, the absence of avisible endpoint during the laser treatment renders difficult thechoice of the proper irradiation dosage for each individualpatient, leaves the physician with no tangible sign of achievedproper threshold for a MTD and creates a potential problem in caseof retreatment. Thus there is a need for a device and a method thatallow the real-time detection of the achieved sub-clinical(invisible) MTD during the treatment, able to control and terminatethe laser emission at a given pre-settable MTD threshold.Furthermore, since from initial clinical studies it was reportedthat some lesions did not become apparent to slit lamp examinationnor to Fluorescein Angiography even after several months, there isalso a need for a device that can allow the recording of allsuccessfully placed MTD applications and of their location in theocular fundus.

[0017] Conventional OVEP treatment has proven to be effective inpreventing or limiting SVL, but causes undesirable collateraldamage. The damage of intense laser burns not only destroys healthyretinal tissue causing some degree of vision deterioration, it mayalso trigger neovascularization, a serious and highly undesirableevent leading to further loss of vision. The mechanism by whichlaser P.C. leads to the beneficial therapeutic effect is poorlyunderstood. It was believed that some damage to the retina isneeded for an effective laser PC. Emerging hypotheses and recentclinical works suggest that a minimum damage, confined around theRPE and with sparing of the neurosensory retina, can suffice totrigger the pathophysiologic responses resulting in the therapeuticbeneficial effects of PCT.

[0018] The threshold of cellular damage for the beneficial outcomeis generally not known and many physicians striving to do no harmare now engaged in the search for the minimal dose response ("howlittle is enough"). The realization that "hot" laser burns candamage the integrity of Bruchs membrane and trigger iatrogenicsubretinal neovascularizations has prompted the adoption of"lighter" laser PC endpoints. New NOVEP techniques, usingrepetitive very short laser pulses and sub-clinical (invisible)endpoints, have been advocated and clinically tried to reduce oreliminate unnecessary damage to the neurosensory retina and toBruch's membrane. Initial results have shown therapeuticallyeffectiveness comparable to conventional OVEP treatments.

[0019] NOVEP laser treatments are appealing, but extremelydifficult to do with current laser photocoagulator devices andsuffer three significant drawbacks:

[0020] (i) the lack of a visible endpoint deprive the physicians ofa reassuring feedback;

[0021] (ii) the lack of visible sign of treatment makes gridtreatments difficult to perform, to complete and to trace in caseof retreatment

[0022] (iii) NOVEP laser lesions are spatially confined (no thermalspread as with conventional OVEP and consequently theoretically amuch higher number of applications is required for the same areacoverage.

[0023] There is a need for an apparatus and method for detectingreal time changes in a target site in response to interaction witha target beam of coherent light. There is a further need for anapparatus and method for detecting real time changes andquantification of changes in a target site in response tointeraction of the target site with a coherent beam of light. Thereis yet a further need for an apparatus and method for detectingreal time changes, quantification of the changes and discriminationof the changes in the target site in response to interaction of thetarget site with a coherent beam of light.

SUMMARY OF THE INVENTION

[0024] Accordingly, an object of the present invention is toprovide an apparatus and method for detecting real time changes ina target site in response to interaction with a target beam ofcoherent light.

[0025] Another object of the present invention is to provide anapparatus and method for detecting real time changes andquantification of changes in a target site in response tointeraction of the target site with a coherent beam of light.

[0026] A further object of the present invention is to provide anapparatus and method for detecting real time changes,quantification of the changes and discrimination of the changes inthe target site in response to interaction of the target site witha coherent beam of light.

[0027] These and other objects of the present invention areachieved in an optical system for use with a target site thatincludes a laser source producing an output beam and a reflector. Abeam splitter is positioned to receive the output beam and splitsthe output beam into a first beam incident on the reflector and asecond beam incident on at least one point of the target site. Thesplitter is positioned to define a target site optical path fromthe splitter to the target site and a reference optical path fromthe splitter to the reflector. The splitter produces a combinedbeam from at least a portion of a reflected first beam receivedfrom the reflector that interacts with at least a portion of areflected second beam received from the target site. A detector iscoupled to the splitter and produces a signal representative of alongitudinal reflectivity profile of the target site. A feedback iscoupled to the detector and the laser source. The feedback providesan a feedback signal to the laser source that controls an energyoutput of the laser source.

[0028] In another embodiment of the present invention, a method ofdetecting changes in a target site in response to interaction witha target beam of light splits an output beam from a laser sourceinto a first beam and a second beam. The first beam is directed toa reflector which reflects a reflected first beam. The second beamis directed to a target site. At least a portion of the second beamcreates a change in the target site and at least a portion isreflected from the target site as a reflected second beam. Thefirst and second reflected beams are combined andinterferometrically interacted. The output beam is adjusted inresponse to the interferometric interaction of the first and secondreflected beams.

BRIEF DESCRIPTION OF THE FIGURES

[0029] FIG. 1 is a schematic view of an embodiment of theinvention.

DETAILED DESCRIPTION

[0030] In one embodiment of the present invention, an opticalsystem is provided for use with a target site and includes a lasersource producing an output beam and a reflector, A beam splitter ispositioned to receive the output beam and splits the output beaminto a first beam incident on the reflector and a second beamincident on at least one point of the target site. The reflector isadjustably positioned and movable along the reference optical pathmoveable along the reference optical path to change a length of thereference optical path.

[0031] The splitter is positioned to define a target site opticalpath from the splitter to the target site and a reference opticalpath from the splitter to the reflector. The splitter produces acombined beam from at least a portion of a reflected first beamreceived from the reflector that interacts with at least a portionof a reflected second beam received from the target site. Adetector is coupled to the splitter and produces a signalrepresentative of a longitudinal reflectivity profile of the targetsite. A feedback is coupled to the detector and the laser source.The feedback provides an a feedback signal to the laser source thatcontrols an energy output of the laser source.

[0032] In another embodiment of the present invention, a method ofdetecting changes in a target site in response to interaction witha target beam of light splits an output beam from a laser sourceinto a first beam and a second beam. The first beam is directed toa reflector which reflects a reflected first beam. The second beamis directed to a target site. At least a portion of the second beamcreates a change in the target site and at least a portion isreflected from the target site as a reflected second beam. Thefirst and second reflected beams are combined andinterferometrically interacted. The output beam is adjusted inresponse to the interferometric interaction of the first and secondreflected beams.

[0033] At least a portion of the splitter and/or detector can be areflectometry device. The splitter and detector interferometricallyreconstruct the reflected second beam received from the targetsite. The reflected first beam experiences time delays whichinteract interferometrically with different reflection phases ofthe reflected second beam at the splitter and detector.

[0034] The splitter and detector create a sequence of longitudinalreflectivity profiles at a high repetition rate. The detectorcontinuously analyzes the longitudinal reflectivity profiles.Changes in the longitudinal reflectivity profiles above a thresholdresult in an adjustment in the amount of power delivered from thelaser source. The splitter and detector provide real timedetection, quantification and discrimination of changes in thetarget site in response to interaction of the first beam at thetarget site.

[0035] The longitudinal reflectivity profiles provide informationabout changes in layers of the target site at and below a surfaceof the target site. The longitudinal reflectivity profiles arerepresented as a plurality of graphed peaks. The detector detectschanges in a height, width and area of one or more of the graphedpeaks. Continuos analysis of the longitudinal reflectivity profilesprovides a real time detection of changes in the target site.Analysis of the longitudinal reflectivity profiles provides a realtime detection of changes in different layers of the targetsite.

[0036] Referring to FIG. 1, an embodiment of an apparatus 10 fortreating ocular pathologies includes a laser photocoagulator device12 which includes a slit lamp delivery system coupled to aninterferometric reflectometry device 14 for performing real-timedetection of sub-clinical laser P.C. Interferometric reflectometrydevice 14 (also called reflectometry device 14) can be configuredto be both optically and electronically coupled to photocoagulatordevice 12 for performing real-time control and recording ofsub-clinical laser P.C.

[0037] Photocoagulator device 12 is configured to produce a tissuephoto-thermal effect within a targeted ocular tissue site 16 as aresult of incident laser energy on the ocular tissue. In anembodiment, photocoagulator device 12 can be a laser device knownin the art. Examples of lasers include, but are not limited to,Argon lasers, Krypton lasers, Dye lasers, YAG lasers,frequency-doubled Nd:YAG lasers, Diode visible and infrared lasers,etc. Laser device 12 can include both an aiming beam and atreatment beam which can have the same or a different wavelength.Other examples of photocoagulator devices include but are notlimited to infrared lamps, flash lamps, mercury vapor lamps and thelike. For ease of discussion photocoagulator device 12, will now bereferred to as laser 12.

[0038] The reflectometry device 14 is configured to detect, controland record laser induced therapeutic sub-clinical(opthalmoscopically invisible) lesions, during the treatment ofvarious ocular disorders with laser 12. Reflectometry device 14 canbe further configured to control the proper dose of laser energy(exposure time and/or number of ultra-short repetitive pulses) tobe delivered to the target ocular tissue 16, sufficient for adesired and pre-settable MTD threshold. In an embodiment,reflectometry device 14 can include logic resources 18 that can becoupled to one or more optical sensing devices 20. Examples oflogic resources 18 include digital computers and microprocessorssuch as a Pentium.RTM. family microprocessor manufactured by theIntel.RTM. Corporation (Santa Clara, Calif.). Examples of opticalsensing device include photomultipliers, photodiodes and CCDS(charged coupled device). The optical sensing device is coupled toa slit lamp delivery system and is part of the low-coherenceinterferometer with filters, beam splitter, lenses, scanning anddeflecting mirrors of the reflectometry device 14.

[0039] Logic resources 18 can be programmed to detect, control andrecord the delivery of energy to target tissue. This can beaccomplished through the use of one or more electronic instructionssets or software programs 19 electronically stored or in electroniccommunication with logic resources 19. Logic resources 18 can alsoinclude or be coupled to memory resources 21 configured to storeprograms 19, data, data sets and databases. Examples of programs 19include control algorithms such as proportional, proportionalderivative and proportional derivative integral (PID) algorithms.Examples of memory resources 21 include RAM, ROM, PROM and flashmemory. Examples of data and databases that can be stored includeoptical interference patterns and profiles data and other opticaldata. A database of such information can be both for a populationor an individual patient and may include baseline (e.g.pretreatment), treatment and post-treatment profiles.

[0040] Reflectometry device 14 including logic resources 18 canalso be coupled to a display device 22 so as to display real timeor stored measurements and data generated by reflectometry device14. In an embodiment display device 22 is configured to display allthe locations within the ocular findus where a change in thelongitudinal reflectivity profile (LRP) described herein hasreached a set MTD threshold. Examples of display devices 22 includecathode ray tubes (CRTs), liquid crystal displays, plasma displays,flat panel displays and the like. Display device 22 can also beincorporated in an external computer/printer 24, coupled toreflectometry device 14.

[0041] In various embodiments, reflectometry device 14 can have anintegrating sphere, annular, ellipsoidal, totally or partiallyreflecting mirrors configuration, fiber optic Michelsoninterferometer or other configuration known in the art. Alsoreflectometry device 14 can have both a probe (e.g. sample) and areference beam. In an embodiment, the probe and the reference beamscan be generated using a low-coherence IR diode laser deviceintegral to or otherwise optically coupled to reflectometry device14 and/or laser device 12.

[0042] Reflectometry device 14 is used to non-invasively detect,monitor, analyze and compare the changes of the reflectanceproperties of the ocular fundus occurring during the treatment withlaser 12 or another eye treatment device or method. Specifically,reflectometry device 14 is configured to direct a low coherence IRlaser beam 13 through the retina to interact with severalchorio-retina structures 17 in ocular tissue 16. The back-scatteredlight from these interactions can be interferometricallyreconstructed by reflectometry device 14 and/or logic resources 19to generate a sequence of longitudinal reflectivity profiles (LRP)26 at very high repetition rate. All LRPs are continuously analyzedand the occurrence of changes above an adjustable value (the MTDthreshold) threshold are detected, processed for on-line control ofthe emission of laser 12, and stored on computer 24 and/or onmemory resources 21 for recording all successful applications,their location and other relevant data pertaining to the treatment.The LRP enables different retinal and sub-retinal tissue layers tobe recognizable by their reflectivity "signature". Any changeoccurring in one of these layers due to the laser treatment willcause a change in the LRP. Therefore, monitoring LRP change allowsthe real-time detection of minute changes induced in sub-retinalstructures by the NOVEP laser treatment, even when they aresub-clinical and not visible to the surgeon. In this invention, anadjustable threshold of LRP change is used to detect andelectronically process the achievement of a desired sub-clinicalMTD threshold. Specifically, laser photocoagulation therapy causescellular and morphological changes to the target oculartissue/structures, which in turn result in changes to the opticalproperties of these structures and hence in their interferometricreflectivity signature. These changes can be detected andquantified by continuously analyzing changes occurring in thesequence of LRPs taken at high sampling rate during the lasertreatment. Quantification of the amount of changes can be madethrough comparison and analysis of the height, width and area ofone or more peaks 27 in the sequence of subsequent LRPs 26. Inrelated embodiments, the amount of laser induced cellular changecan be determined using a polynomial equation using as variablesone or more characteristics of one or more of the LRP's peaks.

[0043] The desired amount of LRP change, correlated to clinicallyestablished therapeutically effective cellular changes, can bepreset accordingly with the condition to be treated. This change inLRP can be used as the endpoint for the NOVEP treatment. Thedetection of a certain threshold of LRP change (e.g. changes innumber of peaks as well as peak width, height etc.) can be used toautomatically terminate the laser emission and/or to provide thesurgeon with a perceptible endpoint signal. Specifically,reflectometry device 14 can be configured (through softwareprograms 19 operating on logic resources 18 or other electroniccontrol means) to control the duration and/or the number ofrepetitive pulses of the laser irradiation by laser 12. In thisway, the laser emission can be stopped at the first detection of apreset therapeutically sufficient cellular change (the MTDthreshold), much earlier than the appearance of an indirect thermalinjury to the retina up to and including an opthalmoscopicallyvisible "blanching".

[0044] As described herein all LRPs changes over a presetadjustable threshold (successful treatment) can be digitally storedwith the coordinates of their retinal location on computer 24.These stored LRPs data can be further mapped (otherwise correlated)onto an image of the retina, retinal fundus or other structure ofthe eye. The mapping can be accomplished via digital manipulation,imaging processing or other computation means or manually. Invarious embodiments these mapping method can be used to record theamount/threshold of LRP change associated with all the successfullydelivered NOVEP laser applications and the coordinates of theirlocations within the eye and/or in relation to the retinal fundusfor a particular patient or a patient population. These stored LRPscans can be used to generate a database of invisible lasertreatment endpoints accomplishment in various locations within theretina, retinal fundus or other structure of the eye.

[0045] In use, reflectometry device 14 allows:

[0046] (i) detection of sub-clinical (ophthalmoscopicallyinvisible) cellular and morphological changes occurring at the timeof therapeutic NOVEP laser treatment;

[0047] (ii) quantification of laser induced changes compared topreset adjustable change thresholds, to signal the achievement of adesired minimum treatment level (MTD);

[0048] (iii) automatic control of the termination of laseremission;

[0049] (iv) recording of all successful applications, their retinallocations and other relevant data pertaining to the treatment.Further, apparatus 10 and reflectometry device 14 allow for thetitration of laser NOVEP treatment to a desired clinical endpoint(the minimum therapeutically effective cellular change) withoutcausing unwanted thermal damage to important structures of the eyesuch as the neurosensory retina.

[0050] The foregoing description of various embodiments of theinvention has been presented for purposes of illustration anddescription. It is not intended to limit the invention to theprecise forms disclosed. Obviously, many modifications, variationsand different combinations of embodiments will be apparent topractitioners skilled in the art. Also, it will be apparent to theskilled practitioner that elements from one embodiment can bereadily recombined with one or more other embodiments.

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