WO2022027105A1

WO2022027105A1 - A method of treating retinal ischaemic diseases

Info

Publication number: WO2022027105A1
Application number: PCT/AU2021/050862
Authority: WO
Inventors: Stephen John Cringle; Dao-Yi Yu
Original assignee: Lions Eye Institute Limited
Priority date: 2020-08-06
Filing date: 2021-08-06
Publication date: 2022-02-10

Abstract

A method of treating a retinal ischaemic disease of a patient is provided, the method comprising the steps of determining local visual function of at least a portion of the retina as a function of location on the retina, analysing the visual function of the patient as a function of location on the retina and identifying at least one area with reduced or no visual function if present, determining both at least one area of the retina for laser radiation treatment and a property of the laser radiation based on the analysis of the visual function of the patient as a function of location on the retina and based on the identified at least one area with reduced or no visual function if present, and exposing the determined at least one area of the retina to the laser radiation having the determined property, whereby at least a portion of photoreceptors in the determined at least one area of the retina exposed to the laser radiation cease functionality, wherein the property of the laser radiation is utilised to control the proportion of photoreceptors that are damaged within the at least one area of the retina exposed to the laser radiation.

Description

A METHOD OF TREATING RETINAL ISCHAEMIC DISEASES

Field of the Invention

The present disclosure relates to a method of treating a retinal ischaemic disease.

Background of the Invention

Retinal ischaemic diseases including diabetic retinopathy often have severe consequences for a patient and can cause loss of vision and sometimes even blindness. When a patient has diabetic retinopathy, retinal blood circulation is affected, and blood flow control is disrupted, which can lead to capillary changes including microaneurysm formation and capillary loss and under-perfusion (ischaemia). This in turn causes a reduction in retinal oxygen levels (hypoxia), which then causes the release of vessel growth factors that leads to abnormal vascular proliferation. The abnormal vessels then leak blood and other components that cause haemorrhage and cause retinal swelling (oedema). In later stages this can result in scar tissue formation and traction detachment of the retina. Importantly such changes are non-uniform structurally and functionally and often there are significant regional differences.

A common form of treatment for diabetic retinopathy is Pan-Retinal Photocoagulation (PRP). In this therapy much of the peripheral retina and of the thickness of the peripheral retina is burned with a laser to destroy the retinal cells, which normally consume oxygen, whereby the oxygen uptake by retinal cells can be reduced. As a result, oxygen flux from the choroid to the inner retina and vitreous is increased and the stimulus for new vessel growth is reduced. Retinal oxygenation is also improved to protect the central visual area (macula) from further degradation. The most widely accepted explanation of the protective effect of such laser therapy is the relief of tissue hypoxia due to a laser induced destruction of the treated area of retina (burning of photoreceptors), which then avoids the oxygen consumption of the retina in the treated area of the retina, resulting in more oxygen being available in the untreated area of the retina. Unfortunately, this comes at the expense of loss of vision in the laser treated area, which often significantly reduces the field of view of the patient. Pathologically the complications such as retinal neovascularisation and microaneurysms often occur at the border of ischemic and non-ischemic regions. It has been shown that the vascular endothelium growth factor (VEGF) is increased.

Summary of the Invention

The present invention provides in a first aspect a method of treating a retinal ischaemic disease of a patient, the method comprising the steps of: determining local visual function of at least a portion of the retina as a function of location on the retina; analysing the visual function of the patient as a function of location on the retina and identifying at least one area with reduced or no visual function if present; determining both at least one area of the retina for laser radiation treatment and a property of the laser radiation based on the analysis of the visual function of the patient as function of location on the retina and based on the identified at least one area with reduced or no visual function if present; and exposing the determined at least one area of the retina to the laser radiation having the determined property, whereby at least a portion of photoreceptors in the determined at least one area of the retina exposed to the laser radiation cease functionality, wherein the property of the laser radiation is utilised to control the proportion of photoreceptors that are damaged within the at least one area of the retina exposed to the laser radiation.

Determining the local visual function of the retina as a function of location on the retina may comprise determining a field of vision of a patient. Determining the field of vision of the patient may comprise forming a map of the field of vision of the patent.

In one embodiment, determining the local visual function of the retina as a function of location on the retina comprises determining a cellular structure of the retina as a function of location on the retina.

The laser radiation typically is pulsed. The property of the laser radiation may include one or more of the following parameters: pulse length, a separation between successive laser pulses, a total dose of the laser radiation, an intensity of the laser radiation, a wavelength or wavelength range of the laser radiation, and a spot size of the laser radiation. The pulsed laser radiation may be generated with each pulse having a pulse duration in a range from femtoseconds to seconds, depending on the therapy required.

Determining at least one area of the retina for laser radiation treatment and a property of the laser radiation may comprise determining an extension or locations of the area for laser radiation treatment and the property such that an impact on the field of vision of the patient by the treatment is avoided or minimised when the at least one area of the retina is exposed to the laser radiation treatment. The inventors have observed that the property of the laser radiation used for treating the determined at least one area of the retina is determinative of the degree to which photoreceptors will be damaged by application of the laser radiation within the treated area(s). By determining the property of the laser radiation based on the analysis of the visual function of the patient as function of location on the retina and based on the identified at least one area with reduced or no visual function if present, the property of the laser radiation used to treat the determined at least one area of the retina can be controlled prior to exposing the determined at least one area of the retina to the laser radiation. By controlling the property of the laser radiation used to treat the determined at least one area of the retina and exposing the determined at least one area of the retina to the controlled determined property, it is possible to control the proportion of photoreceptors that are damaged within the at least one area of the retina exposed to the laser radiation.

In one embodiment the method is conducted such that a redistribution of oxygen uptake by the retina is achieved, an uptake of oxygen in the peripheral area of the retina is reduced, and oxygen delivery to the inner retina and to the central area of the retina (at the macula) is increased. The inventors have observed that the oxygen uptake of the inner retina is relatively low compared to the oxygen uptake of the outer retina. In order to treat diseases, such as diabetic retinopathy, it is especially important to improve the supply of oxygen to the central region of the retina in order to preserve vision. As the oxygen uptake of the outer retina is relatively large, it is possible to achieve a significant redistribution of available oxygen supply to the inner retina and to the central area of the retina (at the macula) by a slight reduction of the oxygen uptake of the outer retina for example in peripheral areas of the retina. The slight reduction of the oxygen uptake in the outer retina in peripheral areas of the retina may be achieved by laser treating an area or a selection of areas of the outer retina with laser radiation having the determined property and in a manner such that, for areas to be treated that have all or reduced visual function, loss of visual function is minimised or avoided within the treated areas, and such that an impact on the field of vision of the patient by the treatment is avoided or minimised when the area or selection of areas of the outer retina is exposed to the laser radiation treatment.

The selection of the area or areas depends on the outcome of analysing the visual function of the patient as a function of location on the retina. In some cases, it is sufficient to laser treat a distribution (such as a random or even distribution) of areas within the peripheral region of the retina using a determined property, such as laser radiation spot size, wavelength or pulse duration. Alternatively, an identified area or areas of no or reduced visual function may be laser treated exclusively using a determined property, such as laser radiation intensity, spot size, wavelength or pulse duration.

Determining at least one area of the retina for laser radiation treatment may comprise determining a single area or a plurality of areas for laser treatment.

In one embodiment exposing the determined at least one area of the retina to the laser radiation comprises reducing a density of the photoreceptors within the determined at least one area by exposing photoreceptors to the laser radiation at a plurality of locations within the determined at least one area in the retina, such as in a peripheral area of the retina, in order to reduce oxygen uptake at the plurality of locations resulting in a redistribution of oxygen uptake and an increase in available oxygen for areas of the retina within and outside of the plurality of locations.

In one embodiment, the determined at least one area for laser treatment is outside the central area of the retina and at the periphery of the retina. In this embodiment, the determined at least one area of the retina may comprise a plurality of determined areas for laser radiation treatment and determining the property of the laser radiation may comprise determining the property such that, when the plurality of determined areas within the periphery of the retina is exposed to the laser radiation having the determined property, a first portion of the photoreceptors in the plurality of determined areas cease functionality and a second portion of the photoreceptors in the plurality of determined areas conserve functionality, whereby oxygen uptake in the peripheral area of the retina is reduced, available oxygen for the inner retina and the central area of the retina is increased, and loss of visual function at the periphery of the retina is minimised.

The determined at least one area for laser radiation treatment may be at, within, in the proximity of, or overlap with an area or areas of reduced visual function or substantially no visual function.

If an area of the retina has reduced visual function, the at least one area for laser radiation treatment and the property of the laser radiation may be determined such that, when the determined at least one area is exposed to the laser radiation having the determined property, a first portion of the photoreceptors cease functionality and a second portion of the photoreceptors conserve functionality in the area with reduced visual function, whereby oxygen uptake at the area of reduced visual function is reduced and loss of visual function at the area of reduced visual function is minimised.

In another embodiment, if an area of the retina has substantially no visual function, the at least one area for laser radiation treatment and the property of the laser radiation may be determined such that at least the majority or all photoreceptors cease visual function in the area of the retina with substantially no visual function when the at least one area is exposed to the laser radiation.

The method is typically conducted such that a re-distribution of intra-retinal oxygen levels to the central area of the retina at the macula is enabled with minimum or no loss of field of vision of the patient.

In one embodiment the laser radiation has a wavelength at least 20, 50 or even 100 nm lower or higher than a wavelength at which the absorbance of blood has a maximum, such as between approximately 530 nm and 600 nm. In one embodiment the selected wavelength is lower than 530 nm, such as 350 - 400 nm. The method may further comprise selecting a condition of the eye such that absorbance of photoreceptors is maximum at a selected wavelength. The condition may be light adaptation of the eye. In this embodiment, the method comprises selecting light adaptation of the eye during treatment and the property of the laser radiation may be a wavelength which is selected to be less than 500 nm, such as in the range of 350 - 400nm. The inventors have observed that for light adaptation photoreceptors have an absorption maximum at a wavelength of approximately 350 - 400 nm, which is more than 100 nm lower than the absorption maximum for dark adaptation and also approximately 200 - 150 nm lower than the absorption maximum of blood, which is in the range 530 - 600 nm. Consequently, this embodiment has the advantage of providing the possibility to choose the wavelength such that absorption of the radiation by the photoreceptors is maximised and an absorption of the laser radiation by blood in blood vessels is minimised.

In an alternative embodiment, the condition is dark adaptation of the eye and the method comprises selecting dark adaptation of the eye during treatment and the property of the laser radiation is a wavelength which is selected to be in the range of 420 - 580 nm. This range of wavelengths overlaps with the wavelength range of an absorption maximum of blood, and this embodiment may be advantageous to selectively target a portion of photoreceptors in the determined at least one area exposed to laser radiation such that the targeted portion of photoreceptors cease functionality after laser radiation treatment.

The laser radiation may have a wavelength selected in the range of 300 to 600 nm, such as 450-550 nm or 350-400 nm.

The method may be conducted such that the field of vision of the patient is at least largely unaffected.

In one embodiment the parameter of the laser radiation is selected such that the laser radiation is pulsed with a pulse duration in a range of 1 ms - 150 ms and a wavelength in the range of 350-400 nm or 400-580 nm. In a second aspect, the present invention provides an apparatus for treating a retinal ischaemic disease in an eye of a patient, the apparatus comprising: an optical transmitter for transmitting electromagnetic radiation from a laser source, the electromagnetic radiation having at least one controllable property; and an optical probe with an optical exit, the optical probe configured to receive the electromagnetic radiation having the controllable property from the optical transmitter and to apply the electromagnetic radiation having the controllable property upon emission from said exit to at least one area of a retina of the eye to be treated, wherein the controllable property of the electromagnetic radiation is determined prior to exposing the at least one area of the retina to be treated to the electromagnetic radiation based on an analysis of a visual function of the patient as a function of location on the retina and based on an identification of at least one area with reduced or no visual function if present, and wherein the controllable property of the electromagnetic radiation is controlled and utilised to control the proportion of photoreceptors that are damaged within the at least one area of the retina exposed to the laser radiation.

In one embodiment, the apparatus further comprises a controller configured to receive an input associated with the determined controllable property and to control the apparatus such that the electromagnetic radiation transmitted by the optical transmitter has the determined controllable property.

In one embodiment, the electromagnetic radiation is pulsed laser radiation.

The controllable property of the electromagnetic radiation may include one or more of the following parameters: pulse duration, a separation between successive laser pulses, a total dose of laser radiation, an intensity of laser radiation, a wavelength or wavelength range of laser radiation, and a spot size of laser radiation.

In one embodiment, the electromagnetic radiation is pulsed laser radiation and generated with each pulse having a pulse duration in a range from femtoseconds to seconds, depending on the therapy required. The invention will be more fully understood from the following description of specific embodiments of the invention. The description is provided with reference to the accompanying drawings.

Brief Description of the

Notwithstanding any other forms which may fall within the scope of the disclosure as set forth in the Summary, specific embodiments will now be described, by way of example only, with reference to the accompanying drawings in which:

Figure 1 a is a colour fundus photograph of the retina of a patient suffering of proliferative retinopathy before laser treatment;

Figure 1 b is a colour fundus photograph of the retina of the patient of Figure 1 a after conventional laser treatment;

Figure 2 is a flow chart of a method in accordance with an embodiment of the present invention;

Figure 3 is a schematic cross-sectional representation of the retina including diagrams schematically illustrating three distinct regions of high oxygen uptake in the inner and outer retina for a normal eye, and intraretinal oxygen distributions under different conditions including: normal; ischemia/hypoxia; and LP-1 , LP-2, LP-3 and LP-4, which are outcomes after laser radiation treatment using different laser parameters;

Figure 4 is a graph illustrating an optical absorption of blood as a function of wavelength;

Figure 5 is a graph illustrating an optical absorption of the human eye as a function of wavelength for dark (dark Rho) and light (Bleaches Rho) adaptation of the human eye; and Figure 6 to 9 are maps of laser radiation treatment areas of the human eye in accordance with embodiments of the present invention.

Detailed Description of Embodiments

Referring initially to Figures 1 a and 1 b, there are shown respective colour fundus photographs 100 and 102 of an eye of a patient suffering of proliferative retinopathy before treatment (Figure 1 a) and after a conventional laser radiation treatment such as PRP treatment (Figure 1 b). Before treatment, photograph 100 illustrates the presence of retinal lesions 104 in the eye, including lesions associated with neovascularisation, vitreous haemorrhage and exudations, with significant regional differences in those lesions. It is evident that retinal lesions in the fundus are remarkably non-uniform in characteristics such as severity and size, as well as in their impact on visual function. After conventional PRP treatment, photograph 102 shows the presence of extensive multiple laser burns 106 at the peripheral area of the retina resulting from the application of laser radiation at this area using PRP. While retinal lesions 104 have however been reduced significantly, PRP treatment typically results in a destruction of the full thickness of the retina at the treated areas and loss of peripheral and night vision. Thus, while the pathological changes may be improved, the treatment results in a loss of vision at the treated areas.

Embodiments of the present invention seek to provide a method of treating a retinal ischaemic disease, such as diabetic retinopathy, that allows treating areas of the retina in a manner such that retinal oxygenation is improved while substantially preserving visual function at the treated areas.

Referring to Figure 2, a method in accordance with an embodiment of the present invention is now described. The method 200 includes an initial step 202 of determining the local visual function of the retina as a function of location on the retina. In this embodiment step 202 includes determining a field of vision of a patient and forming a map of the field of vision. A person skilled in the art will appreciate that there are different known ways to determine a field of vision of a patient and to form a map of the field of vision of the patient. For example, a field of vision may be determined using a conventional technique such as by performing a visual field test.

It will be understood that the local visual function of the retina as a function of location on the retina may be determined using other conventional techniques including fundus photography, fluorescein angiography, and non-invasive functional examination techniques such as ophthalmic electrophysiological examination, retinal blood flow measurements and haemoglobin oxygen saturation measurements of retinal blood vessels.

In another embodiment, step 202 includes determining a cellular structure of the retina. The cellular structure of the retina may be determined using available non- invasive imaging techniques such as Optical Coherence Tomography and Optical Coherence Tomography Angiography, which provide retinal structural images of the retinal cellular layers and vasculature and from which information regarding the cellular structure of the retina can be extracted. Information extracted from the retinal structural images can be used to determine the local visual function of the retina as a function of a location on the retina.

The method 200 further includes step 204 which analyses the visual function of the patient as a function of location on the retina. The outcome of the analysis may be visualised in the form of a map, such as the map shown in Figure 7 which includes area 702 in which the retina has no visual function. Alternatively, or additionally, the analysis may comprise identifying an area or areas in which the patient has reduced visual function. Further, the analysis may comprise identifying that the entire retina or large areas of retina have (slightly) reduced visual function.

It is known that a number of diseases, such as diabetic retinopathy and other retinal ischaemic diseases, can result in reduced visual function of the retina or even loss of the visual function of the retina as a supply of oxygen to the inner retina by blood vessels is reduced. It is of main importance to avoid or reduce the loss of oxygen supply to the inner retina and central region of the retina at the macula in order to treat this effect of the disease. As mentioned previously, it is also known that by laser treating areas at the periphery of the retina (outside the macula area of the retina), it is possible to redistribute the oxygen and ensure that more oxygen is available at the inner retina and central area of the retina to improve vision. However, available laser treatments typically result in damage to the retina at treated areas at the periphery of the retina and loss of the visual function at these treated areas.

Embodiments of the present invention seek to provide a method 200 of treating a retinal ischaemic disease by using laser radiation treatment of areas of the retina, the method 200 being conducted such that a re-distribution of intra-retinal oxygen levels to the inner retina is enabled by partially reducing oxygen uptake by the photoreceptors with minimum or no loss of visual function at the treated areas and minimum or no loss of field of vision of the patient.

Step 206 of the method 200 carefully determines at least one area for laser treatment by selecting the at least one area based on the analysis of the visual function of a patient as function of location on the retina and based on the identified area or areas of the retina with reduced or no visual function. Further, step 206 determines a property of the laser radiation based on the analysis of the visual function of a patient as function of location on the retina and based on the identified area or areas of the retina with reduced or no visual function. The laser radiation is typically pulsed, and the property of the laser radiation may include at least one of the following parameters: pulse duration, a separation between successive laser pulses, a total dose of the laser radiation, an intensity of the laser radiation, a wavelength or wavelength range of the laser radiation, and a spot size of the laser radiation. Controlling the property of the laser radiation by adjusting the value of one or more of these parameters can affect the degree to which photoreceptors subject to the laser radiation are damaged. For example, by reducing the degree of damage inflicted, there is an expectation that not all photoreceptors will be caused to cease function as a result of the laser radiation.

The method 200 then comprises step 208 of exposing the determined at least one area of the retina to the laser radiation having the determined property, whereby at least a portion of photoreceptors in the determined at least one area on the retina cease functionality.

In one embodiment, the method 200 is carried out using an apparatus that comprises an optical transmitter for transmitting electromagnetic radiation from a laser source, the electromagnetic radiation having the determined property as described above. It is noted that in the present disclosure, the electromagnetic radiation from the laser source is generally referred to as laser radiation. As described above, the property of the laser radiation is controlled by adjusting the value of one or more of the parameters of the laser radiation and is controllable so as to control the proportion of photoreceptors that are damaged within the treated at least one area of the retina exposed to the laser radiation.

The apparatus further includes an optical probe with an optical exit, the optical probe configured to receive the electromagnetic radiation having the property from the optical transmitter and to apply the electromagnetic radiation having the determined controllable property upon emission from said exit to at least one area of a retina of the eye to be treated. The optical probe may comprise, for example, an optical fibre.

The optical transmitter may comprise one or more optical elements as considered appropriate by a person skilled in the art to transmit the electromagnetic radiation having the determined controllable property.

The apparatus may further comprise a controller configured to receive an input associated with the determined controllable property and to control the apparatus such that the electromagnetic radiation transmitted by the optical transmitter has the determined controllable property.

In one embodiment, the controller may be provided in the form of an optical system comprising one or more optical elements, including, however not limited to, any one or more of: mirrors such as reflective mirrors, a dispersing prism, and beam blocks. The one or more optical elements may be arranged in a manner such that an output of the laser source is converted into laser radiation having the desired determined property, i.e having one or more desired parameters, such as having a desired wavelength, a desired intensity and/or spot size. In this manner, one or more parameters of the laser radiation can be adjusted and controlled using the one or more optical elements, whereby the overall property of the laser radiation can be controlled. For example, if a pulsed laser is used, and/or if a property of the electromagnetic radiation for treating the at least one area of the retina is determined (prior to exposure of the at least one area of the retina to the laser radiation) to include the parameter of a wavelength or range of wavelengths within the range 300 - 600 nm and a spot size within the range 200 jim to 300 |im, a person skilled in the art will understand that any optical system, optical transmitter, laser source, and optical probe suitable for achieving and emitting such pulsed laser having such wavelength or range of wavelengths from the exit of the optical probe to the determined at least one area of the retina of a patient’s eye for treatment may be used.

In another embodiment, the controller may be provided in the form of a computing device connected to the optical system including the laser source, one or more optical elements such as mirrors, and/or the optical transmitter, and adapted to receive an input indicative of the one or more parameters associated with the determined property. The computing device may further be arranged to generate an output causing the optical transmitter to transmit electromagnetic radiation having the determined property. In this way, one or more parameters of the electromagnetic radiation transmitted by the optical transmitter and directed to the determined at least one area of the retina for treatment can be adjusted, whereby the property of the laser radiation is controllable.

By selecting areas for laser treatment and specific laser parameters as a function of the area to be treated, i.e. based on the analysis of the visual function of the retina as a function of location on the retina and based on an identification of one or more areas with reduced or no visual function if present, embodiments of the present invention provide a method of treating a retinal ischaemic disease of a patient wherein the property of the laser radiation is determined as a function of the area to be treated so as to selectively damage the photoreceptors at the treated areas, i.e. within the determined at least one area of the retina when the at least one area of the retina is exposed to the laser radiation having the determined property. This selective damage of photoreceptors enables a relief of hypoxia in the retina and an increase in the oxygen delivery to the central area of the retina while minimising a loss of visual function at the treated areas.

Depending on the outcome of the analysis and identification step 204, a single area or a plurality of areas may be determined for laser radiation treatment. The step 206 of method 200 will now be described in further detail with reference to Figures 3 to 9 and the following embodiments will be discussed: i) a plurality of areas may be determined for treatment at the periphery of the retina and the laser property may be determined such that, when the plurality of determined areas is exposed to the laser radiation having the determined property, a first portion of the photoreceptors in the plurality of determined areas cease functionality and a second portion of the photoreceptors in the plurality of determined areas is not destroyed and maintains functionality. A random or even distribution of areas may be selected around the periphery of the retina and the determined areas are exposed to the laser radiation having the determined laser property by exposing the photoreceptors to the laser radiation at a plurality of locations within the determined areas at the periphery of the retina. As a result of the process, oxygen uptake at the periphery of the retina can be reduced, leading to an increase in available oxygen for the inner retina and the central area of the retina at the macula. By preserving the functionality of the second portion of photoreceptors at the periphery of the retina, loss of visual function at the periphery of the retina is minimised and the field of vision of the patient can be substantially preserved or suffer minimal loss. ii) if an area of the retina is identified with reduced visual function, an area for laser radiation treatment is determined that is at, within, or overlaps with the areas having reduced visual function. Then, the property of the laser radiation is determined such that, when the determined area for treatment is exposed to the laser radiation, a portion of photoreceptors cease functionality and another portion of photoreceptors conserve functionality in the area with reduced visual function. Thus, the oxygen uptake at this area of reduced visual function is reduced however the visual function of a portion of photoreceptors is preserved and loss of vision in this area is minimised; and iii) if an area of the retina is identified as having substantially no visual function, an area for laser radiation treatment is determined that is at, within, or overlaps with the area having substantially no visual function. Then, the property of the laser radiation is determined such that, when the determined area for treatment is exposed to the laser radiation, at least the majority or all photoreceptors in these areas with no visual function cease functionality, whereby the unnecessary uptake of oxygen at these areas with no visual function is eliminated or substantially reduced.

It will be appreciated that in the embodiments ii) and iii), it is also envisaged that the area determined to be treated is in proximity to the area having reduced or no visual function to achieve similar results.

Figure 3 shows a schematic cross-sectional representation 300 of the retina and oxygen gradient profiles illustrating a delivery of oxygen to different areas of the retina and from the choroid. The regions 302, 304, 306 in the outer retina and inner retina correspond to three distinct oxygen consumption zones of the retina that are the inner plexiform layer 302, the outer plexiform layer 304 and inner segments of photoreceptors 306. The dashed line indicates the intra-retinal oxygen distribution in a healthy patient. As can be seen for a healthy patient, the oxygen distribution across the various retinal regions is non-uniform and less oxygen is delivered to the inner retina compared to the outer retina as the inner segments of photoreceptors are dominant oxygen consumers. The heterogeneous oxygen distribution across the retinal regions is indeed largely dependent on the oxygen sources (retinal and choroidal blood circulations) and the oxygen uptakes from the retinal neurons. For a patient with ischemia or hypoxia (dark solid line), this difference is more significant and significantly less oxygen is delivered to the inner retina while the oxygen supply from choroidal blood circulation is usually less affected.

Figure 3 further schematically indicates intra-retinal oxygen gradients, LP-1 , LP-2, LP-3, and LP-4, in a patient who underwent laser treatment of the retina in accordance with embodiments of the present invention. Step 206 of the method 200 was conducted such that areas determined for laser treatment were exposed to laser radiation characterised by different determined laser parameters (LP). In the present example, different laser powers (corresponding to respective different laser intensities) were determined and used with the laser power increasing from LP-1 , LP-2, LP-3 to LP-4 within a range from approximately 200 mW up to approximately 1500 mW. It is observed that, in comparison to an untreated patient with ischemia or hypoxia, the distribution of oxygen through the outer retina is increasingly improved as a result of laser radiation treatment with increasing laser intensity, such that more oxygen can be supplied to the inner retina and further towards the inner surface of the retina and vitreous of the eye. For example, using a continuous wave laser with a power of approximately 200 mW and a spot size of approximately 300 pm, and an exposure duration around 200 ms could induce a full thickness of retinal damage without significant effect on the choroid. It will be appreciated that alternatively or simultaneously, laser parameters other than the laser power may be determined and varied to achieve similar results associated with different improvements in the distribution of oxygen through the outer retina and towards the inner retina. For example, if using a pulsed laser, one or more of the following may be determined and varied: the pulse duration of the laser radiation may be selected within a range from one or a few femtoseconds to hundreds of nanoseconds up to a thousand nanoseconds; a separation or duration between successive laser pulses may be selected within a range from 1 to 250 ms; the wavelength of the laser radiation may be selected in a range from 300 to 600 nm (such as 350-400 nm or 450-580 nm); and the laser spot size may be selected within a range from 50 pm to 350 pm. Dependent on the laser power and the spot size, the exposure duration of the laser radiation may further be determined and varied between 100 ms and 2000 ms. Additionally, or alternatively, a total dose of the laser duration may also be determined and varied to contribute to different improvement in the distribution of oxygen through the outer retina towards the inner retina.

Thus, different intra-retinal oxygen distributions (LP-1 , LP-2, LP-3, and LP-4) can be achieved using different laser parameters to modulate the intra-retinal oxygen distributions allowing more oxygen to diffuse from the choroid to the inner retina. A wavelength or wavelength range of the laser radiation may be determined with reference to the absorption spectrum of blood and the electromagnetic radiation absorption of photoreceptors as a function of wavelength. Figure 4 schematically illustrates the absorption spectrum of blood (HbO2 and Hb) as a function of wavelength. The absorbance of blood has a maximum within 530 - 600 nm. Figure 5 is a graph illustrating the electromagnetic radiation absorption of photoreceptors as a function of wavelength for dark adaptation (dark Rho) and light adaptation (Bleached Rho). For dark adaptation the absorption of the photoreceptors has a maximum within the range of 420 - 580 nm, peaked at around 490nm. The range in which the absorption of the photoreceptors has a maximum for dark adaptation overlaps with the wavelength range in which absorption of blood has a maximum. As the inner region of the retina is vascularised, if laser treatment is performed at a wavelength chosen close to the wavelength at which absorption of blood is maximum, i.e. around 570 nm, a large portion of the radiation will be absorbed by blood vessels and consequently more damage will be induced to the inner vascularised retina. Such condition of laser treatment may be appropriate if severe damage to the photoreceptors is desired, for example for the treatment of areas with substantially no visual function. For light adaptation, the absorption maximum of the photoreceptors is shifted to shorter wavelengths (maximum at approximately 370 nm) and does not overlap with the absorption maximum of the blood. Such condition may be more appropriate where damage to the inner retina is to be substantially avoided. Depending on the desired outcome (with reference to embodiments i) - iii) mentioned above), it may be appropriate to conduct laser treatment at a wavelength or range of wavelengths at which the absorption of the photoreceptors has a maximum for either dark or light adaptation of the eye. This may be useful to selectively damage the photoreceptors, i.e. to control the proportion of photoreceptors that are damaged within areas of the retina exposed to laser radiation having the determined property. However, to avoid damage to the choroid, which is a high oxygen source for the retina, it is preferable to avoid a use of wavelengths in close proximity to the oxygenated haemoglobin (HbC ) absorption peak.

Further, the pulse duration of the laser radiation may be determined such that ultra- short pulses are used, which may be advantageous to avoid thermal damage spreading to retinal layers other than the targeted retinal layer to dominantly absorb the laser radiation, i.e. the inner segments of photoreceptors layer 306.

Figure 6 is a schematic view 600 of the retina of a patient for whom the analysis of the visual function as function of location on the retina (step 204) indicated that there are no specific areas in the peripheral region of the retina in which the patient has no visual function. The view 600 of the retina indicates the optic nerve 602, from which the major blood vessels 604 of the retina radiate, and the macula 606. In this embodiment the method 200 is conducted such that there is just sufficient laser treatment in order to reduce oxygen consumption in the treated area and restore satisfactory supply of oxygen to other areas of the retina (such as the inner retina) and without reducing the field of vision of the patient. In this case, a larger number of relatively small areas of the peripheral region of the retina are laser treated by exposing photoreceptors to the laser radiation at a plurality of locations within the small areas, which is illustrated by the laser spots 608. In the present example, a continuous wave laser is used and the parameters of the laser radiation are chosen such that (1 ) the laser power is relatively low, for example around 200 mW, which may be in the range of the laser power that was determined and resulted in the improvement observed in oxygen gradient LP-1 illustrated in Figure 3, (2) the spot size is relatively small, for example in the range between 50 pm and 100 pm, and (3) the exposure duration is relatively short, for example between 100 ms and 200 ms. In this manner it is possible to select an even or random distribution of locations for the laser treatment at which a relatively small number of photoreceptors cease function and a portion of photoreceptors preserve their functionality, just sufficient such that there is a required increase in oxygen supply to other areas of the retina from the choroid to the inner retina and/or vitreous, and an increase in oxygen provided to the central area of the retina (the macular area 606) while minimising an impact on the field of view of the patient as a portion of photoreceptors preserve their visual function. The intra-retinal oxygen distribution after laser radiation treatment of the peripheral area of the retina is expected to be substantially similar to the oxygen distributions LP-1 illustrated in Figure 3.

Figure 7 is a schematic view 700 of the retina of a patient for whom step 204 indicated that there is an area 702 in the peripheral region of the retina in which the retina of the patient has no visual function. The view 700 of the retina also indicates the optic nerve 704, from which the major blood vessels 706 of the retina radiate, and the macula 708. In this case the laser treatment is chosen so as to cause severe damage to the full thickness of the retina at the area 702 and among other determined laser parameters, a relatively laser spot size is preferred, which is illustrated by the laser spots 710. The laser treatment is focused on the area 702 and the laser parameters are chosen so as to significantly reduce the oxygen uptake at area 702, not only in the inner segments of photoreceptors but also in the inner and outer plexiform layers of the retina, resulting in a redistribution of oxygen from the area 702 to other areas of the retina. In a particular example, a micropulse laser is used and the property of the laser radiation is chosen such that (1 ) the duty cycle is in a range between 5% and 15%, (2) the laser power is relatively high, for example in the range between 1000 mW and 1500 mW, which may be in the range of the laser power that was determined and resulted in the improvement observed in oxygen gradient LP-3 or LP-4 illustrated in Figure 3, (3) the wavelength of the laser radiation is within the range 550 nm - 600 nm (in the vicinity of the wavelength at which the absorption of blood is maximum), (4) the spot size is relatively large such as for example within a range between 200 pm and 300 pm, (5) the exposure duration of the laser radiation is relatively long, for example between 500ms and 1500 ms, and (6) the duration between successive laser pulses is relatively short, such as within a range 1 ms - 50 ms. In this manner it is possible to laser treat the area 702 such that at least the majority or all of photoreceptors cease function in the area 702 (in which the patient has no visual function anyway) to increase the supply of oxygen supply to the inner retina and/or vitreous and improve oxygenation at the central region of the retina (the macular area 708) without having a further impact on the field of view of the patient. The intra-retinal oxygen distribution after laser radiation treatment of the area 702 is expected to be substantially similar to the oxygen distributions LP-3 or LP-4 illustrated in Figure 3.

Figure 8 is a schematic view 800 of the retina of a patient for whom step 204 indicated that there is an area 802 in the peripheral region of the retina at which the retina of the patient has highly reduced or no visual function. Further analysis indicated that in the area 802 the retina shows neo-vascularisation, micro aneurysms or proliferative changes. The view 800 of the retina also indicates the optic nerve 804, from which the major blood vessels 806 of the retina radiate, and the macula 808. In this embodiment the laser treatment, which is illustrated by the laser spots 810, is focused on the area 802 and the laser spots 810 cover an area large enough to cover and overlap with all retinal lesions at the area 802 in order to redistribute oxygen from the area 802 to other areas of the retina. In a particular example, a micropulse laser is used and the parameters of the laser radiation are chosen such that (1) the duty cycle is in a range between 5% and 15%, (2) the laser power is relatively high, however milder than for the case of treating an area with no visual function, such as between 800 mW and 1250 mW and (3) the spot size is relatively large, such as for example within a range between 200 pm and 300 pm, however may be smaller than for the case of treating an area with no visual function, and (4) the exposure duration of the laser radiation is relatively short, for example 100 ms and 300 ms. For example, laser power may be chosen to be within the range of the power that resulted in the improvement observed in oxygen gradient LP-2 illustrated in Figure 3, and to preserve visual function, the laser spot size is chosen such that the laser spots 810 can cover a large area overlapping with the area 802 while being relatively widely spaced apart. In this manner it is possible to laser treat the region 802 such that at least the majority of photoreceptors cease function in this area to increase the supply oxygen supply to the inner retina and/or vitreous and improve oxygenation at the central region of the retina (the macular area 708) and without having a (further) impact on the field of view of the patient. The intra-retinal oxygen distribution after laser radiation treatment of the area 802 is expected to be substantially similar to the oxygen distribution LP-2 illustrated in Figure 3.

Figure 9 is a schematic view 900 of the retina of a patient for whom the analysis of the visual function (step 204) indicated that there is an area 902 in the peripheral region of the retina at which the retina of the patient has reduced visual function, but some visual function is remaining in that area. The view 900 of the retina also indicates the optic nerve 904, from which the major blood vessels 906 of the retina radiate, and the macula 908. Further analysis indicated that in the area 902 the retina also shows neo-vascularisation, micro aneurysms or proliferative changes. In this embodiment the laser treatment, which is illustrated by the laser spots 910, is focused on the area 902 and the laser spots 910 cover an area large enough to cover and overlap with all retinal lesions at the area 902 in order to redistribute oxygen from the area 902 to other areas of the retina. In a particular example, a micropulse laser is used and the parameters of the laser radiation are chosen such that: (1 ) the duty cycle is in a range between 5% and 10%, (2) the wavelength of the laser radiation is within the range 450 nm - 500 nm (in the vicinity of the wavelength at which the absorption of blood is maximum), (3) the laser power is relatively low, for example in a range between 200 mW and 1000 mW, (4) the spot size is relatively small, in comparison with the parameters of the laser radiation chosen for treating the area 802, and may be in the range between 50 pm and 100 pm, and the exposure duration is relatively short, for example between 100 ms and 200 ms, and (4) the duration between successive laser pulses is relatively long, such as within a range 100 ms - 200 ms. For example, laser power may be chosen to be within a range between the power that resulted in the improvement observed in oxygen gradient LP-1 and the power that resulted in the improvement observed in oxygen gradient LP-2 illustrated in Figure 3, and to preserve visual function, the laser spot size is further chosen such that the laser spots 910 can cover a large area overlapping with the area 902 while being relatively widely spaced apart. In this manner it is possible to laser treat the region 902 such that some (but not all) photoreceptors in that area cease function to increase the supply oxygen supply to the inner retina and/or vitreous and improve oxygenation at the central region of the retina (the macular region 908) and without having an impact on the field of view of the patient. The intra-retinal oxygen distribution after laser radiation treatment of the area 902 is expected to be substantially in-between the oxygen distributions LP-1 and LP-2 illustrated in Figure 3.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features in various embodiments of the invention.

It will be appreciated that modifications and variations as would be apparent to a skilled addressee are determined to be within the scope of the present invention.

Claims

1 . A method of treating a retinal ischaemic disease of a patient, the method comprising the steps of: determining local visual function of at least a portion of the retina as a function of location on the retina; analysing the visual function of the patient as a function of location on the retina and identifying at least one area with reduced or no visual function if present; determining both at least one area of the retina for laser radiation treatment and a property of the laser radiation based on the analysis of the visual function of the patient as a function of location on the retina and based on the identified at least one area with reduced or no visual function if present; and exposing the determined at least one area of the retina to the laser radiation having the determined property, whereby at least a portion of photoreceptors in the determined at least one area of the retina exposed to the laser radiation cease functionality, wherein the property of the laser radiation is utilised to control the proportion of photoreceptors that are damaged within the at least one area of the retina exposed to the laser radiation.

2. The method of claim 1 , wherein determining the local visual function of the retina as a function of location on the retina comprises determining a field of vision of a patient.

3. The method of claim 2, wherein determining a field of vision of the patient comprises forming a map of the field of vision of the patent.

4. The method of claim 1 or 2, wherein determining a local visual function of the retina as a function of location on the retina comprises determining a cellular structure of the retina as a function of location on the retina.

5. The method of any one of the preceding claims, wherein the laser radiation is pulsed.

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6. The method of any one of the preceding claims, wherein the property of the laser radiation includes one or more of the following parameters: pulse duration, a separation between successive laser pulses, a total dose of the laser radiation, an intensity of the laser radiation, a wavelength or wavelength range of the laser radiation, and a spot size of the laser radiation.

7. The method of any one of the preceding claims, wherein the laser radiation is pulsed and generated with each pulse having a pulse duration in a range from femtoseconds to seconds, depending on the therapy required.

8. The method of any one of the preceding claims, wherein determining at least one area of the retina for laser radiation treatment and a property of the laser radiation comprises determining an extension of the at least one area of the retina for laser radiation treatment and the property such that an impact on the field of vision of the patient by the laser radiation treatment is avoided or minimised when the at least one area of the retina is exposed to the laser radiation treatment.

9. The method of any one of the preceding claims, wherein the method is conducted such that a redistribution of oxygen uptake by the retina is achieved, an uptake of oxygen in the peripheral area of the retina is reduced, and oxygen delivery to the inner retina and to the central area of the retina (at the macula) is increased.

10. The method of any one of the preceding claims, wherein determining at least one area of the retina for laser radiation treatment comprises determining a single area for laser radiation treatment.

11 . The method of any one of claims 1 to 9, wherein determining at least one area of the retina for laser radiation treatment comprises determining a plurality of areas for laser radiation treatment.

12. The method of any one of the preceding claims, wherein exposing the determined at least one area of the retina to the laser radiation comprises reducing a density of the photoreceptors within the determined at least one area by exposing photoreceptors to the laser radiation at a plurality of locations within the determined at least one area in the retina, such as in a peripheral area of the retina, in order to reduce oxygen uptake at the plurality of locations resulting in a redistribution of oxygen uptake and an increase in available oxygen for areas of the retina outside of the plurality of locations.

13. The method of any one of the preceding claims, wherein the determined at least one area for laser treatment is outside a central area of the retina and at a periphery of the retina.

14. The method of claim 13, wherein the determined at least one area of the retina comprises a plurality of determined areas for laser radiation treatment and wherein determining the property of the laser radiation comprises determining the property such that, when the plurality of determined areas within the periphery of the retina is exposed to the laser radiation having the determined property, a first portion of the photoreceptors in the plurality of determined areas cease functionality and a second portion of the photoreceptors in the plurality of determined areas preserve functionality, whereby oxygen uptake in the peripheral area of the retina is reduced, available oxygen for the inner retina and the central area of the retina is increased, and loss of visual function at the periphery of the retina is minimised.

15. The method of any one of the preceding claims, wherein the determined at least one area of the retina for laser radiation treatment is at, within, in the proximity of, or overlaps with an area or areas of reduced visual function or substantially no visual function.

16. The method of claim 15 wherein, if an area of the retina has reduced visual function, the at least one area for laser radiation treatment and the property of the laser radiation are determined such that, when the determined at least one area is exposed to the laser radiation having the determined property, a first portion of the photoreceptors cease functionality and a second portion of the photoreceptors conserve functionality in the area with reduced visual function, whereby oxygen uptake at the area or areas of reduced visual function is reduced and loss of visual function at the area or areas of reduced visual function is minimised.

17. The method of claim 15 wherein, if an area of the retina has substantially no visual function, the at least one area for laser radiation treatment and the property of the laser treatment are determined such that at least the majority or all photoreceptors cease visual function in the area of the retina with substantially no visual function when the determined at least one area is exposed to the laser radiation.

18. The method of any one of the preceding claims, wherein the method is conducted such that a re-distribution of intra-retinal oxygen levels to the central area of the retina at the macula is enabled without loss of field of vision of the patient.

19. The method of any one of the preceding claims, wherein the laser radiation has a wavelength at least 20, 50 or even 100 nm lower or higher than a wavelength at which the absorbance of blood has a maximum.

20. The method of claim 19, wherein the wavelength is lower than 530 nm, such as 350-400 nm.

21 . The method of any one of the preceding claims, comprising selecting a condition of the eye such that absorbance of photoreceptors is maximum at a selected wavelength.

22. The method of claim 21 , wherein the condition is one of light adaptation of the eye and dark adaptation of the eye.

23. The method of any one of the preceding claims, wherein the method is conducted such that the field of vision of the patient is at least largely unaffected.

24. An apparatus for treating a retinal ischaemic disease in an eye of a patient, the apparatus comprising: an optical transmitter for transmitting electromagnetic radiation from a laser source, the electromagnetic radiation having at least one controllable property; and an optical probe with an optical exit, the optical probe configured to receive the electromagnetic radiation having the controllable property from the optical

25 transmitter and to apply the electromagnetic radiation having the controllable property upon emission from said exit to at least one area of a retina of the eye to be treated, wherein the controllable property of the electromagnetic radiation is determined prior to exposing the at least one area of the retina to be treated to the electromagnetic radiation based on an analysis of a visual function of the patient as a function of location on the retina and based on an identification of at least one area with reduced or no visual function if present, and wherein the controllable property of the electromagnetic radiation is controlled and utilised to control the proportion of photoreceptors that are damaged within the at least one area of the retina exposed to the laser radiation.

25. The apparatus of claim 24, further comprising a controller configured to receive an input associated with the determined controllable property and to control the apparatus such that the electromagnetic radiation transmitted by the optical transmitter has the determined controllable property.

26. The apparatus of claim 24 or 25, wherein the electromagnetic radiation is pulsed laser radiation.

27. The apparatus of any one of claims 24 to 26, wherein the controllable property of the electromagnetic radiation includes one or more of the following parameters: pulse duration, a separation between successive laser pulses, a total dose of laser radiation, an intensity of laser radiation, a wavelength or wavelength range of laser radiation, and a spot size of laser radiation.

28. The apparatus of any one of claims 24 to 27, wherein the electromagnetic radiation is pulsed laser radiation and generated with each pulse having a pulse duration in a range from femtoseconds to seconds, depending on the therapy required.

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