Fluid tracking in patients with wet AMD using thickness change analysis

Abstract

The present system / method / device uses an (e.g., self-use) OCT system for personalized monitoring of wet AMD patients, where the patient self-performs an OCT scan, which is automatically analyzed and notifies the patient and / or a designated licensed physician / technologist when medication or specialized medical care is required.

Description

[Technical Field]

[0001] The present invention is generally directed to systems and methods for (e.g., remotely) monitoring wet AMD patients and determining when intraocular fluid levels require medical attention and / or medical treatment. [Background technology]

[0002] OCT is a noninvasive imaging technique that uses light waves to penetrate tissue and generate image information at different depths within tissues, such as the eye. Generally, OCT systems are interferometric imaging systems based on detecting the interference between a reference beam and backscattered light from a sample illuminated by the OCT beam. Each scattering profile in the depth direction (e.g., z-axis or axial direction) can be individually reconstructed into an axial scan or A-scan. Cross-sectional slice images (e.g., two-dimensional (2D) separation scans, i.e., B-scans) and volume images (e.g., 3D cube scans, i.e., C-scans) can be constructed from multiple A-scans acquired as the OCT beam scans / moves through a set of transverse (e.g., x-axis and / or y-axis) locations on the sample. When applied to the retina of the eye, OCT generally provides structural data that allows, for example, the unique tissue layers and vascular structure of the retina to be at least partially identified. OCT angiography (OCTA) extends the capabilities of OCT systems to also identify (e.g., render in image form) the presence or absence of blood flow in retinal tissue. For example, OCTA can identify blood flow by identifying differences (e.g., contrast differences) over time in multiple OCT scans of the same retinal region and designating differences in the scans that meet predetermined criteria as blood flow.

[0003] OCT systems also enable the construction of planar (2D) en face (e.g., en face) images of selected portions of a tissue volume (e.g., a target tissue slab (subvolume) or target tissue layer(s), such as the retina of the eye). Examples of other 2D representations (e.g., 2D maps) of ophthalmic data provided by OCT systems include layer thickness maps and retinal curvature maps. For example, to generate a layer thickness map, an OCT system may use an en face image, a 2D retinal vasculature map, and multi-layer segmentation data. The thickness map may be based, at least in part, on measured thickness differences between retinal layer boundaries. The vasculature map and OCT en face images may be generated, for example, by projecting a subvolume (e.g., a tissue slab) defined between two layer boundaries onto a 2D surface. The projection may use the average, sum, percentile, or other data aggregation method of the subvolumes. Therefore, the creation of these 2D representations of 3D volumetric (or subvolume) data often relies on the effectiveness of automated segmentation algorithms to identify the layers on which the 2D representation is based.

[0004] Wet macular degeneration (wet age-related macular degeneration, or wet AMD) is a chronic disease characterized by abnormal blood vessels growing under the retina. Fluid leakage from these blood vessels at the back of the eye can lead to swelling and damage to the macula. If this fluid is not controlled, central vision gradually deteriorates. Current treatments that can help control this fluid and slow the progression of wet macular degeneration are periodic injections of anti-vascular endothelial growth factor (anti-VEGF) drugs (e.g., every 4–6 weeks, depending on the progression of fluid leakage). Response to anti-VEGF therapy is known to depend on various factors, including the patient's age, lesion characteristics, lesion duration, baseline visual acuity, and the presence or absence of certain genotypic risk alleles. Therefore, because different patients may respond differently to anti-VEGF medication, the interval between injections may need to be shortened or extended for individual patients. Typically, the only way to determine whether the injection interval needs to be changed is for the patient to have a regular office visit with an ophthalmologist for an OCT scan, where the doctor reviews the patient's visual acuity, OCT B-scan, and macular thickness map to determine whether to prescribe (e.g., approve) an injection. A discussion of the use of expert-level OCT systems (e.g., as used in doctors' offices) in AMD monitoring, and how changes in retinal thickness can affect vision, can be found in U.S. Patent No. 5,629,997 and U.S. Patent No. 5,629,997.

[0005] However, frequent doctor visits to monitor wet AMD are generally not practical. Options for remote (e.g., at home) monitoring of wet AMD are desirable. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 7,301,644 [Non-patent literature]

[0007] [Non-Patent Document 1] Evans et al., "Associations of Variation in Retinal Thickness with Visual Acuity and Anatomic Outcomes in Eyes with Neovascular Age-related Macular Degeneration Lesions Treated with Anti-Vascular Endothelial Growth Factor Agents," JAMA Ophthalmology, 2020, Vol. 138, No. 10, pp. 1043-1051 Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of the present invention to provide a system and method that provides a personalized analysis for monitoring wet AMD that is customized for an individual patient. Another object of the present invention is to provide a system and method for remote monitoring of wet AMD.

[0009] It is a further object of the present invention to provide a system and method that automatically customizes the analysis of wet AMD to the characteristics of a particular patient's ocular tissue. It is yet another object of the present invention to provide a system and method to assist a physician in determining when changes in macular thickness are significant and require medication and / or changes to current treatment. [Means for solving the problem]

[0010] The above objects are achieved in a method / system that provides monitoring of ocular pathologies (such as age-related macular degeneration, AMD, etc.) such as by automated analysis of ophthalmic OCT scans of patients (e.g., AMD patients). The present systems and methods are presented herein as applied to remote (e.g., home or self-applied) OCT systems, which are typically low-cost devices, but may optionally be used in professional-grade OCT systems, such as those used in clinics or doctors' offices, to help distinguish between normal retinal thickness variations that do not require treatment (such as with anti-VEFG injections) and retinal thickness variations that are significant and require treatment.

[0011] In the present system / method for monitoring age-related macular degeneration (AMD), e.g., wet AMD, a patient's eye is scanned with an OCT system. For example, the patient may perform an OCT scan themselves using a home (e.g., telecare or telemedicine) OCT system. The system automatically identifies the macula of the eye and identifies at least one macular region of interest (ROI) (or area / sector of interest) within the OCT scan. For example, the system may identify at least one sector, preferably two or more (e.g., three concentric) sectors. Optionally, the three concentric macular ROIs may approximately follow the composite grid shape of a typical Early Treatment Diabetic Retinopathy Study (ETDRS) grid. For example, the first macular ROI may be a "central" area / sector corresponding to the central subfield of the ETDRS grid and may have a circular / disc shape with a diameter of 1 mm. The second macular ROI surrounding the first macular ROI may be an "inner" area / sector that corresponds to the combination of all inner subfields of the ETDRS grid and may have an annular shape with an inner diameter of 1 mm and an outer diameter of 3 mm. The third macular ROI surrounding the second macular ROI may be an "outer" area / sector that corresponds to the combination of all outer subfields of a typical ETDRS grid with an inner diameter of 3 mm and an outer diameter of 6 mm.

[0012] The system / method then determines a representative macular thickness measurement for each of the (e.g., three) macular ROIs, each of which is characteristic of the overall thickness of that individual macular ROI. For example, the representative macular thickness measurement can be the average macular thickness within the individual macular ROI, the highest macular thickness within the macular ROI, or the average of a predetermined number (e.g., two or more, or the top 25%-50%) of the highest macular thickness measurements within the individual macular ROI.

[0013] The system establishes / determines a separate lowest previous (or patient-personalized) baseline thickness (e.g., of macular retinal tissue) for each separate macular ROI (e.g., for the central sector, inner sector, and outer sector). Thus, the patient-personalized baseline thicknesses for each separate macular ROI may differ from one another. These patient-personalized baseline thicknesses may be based on the patient's personal medical history during the OCT scan of the eye. For example, the patient-personalized baseline thickness for each separate macular ROI may be based on the average of (e.g., representative) retinal macular thickness measurements for each corresponding macular ROI during a period of dry AMD (e.g., a doctor's visit during which no injection treatment was administered). Alternatively, the patient-personalized baseline thickness for each separate macular ROI may be based on the average of the lowest previous (e.g., representative) retinal macular thickness measurements for a predetermined number (e.g., three) of each separate macular ROI. These previous retinal macular thickness measurements may have been obtained at a previous visit or may have been obtained by the same self-operated OCT system used to perform the current OCT scan. Optionally, the number of lowest previous retinal macular thickness measurements is a measurement from consecutive OCT scans at a time interval corresponding to a previously scheduled macular thickness examination (e.g., every 4-6 weeks). For example, the patient-personalized baseline thickness may be based on an average of the lowest previous representative macular thickness measurements for a predetermined number of macular ROIs, determined according to the macular thickness examination period scheduled by the medical professional, e.g., if the medical professional schedules the examination period. As another example, the number of lowest previous retinal macular thickness measurements may be selected from a previous visit (contiguous or non-contiguous) in which no medication was injected into the eye. Further optionally, the patient-personalized baseline thickness for each macular ROI may be user-adjustable by freely entering any value or by fixed-size intervals within a predetermined range (e.g., a range of 15 μm to 30 μm in 5 μm increments).

[0014] The representative macular thickness measurement determined for each macular ROI is then compared with its corresponding patient-specific baseline thickness using the corresponding upper and lower threshold offsets. For example, the upper specification limit (USL) for each macular ROI can be defined as its corresponding patient-specific baseline thickness plus its corresponding upper threshold offset. Similarly, the lower specification limit (LSL) for each macular ROI can be defined as its corresponding patient-specific baseline thickness minus its corresponding lower threshold offset. In some applications, the upper and lower threshold offsets can be set individually or can be the same for all macular ROIs. Optionally, at least one of the upper threshold offset and the lower threshold offset may be based on a statistical analysis of a population of macular thickness measurements from corresponding macular ROIs in a population of test eyes that does not include the patient's eyes, and may be obtained during a stable period, which may be defined as a period of dry AMD, or a period during which the macular thickness of the test eye has not changed by more than a predetermined percentile (e.g., 5%), or a period during which no medication (e.g., anti-VEGF injection) has been applied. The statistical analysis may provide a statistical deviation (e.g., standard deviation) between the population of macular thickness measurements, in which case at least one of the upper threshold offset and the lower threshold offset may be based on the statistical analysis.

[0015] In response to a representative macular thickness measurement of any macular ROI being higher than (or equal to or greater than) its respective upper specification limit, the system emits a signal (e.g., an electronic, audio, visual, tactile, etc.) indicating an irregularity. This irregularity may be interpreted as indicating that medical care is warranted. For example, a medical practitioner, such as a retina specialist or physician, may examine the patient and provide a medical diagnosis based on a workup that may include collecting and examining OCT images and other medical data. For example, the emitted signal may be an electronic message remotely transmitted to the patient's physician (or clinic) via a telecommunications network (e.g., text message, email, internet, telephone, etc.).

[0016] In response to any representative macular thickness measurement of the macular ROI being lower than (or equal to) its respective lower specification limit, the patient-personalized baseline thickness of the affected macular ROI may be adjusted. For example, the patient-personalized baseline thickness may be adjusted based on the representative macular thickness measurement of the affected macular ROI. In some applications, the subject's patient-personalized baseline thickness is adjusted not the first time the measurement falls below the lower specification limit, but rather the second or third time that the eye's representative macular thickness measurement falls below the lower specification limit. The subject's patient-personalized baseline thickness may be adjusted to the average of two or more representative macular thickness measurements of the eye (optionally including the current value) that are lower than the lower specification limit.

[0017] Optionally, at least one of the upper and lower specification limits of the target macular ROI may be adjusted in response to its representative macular thickness measurement being higher than (or equal to) the upper specification limit or lower than (and equal to) the lower specification limit. For example, the upper and / or lower specification limits may be automatically adjusted by a preset increment within a predetermined range (e.g., optionally by adjusting their respective offset values). Alternatively, the upper and / or lower specification limits (or their respective offsets) may be automatically adjusted by incorporating the representative macular thickness measurement of the target macular ROI into a recalculation of the upper and / or lower specification limits. This recalculation may include, for example, averaging a deviation measurement of the representative macular thickness measurement of the target macular ROI with a deviation measurement that serves as a reference for the upper and / or lower specification limits. Alternatively, this value may be incorporated by recalculating the statistical deviation(s) underlying the upper / lower limits and incorporating the representative macular thickness measurement of the target macular ROI into this recalculation. Another option is for an authorized user to remotely adjust the upper and / or lower specification limits (or their respective offset values) in response to receiving an electronic message over a telecommunications network.

[0018] Other objects and achievements of the present invention, together with a fuller understanding of the invention, will become apparent and understood by reference to the following description and claims taken in conjunction with the accompanying drawings.

[0019] To facilitate the understanding of the present invention, several publications are cited or referenced herein. All publications cited or referenced herein are incorporated by reference in their entirety.

[0020] The embodiments disclosed herein are merely examples, and the scope of the present disclosure is not limited thereto. Features of any embodiment described in one claim category, e.g., a system, may also be claimed in other claim categories, e.g., a method. Dependencies or back-references in the appended claims are selected for formality reasons only. However, any subject matter available from a careful back-reference to a previous claim may also be claimed, thereby disclosing any combination of claims and their features and may be claimed regardless of the dependencies selected in the appended claims. [Brief explanation of the drawings]

[0021] In the drawings, like reference numbers / letters refer to like elements. [Figure 1A] An example is provided in which three specified sectors on the retina (e.g., three macular regions of interest, ROIs) are used to investigate / monitor changes in retinal thickness, such as to determine a person's patient-specific (or personalized) baseline thickness and macular thickness variation threshold levels (e.g., upper and / or lower specification limits). [Figure 1B] An example of a typical Early Treatment Diabetic Retinopathy Study (ETDRS) grid is provided. [Figure 2] Shown are three data plots of macular thickness (μm) for each of three corresponding retinal sectors (e.g., macular ROI as shown in Figure 1) for all available physician office visits for one of the 22 wet AMD patients used in the statistical study. [Figure 3A] Two additional data plot examples for two patients (e.g., Patient A and Patient B) are shown, showing macular thickness data for the central sector, inner sector, and outer sector (macular ROI) in Figure 1. [Figure 3B] Two additional data plot examples for two patients (e.g., Patient A and Patient B) are shown, showing macular thickness data for the central sector, inner sector, and outer sector (macular ROI) in Figure 1. [Figure 4A] 1 shows the standard deviation of retinal thickness in each of the central, inner, and outer sectors during the stable period in patients with wet AMD (wAMD). [Figure 4B] 1 shows a table providing a summary of the variation and standard deviation of normal retinal thickness over 30 stable periods in 22 patients with wet AMD. [Figure 5A] We provide a summary of injections and clinic visits for two wAMD patients over a 2-year period (Figure 5A) and a 3-year period (Figure 5B). [Figure 5B] We provide a summary of injections and clinic visits for two wAMD patients over a 2-year period (Figure 5A) and a 3-year period (Figure 5B). [Figure 6] 1 illustrates two stages of an exemplary workflow for remote monitoring of fluid leakage in wAMD patients (e.g., for setting lower / upper specification limits) according to the present invention. [Figure 7] 1 illustrates two stages of an exemplary workflow for remote monitoring of fluid leakage in wAMD patients (e.g., for setting lower / upper specification limits) according to the present invention. [Figure 8A] A first example of the application of the present invention to retinal thickness data of another wAMD patient (Patient C) over an 8-year period is shown. [Figure 8B] A first example of the application of the present invention to retinal thickness data of another wAMD patient (Patient C) over an 8-year period is shown. [Figure 8C] A first example of the application of the present invention to retinal thickness data of another wAMD patient (Patient C) over an 8-year period is shown. [Figure 8D] A first example of the application of the present invention to retinal thickness data of another wAMD patient (Patient C) over an 8-year period is shown. [Figure 9A] A second example of the application of the present invention to retinal thickness data of another wAMD patient (Patient D) over an 8-year period is shown. [Figure 9B] A second example of the application of the present invention to retinal thickness data of another wAMD patient (Patient D) over an 8-year period is shown. [Figure 9C]A second example of the application of the present invention to retinal thickness data of another wAMD patient (Patient D) over an 8-year period is shown. [Figure 9D] A second example of the application of the present invention to retinal thickness data of another wAMD patient (Patient D) over an 8-year period is shown. [Figure 10] 1 illustrates a generalized frequency domain optical coherence tomography system used to collect 3D image data of the eye suitable for use with the present invention. [Figure 11] Illustratively, an exemplary OCT B-scan image of a normal retina of a human eye is shown, identifying various typical retinal layers and boundaries. [Figure 12] Examples of en face vasculature images are shown. [Figure 13] 1 shows an exemplary B-scan of a vasculature (OCTA) image. [Figure 14] 1 illustrates an exemplary computer system (or computing device or computer) suitable for use with the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0022] The ability to monitor the progression of retinal fluid leakage is important for remote monitoring of wet age-related macular degeneration (wet AMD, wAMD). Remote monitoring requires patients to periodically obtain OCT scans, without requiring clinic visits, an operator / technician to obtain OCT scans, or a doctor (or specialized technician) to review all scans. Therefore, it is desirable for a home-use, self-use, portable, or remote / telemedical OCT device / system (e.g., an OCT device used for remote monitoring) to be capable of monitoring the progression of fluid leakage itself. By understanding the normal fluctuations in retinal physiological changes, the system can determine when the changes are significant (e.g., when they are irregular or indicate the possible need for anti-VEGF medication and / or medical consultation) and notify the patient's physician (e.g., locally or remotely, via an electronic message / signal on an electronic display or speaker, or via the Internet or other wired / wireless telecommunications network / system and / or computer network) for further medical assistance. For example, a medical professional, such as a retina specialist or physician, may examine the patient and provide a medical diagnosis based on a workup that may include collecting and examining OCT images and other medical data.

[0023] Generating macular thickness maps based on OCT scans is a technique implemented in many commercially available OCT systems. As mentioned above, retinal specialists can now use visual acuity data, B-scans, and thickness maps to make decisions regarding the best treatment scenario for a patient; see, for example, Amoaku et al., "Defining Response to Anti-VEGF Therapies in Neovascular AMD," Eye, Vol. 29, 2015, pp. 721-731, incorporated herein by reference in its entirety. Furthermore, CIRRUS® and other commercially available OCT systems now perform macular thickness change analysis between any two visits available in their databases, which helps identify changes at each site of the Early Treatment of Diabetic Retinopathy Study (ETDRS) macular grid. However, these data are collected during a physician visit and are therefore only available after a patient's OCT scan is obtained during the clinic visit.

[0024] Analysis of changes in retinal thickness over time has been demonstrated herein as an effective tool for assessing fluid tracking in patients with wet AMD. Applicants have discovered that by monitoring changes in macular thickness over time in specific regions, the system can determine a patient-specific (e.g., individualized) baseline thickness (e.g., a standard level that does not require medical intervention) and a patient-specific (upper / lower) threshold (e.g., upper / lower specification limits) that indicates when medical intervention is required. Figure 1A provides examples of three sectors (or macular areas / regions of interest (ROIs)) on the retina 9 for investigating changes in retinal thickness, such as for determining a patient-specific baseline and (e.g., patient-specific) macular thickness variation threshold levels (e.g., upper and / or lower specification limits). For illustrative purposes, Figure 1B provides an example of a typical ETDRS grid 10 known in the art. In FIG. 1A, three sectors (e.g., three concentric macular ROIs) are identified as a central area 11, which may optionally correspond to the central subfield of a typical ETDRS grid (C1 in FIG. 1B) and is shown as a circle (or solid disk area) 11 having a diameter of 1 mm; an inner sector 13, which may optionally correspond to the combination of all inner subfields of the ETDRS grid (S3, N3, I3, and T3) and is shown as a first annular body (or shell or disk with a hole) 13 concentric with the central area 11 and having an inner diameter of 1 mm and an outer diameter of 3 mm; and an outer sector 15, which may correspond to the combination of all outer subfields of the ETDRS grid (S6, N6, I6, and T6) and is shown here as a second annular body (or shell) concentric with the inner sector 13 and having an inner diameter of 3 mm and an outer diameter of 6 mm. These three sectors or regions of interest have been found to simplify the collection of information while still providing sufficient information regarding the position (and changes) of the liquid for the purposes of the present invention.

[0025] In an exemplary implementation, OCT scans of 22 patients with wet AMD collected over a three-year period using a Cirrus™ OCT system were reviewed. This three-year period covered approximately 6 months of dry AMD and approximately 30 months of wet AMD (wAMD). The data was appropriately annotated to indicate clinic visits with and without injections (e.g., anti-VEGF injections). Changes in macular thickness over time were plotted for each of these 22 patients. As an example, Figure 2 shows three plots 21, 23, and 25 of macular thickness (μm) for each of the three corresponding sectors 11, 13, and 15 (shown in Figure 1A) for all available clinic visits for one of the 22 patients with wet AMD. For example, plot 21 follows the macular thickness of the central area 11, plot 23 shows the macular thickness of the inner sector 13, and plot 25 shows the macular thickness of the outer sector 15. Each plotted macular thickness measurement is a representative macular thickness measurement characteristic of the overall thickness of its respective macular ROI. For example, multiple individual thickness measurements may be determined distributed across each macular ROI, and the representative macular thickness measurement for the macular ROI may be based on these multiple individual macular thickness measurements. For example, the representative thickness measurement for a macular ROI may be determined as the average of all of its individual macular thickness measurements, the highest individual macular thickness measurement, the average of two or more (e.g., 10% to 50%) of its highest individual macular thickness measurements, or a combination of these methods.

[0026] In Figure 2, each dot on the three plots 21, 23, and 25 represents a representative retinal (e.g., macula) thickness measurement determined at the clinic visit when the OCT scan was performed. To better understand the changes in macular thickness, corresponding pairs of central B-scans and macular thickness maps 27a, 27b, 27c, and 27d are shown for four selected clinic visits, as indicated by the circled dates on the horizontal axis of the plots. Vertical dashed lines indicate clinic visits where injections were administered; the absence of a vertical dashed line at any clinic visit indicates that no injections were administered. In this example, for the first 6 months (August 2016 to February 2017), this particular patient was in the dry period (e.g., dry AMD, with no observed fluid accumulation). However, on February 3, 2017, the patient received his first injection. This indicates that the patient's dry AMD transformed / progressed to wet AMD.

[0027] As used herein, the term "stable period" is defined as a period during which there has been no significant change in retinal thickness in any sector across multiple (or alternatively, three or more) clinic visits (e.g., a change of 5% or less, or no medication injections were prescribed or administered to the eye), and the patient likely did not require injections. Generally, during a stable period, B-scans do not reveal significant fluid pockets. It has been observed that if a patient responds well to medication, this typically becomes evident (e.g., by entering a stable period) approximately one month after the patient has received three consecutive injections. However, it should be understood that not all patients who receive three consecutive injections necessarily enter a stable period, e.g., not all patients respond well to an injection regimen. However, if a patient enters a stable period, that stable period will continue until the next major peak requiring medical care. As an example, based on the available scans of the patient in Figure 2, three stable periods, i.e., - First stable period: July 11, 2017 to November 3, 2017 (this period follows the main period of injections after receiving the first three consecutive injections), - Second stable period: May 11, 2018 to August 15, 2018 (this period follows three consecutive injections after the first major peak in February 2018), - The third stable period can be identified: March 12, 2019 to March 17, 2020 (this period follows three consecutive injections after the second major peak in September 2018). Considering the nature of retinal thickness changes during the atrophic phase and based on the inventor's data, the patient-personalized baseline thickness of each sector (macular ROI) can be defined as the average of the representative macular thickness measurements of each corresponding sector during the atrophic phase. It should be understood that each patient has their own individualized specific baseline based on their individual ocular physiology. If the patient's retinal thickness information during the atrophic phase is not available, the patient-personalized baseline thickness of each sector can be determined based on the average of the lowest representative macular thickness measurements of each corresponding sector during treatment, known as the most atrophic point.

[0028] For example, Figures 3A and 3B show two additional examples from two respective patients (e.g., patient A and patient B), where reference letters 31A / B, 33A / B, and 35A / B identify individual plots of macular thickness corresponding to each of the three sectors 11, 13, and 15 identified in Figure 1. Referring to Figure 3A, the macular thickness plot for patient A shows the patient's history, including periods of dry AMD, and its thickness data values ​​are surrounded by region 30. Using the respective averages of the data points of plots 31A, 33A, and 35A within region 30, patient-personalized baseline (macular) thickness values ​​for each of patient A's central area, inner sector, and outer sector can be defined.

[0029] Referring to Figure 3B, the plot of macular thickness for patient B shows a patient history that does not include consecutive periods of dry AMD prior to the onset of wet AMD. In other words, there is not enough history for patient B during dry AMD periods to define a baseline thickness for each macula in a manner similar to that of Figure 3A. In Figure 3B, the patient-specific baseline (macular) thickness can be defined as the average thickness between the "atrophy visit" or "most atrophic visit" (highlighted by regions 32, 34, and 36). These visits can be doctor's visits (e.g., exam times) scheduled by a healthcare professional. Essentially, Figure 3B shows that injections were administered approximately from the first clinic visit, and therefore, there is no extended period of dry AMD (e.g., three consecutive visits). In this case, the lowest three corresponding data points (e.g., most atrophic visits) in plots 31B, 33B, and 35B are separately identified as data groups 32, 34, and 36, even though injections were administered at these visits. Optionally, these may correspond to clinic visits where no injections were required, but are not limited to visits without injections. Further optionally, the identified regions may correspond to three consecutive doctor's visits (e.g., OCT scans taken at predetermined intervals (e.g., 4-6 week intervals) corresponding to previously scheduled macular thickness testing times), but again, are not necessarily limited to such, and are not limited to consecutive visits. The averages of the data points of plots 31B, 33B, and 35B within regions 32, 34, and 36, respectively, may be used to define baseline macular thickness values ​​for each of patient B's central area, inner sector, and outer sector.

[0030] In addition to the patient-specific baseline thickness, normal / typical variations in retinal thickness (for the general population) were also obtained for each of the three sectors (central area / sector, inner sector, and outer sector). In an exemplary embodiment, normal variations in retinal thickness that do not require medical intervention were determined by examining the changes in retinal thickness for each of the three sectors over 30 stable periods in 22 wAMD patients. Figure 4A shows the standard deviation (variation) of retinal thickness for representative retinal thickness measurements for each of the three sectors during stable periods for 22 wAMD patients (e.g., periods 30, 32, 34, and 36 in Figures 3A and 3B). Figure 4B shows a table providing a summary of normal retinal thickness variations over 30 stable periods in 22 wet AMD patients. Figure 4B provides the mean macular thickness variation and standard deviation of thickness change for each of the central area / sector, inner sector, and outer sector. A minimum threshold (e.g., offset) value may be defined from the table of FIG. 4B and may be determined, for example, based on the statistical deviations observed for each sector. This threshold (e.g., offset) value may then be used to define an upper specification limit (e.g., an upper threshold at which thickness deviations may be considered irregular (outside of the norm) and medication or medical care may be recommended) and / or a lower specification limit (e.g., a lower threshold that may indicate a period of atrophy). For example, a patient's upper specification limit may be determined as the patient's patient-personalized baseline thickness plus a first offset (upper threshold offset), and the patient's lower specification limit may be determined as the patient's patient-personalized baseline thickness minus a second offset (lower threshold offset). The first and second offsets may be the same or may be determined independently. For example, it has been observed that central areas / sectors are typically, but not necessarily, more sensitive to fluid accumulation, so even though one may want to avoid false negatives (e.g., a situation where the system recommends remote monitoring even though the patient has a lot of fluid and requires medical care), one may still want to pay more attention to thickness variations within the central areas / sectors.From Figure 4A, we can see that a statistical deviation of 15 μm (e.g., maximum / highest standard deviation in μm for the central area / sector) may be sufficient to not only accommodate normal thickness variations in the central area / sector but also avoid most false negatives in the inner and outer sectors. In this case, a common offset can be set using one selected sector (the central area / sector) to determine the upper (and / or lower) specification limits for all sectors (the macular ROI). Alternatively, a different statistical deviation, such as 6–7 standard deviations, as shown in Figure 4B, can be used for any or all sectors.

[0031] The above analysis is useful for determining / identifying normal variations in a patient's retinal thickness that may not require (e.g., immediate) medical intervention (e.g., an anti-VEGF drug injection or a clinic visit). That is, the system can monitor the patient's medical condition. Using this analysis, the system can set a threshold (i.e., upper specification limit) (e.g., optimized or individualized for the patient) to identify changes in retinal thickness that may indicate that the patient may benefit from a clinic visit for further medical analysis (e.g., it is desirable for the patient to be examined), at which point a healthcare provider can determine whether the patient's condition has significantly changed and whether medical treatment (e.g., an anti-VEGF drug injection) would be beneficial. For example, the system can notify the patient that a doctor's visit is recommended, or can use the communication network to issue an automatic alert to the doctor (or a predetermined healthcare provider) or send a request to schedule a doctor's appointment. The communication network can be a wired communication network or a wireless communication network such as the Internet or a cellular network. Applicant has determined that each patient's individualized (patient-specific) baseline and threshold values ​​depend on the patient's disease state, fluid type, and the patient's ocular response to treatment. For example, some patients have inherently thicker retinal tissue and therefore may require a higher baseline than patients with inherently thinner retinal tissue. In addition to taking the above-mentioned parameters into account when setting the patient's initial upper specification limit (macular thickness threshold), the system further adjusts (e.g., changes / updates) the threshold parameter during the course of treatment (e.g., based on the patient's personal response to treatment) and also allows this parameter to be manually adjusted by a retinal specialist, physician, or other authorized medical professional. For example, the system may suggest personalized threshold values ​​for a particular patient, but the patient's physician may override the system-suggested (e.g., patient-specific upper and / or lower) threshold values ​​and manually adjust the threshold values.In some embodiments, the threshold may be adjustable (e.g., by a physician, technician, or other authorized user) in intervals of a certain size within a recommended range, such as a threshold range of 15 μm to 30 μm in increments of 15 μm, 20 μm, 25 μm, or 30 μm. However, higher or lower thresholds outside the system's recommended range (not limited to the system's recommended increments) may also be set by a physician based on the physician's opinion.

[0032] By performing the analysis in this work in a remote monitoring OCT system, the system can personalize treatment for each patient, which is highly suitable for personal, remote, or home OCT applications. Furthermore, based on the results of this study, the system can identify excessive amounts of fluid (e.g., retinal fluid leakage or accumulation) early and guide / recommend timely treatment. In addition, the system's ability to review the patient's OCT database / history (e.g., previous scan results can be stored in the remote OCT system) allows the system to analyze the patient's individualized response to treatment and predict / recommend better drug and treatment interval selection for that patient.

[0033] To better illustrate the above application, Figures 5A and 5B provide summaries of injections and clinic visits for two other wAMD patients over a two-year period (Figure 5A) and a three-year period (Figure 5B). These two examples demonstrate that remote monitoring of wet AMD can help provide physicians with more information. Figure 5A showcases the first wAMD patient's doctor visits over a two-year period, showing example thickness maps 50 obtained at each visit. In 2016, the first wAMD patient began regular clinic visits and initially received frequent injections, as indicated by period 51 and injection symbol 52. In 2017, due to a favorable response to medication, the first wAMD patient's doctor applied a treatment and extension protocol, where the time intervals between injections were extended as needed, as indicated by period 53. However, after some time, the first wAMD patient's retina developed significant fluid leakage, which was not confirmed until January 2018 (see period 54). Due to a lack of data between September 2017 and January 2018, this massive leakage was not recognized until it reached a late / advanced stage. If remote monitoring of wet AMD had been available for the first wAMD patients, the massive leakage may have been caught / identified earlier, improving the chances of preventing permanent vision loss.

[0034] Figure 5B provides an example of a clinic visit by a second wAMD patient spanning a total period of 3 years. Similar to the example in Figure 5A, the second wAMD patient also initially received frequent injections during the initial period 55 and then transitioned to the treatment and extension protocol period 56, with the time intervals between injections increased as needed. However, due to a favorable response to treatment, the second wAMD patient did not require / receive medication in 2020. Nevertheless, the second wAMD patient had to regularly visit the clinic for monitoring, as indicated by period 57. Patients with wet AMD are often elderly, and clinic visits can be difficult and burdensome. If remote monitoring of wAMD had been available to the second wAMD patient, the burden of frequent and regular clinic visits could have been eliminated or reduced.

[0035] 6 and 7 illustrate two stages of an exemplary workflow for remote monitoring of fluid leakage in patients with wet AMD according to the present invention. FIG. 6 illustrates an initialization stage in which a remote monitoring system according to the present invention is initialized / prepared for home / remote use. To perform remote monitoring of retinal fluid leakage in patients with wet AMD, the first step 61 is to determine a personalized baseline of retinal thickness (e.g., a patient-personalized baseline thickness) for a particular patient for one or more, preferably three, of the three ocular sectors described above (see FIG. 1 ). This step can be performed based on a medical history of the patient's clinic visits during the dry AMD period, if available, or on a doctor's visit with minimal fluid. This baseline can be adjusted as doctor's visit data accumulates. Alternatively, this data is available to the physician, allowing the physician (or a designated technician) to determine a personalized baseline for the patient. Alternatively, the physician can select from a list of recommended thresholds provided by the system. The next step 63 is to assign a threshold offset to each ocular sector (e.g., each of the central, inner, and outer sectors). The threshold offset may be the same for all sectors (e.g., 15 μm) or may vary between sectors (e.g., 15 μm for the central sector, 25 μm for the inner sector, and 20 μm for the outer sector). An upper specification limit (USL) 64 and a lower specification limit (LSL) 65 for each ocular sector may be determined based on the determined baseline value(s) and selected threshold offset(s). For example, the upper specification limit 64 for each ocular sector may be set by adding each sector's corresponding patient-personalized baseline thickness value and its selected (e.g., upper) threshold offset (step 67), and the lower specification limit 65 for each ocular sector may be set by subtracting each sector's corresponding selected (e.g., lower) threshold offset from each sector's corresponding patient-personalized baseline thickness value (step 69).

[0036] After the initialization sequence of Figure 6, the active remote monitoring method of Figure 7 can be initiated. In step 711, a patient may remotely acquire / collect an OCT scan of the patient's eye using a personal / portable OCT system according to the present invention. The scan data is then segmented (automatically by the portable OCT system) (step 713), for example, by retinal layer(s), and retinal thickness values ​​(e.g., a thickness map is created) are calculated (step 715) for at least one, and preferably all, of three designated ocular sectors (e.g., central, inner, and outer sectors), and individual representative macular thickness values ​​for each sector (e.g., based on individual thickness measurements within the sector or sector-average thickness measurements) are compared with their respective designated upper specification limits (USLs) (step 717). Techniques for segmenting OCT data and determining thickness values ​​from the segmented data are well known and need not be described herein. If any representative macular thickness value / measurement for a designated ocular sector exceeds its respective upper specification limit (step 719=YES), the device issues a flag / signal to notify the physician (and / or patient) locally or remotely of the potential need for an office visit (step 721). If none of the sectors have a representative macular thickness measurement that exceeds its respective upper threshold (step 719=NO), the representative macular thickness measurements are compared to their respective lower specification limits (LSL) (step 723). If all thickness measurements exceed their respective lower specification limits (step 725=YES), the current scan sequence is complete, a report is generated, and the patient may be notified of their next scheduled remote scan (step 727).If the representative macular thickness measurements for any ocular sector do not exceed their respective lower specification limits (step 725=no), the system optionally checks whether this is the first time any thickness measurements have fallen below their respective lower specification limits (step 729), and if so (step 729=yes), the process again proceeds to step 727, the scan sequence is completed, a report is generated, and a notification / reminder for the patient's next scheduled remote scan may be issued. If this is not the first time a thickness measurement has fallen below its respective lower specification limit (step 729=no), the system may check the consecutive number of times (e.g., consecutive scheduled OCT scans) that the representative macular thickness measurements have fallen below their respective lower specification limits, and may update the patient's patient-personalized baseline thickness, upper specification limit (USL), and / or lower specification limit (USL) (see FIG. 6) for the sector of interest (e.g., the ocular sector in which the representative macular thickness value(s) / measurement(s) fell below their respective lower specification limits). For example, if thickness measurements in any of three ocular sectors are below their respective lower specification limits for two or more (e.g., at least three) consecutive sessions, this may be an indication that the patient's eye is responding well to treatment, and the patient-personalized baseline thickness for the sector(s) of interest may be changed to the average thickness of the scans with low values ​​for the sector(s) of interest (e.g., the average of the thickness measurement(s) below their respective lower specification limits in three consecutive scans of the sector(s) of interest, or the average of all thickness measurements within the sector(s) of interest) (step 731). At this point, the patient-personalized baseline thickness may be updated, and optionally, the upper and / or lower specification limits may be changed, either automatically or in response to physician approval / input (step 733). If automatic, the upper and / or lower specification limits may be changed to the next higher or lower increment within the recommended range, or may be changed by incorporating thickness measurements of patients having lower values ​​into the statistical analysis to determine the upper and / or lower threshold offsets, as described above.Alternatively, the remote OCT system may optionally notify the physician remotely (e.g., via the Internet or other telecommunications system or network) of the patient's reduced thickness measurements and their recommendation(s) for adjusting the baseline, upper specification limits, and / or lower specification limits. The physician may then remotely instruct the OCT system to update its baseline, upper specification limits, and / or lower specification limits. The remote OCT system then proceeds to step 727 and ends the current session.

[0037] Figures 8A-8D and 9A-9D show how application of the present invention to two exemplary test patients (Patient C and Patient D, respectively) identified cases in which medical intervention was absolutely necessary and cases in which the patient did not need to be seen in a clinic. This example demonstrates its effectiveness by retrospectively applying the present invention to existing medical history, thereby applying the automated procedure without physician input. Figures 8A-8D show the retinal thickness levels of wAMD patient C over an eight-year period. Figure 8A shows representative macular thickness measurements determined based on OCT scans (e.g., taken at the time of a clinic visit, as indicated by the date) for each of the three monitored retinal sectors (i.e., the central sector, the inner sector, and the outer sector). This data was obtained during patient C's clinic visits; the dates of the OCT scans are listed, and the time of injections (e.g., anti-VEGF medication) is indicated by a vertical dotted line. Patient C was initially diagnosed with dry AMD for the first 4 years, from January 11, 2012, to March 2, 2016. Six months later, on September 7, 2016, Patient C received his first injection, as indicated by the vertical dotted line. After this first injection, Patient C received multiple injections approximately 3 months apart for the next 2.5 years, with his final injection for this observation period on February 20, 2019. Patient C then stopped taking medication, but still had to continue clinic visits for the remainder of this observation period to undergo OCT scans to monitor the progression of his fluid leakage.

[0038] Applying the present invention to Patient C's history, a patient-personalized baseline was defined for each of the central, inner, and outer sectors as the average retinal thickness during a stable period (e.g., during Patient C's dry AMD period). In this example, an upper threshold offset and a lower threshold offset of 15 microns were used from the patient-personalized baseline thickness for each of the central, inner, and outer sectors to determine the respective upper and lower specification limits. For ease of illustration, Figure 8B shows the central sector (patient-personalized) baseline (thickness), patient-specific upper threshold (upper specification limit), and patient-specific lower threshold (lower specification limit) (as determined using the present invention, e.g., see Figures 6 and 7) superimposed on the central sector macular thickness data from Figure 8A. Similarly, Figure 8C shows the baseline (thickness), patient-specific upper threshold (USL), and patient-specific lower threshold (LSL) on the macular thickness data of the inner sector, and Figure 8D shows the determined baseline (thickness) and patient-specific upper and lower thresholds on the macular thickness data of the outer sector.

[0039] In this example, as shown in Figures 8C and 8D, the macular thickness of Patient C's inner and outer sectors remained within their respective upper and lower thresholds. However, Patient C experienced significant leakage, primarily in the central sector. Using the current threshold of 15 microns, Figure 8B identifies three instances (circles 81 and 83) where the macular thickness exceeded the upper threshold in the central sector. For illustrative purposes, macular thickness values, B-scans, and thickness maps are shown for two of these instances. These instances could be triggers indicating the need for injections or at least direct medical intervention / examination.

[0040] For the second exemplary study patient, Patient D, Figures 9A-9D show retinal thickness levels over an 8-year period. Figure 9A shows representative macular thickness measurements determined by OCT scans for each of the three monitored retinal sectors (i.e., the central sector, the inner sector, and the outer sector). In a similar manner to Figure 8A, this data was obtained during Patient D's clinic visits, with the dates of the OCT scans listed and injections indicated by vertical dotted lines. Referring to Figure 9A, Patient D was shown to have had dry AMD for the first 7 years, from November 21, 2012, to approximately January 30, 2019. However, Patient D did not receive his first injection until approximately 4 months later, on May 22, 2019. Patient D continued injection treatment for the remainder of the 8-year observation period.

[0041] As in the previous example, Figures 9B, 9C, and 9D show the central, inner, and outer sectors of patient D, respectively, along with their determined baselines, upper and lower specification limits. Each individual (patient-personalized) baseline is defined as the average (optionally a running average of three consecutive visits) of (representative) retinal thickness measurements determined at the time of a doctor's visit in the dry AMD state. As in the first example, a 15 μm offset from the baseline is set to define the upper and lower specification limits for each ocular sector.

[0042] As shown in FIG. 9B, while the majority of Patient D's fluid leakage is in the peripheral region, this 15 μm threshold for all sectors identifies the first trigger event in the central sector on January 30, 2019. Multiple other trigger events based on macular thickness are subsequently found in the inner and outer sectors, as shown in FIGS. 9C and 9D, respectively. If the system had been used during Patient D's observation period, the early trigger event on January 30, 2019, would have been flagged as significant and requiring medication injection. Patient D could have started medication four months earlier than he did. As is known in the art, early diagnosis and treatment of wet AMD is important because vision loss caused by fluid leakage is currently not reversible.

[0043] Thus, the present invention offers several advantages. The system / method provides monitoring of retinal stability and recurrent fluid leakage events based on statistical analysis of retinal thickness measurements, such as those obtained by OCT scans and / or thickness maps. The monitoring system can flag the presence of a significant amount of fluid in a patient's retina based on a clinician-set threshold, an automatically determined / calculated threshold, or a preset fixed threshold. In addition, the monitoring system provides a baseline and threshold (indicating when an injection is required) that can be individually set for each patient and further updated as the patient accumulates additional macular thickness measurements in subsequent OCT scans. Thus, the monitoring system can adjust the baseline and threshold when the patient's eye is responding well to treatment, as determined by changes in macular thickness. The monitoring system can also help physicians understand a patient's individualized response to treatment and guide better selection of medications and treatment intervals for the patient. For example, the monitoring system can determine the optimization of patient-treatment schedules based on statistical variations in retinal thickness changes.

[0044] The following describes various hardware and architectures suitable for the present invention. Optical coherence tomography imaging system Generally, optical coherence tomography (OCT) uses low-coherence light to generate two-dimensional (2D) and three-dimensional (3D) internal views of biological tissues. OCT enables in vivo imaging of retinal structures. OCT angiography (OCTA) generates flow information, such as vascular flow, from within the retina. Examples of OCT systems are provided in U.S. Patent Nos. 6,741,359 and 9,706,915, and examples of OCTA systems are provided in U.S. Patent Nos. 9,700,206 and 9,759,544, all of which are incorporated herein by reference in their entireties. An exemplary OCT / OCTA system is provided herein.

[0045] FIG. 10 illustrates a generalized frequency-domain optical coherence tomography (FD-OCT) system for collecting 3D image data of the eye suitable for use with the present invention. The FD-OCT system OCT_1 includes a light source LtSrc1. Typical light sources include, but are not limited to, a broadband light source with a short temporal coherence length or a swept laser source. A beam of light from the light source LtSrc1 is typically guided by an optical fiber Fbr1 to illuminate a sample, such as an eye E, a typical sample being human intraocular tissue. The light source LrSrc1 may be, for example, a broadband light source with a short temporal coherence length in the case of spectral-domain OCT (SD-OCT) or a tunable laser source in the case of swept-source OCT (SS-OCT). The light may typically be scanned using a scanner Scnr1 between the output of the optical fiber Fbr1 and the sample E, such that the beam of light (dashed line Bm) is scanned laterally across the region of the sample to be imaged. The light beam from scanner Scnr1 passes through scan lens SL and ophthalmic lens OL and can be focused onto the sample E to be imaged. Scan lens SL receives the light beam from scanner Scnr1 at multiple angles of incidence, producing substantially collimated light, which the ophthalmic lens OL can then focus onto the sample. This example shows a scanning beam that needs to be scanned in two lateral directions (e.g., the x and y directions on a Cartesian plane) to scan a desired field of view (FOV). This example is point-field OCT, which uses a point-field beam to scan across the sample. Thus, scanner Scnr1 is illustratively shown to include two sub-scanners: a first sub-scanner Xscn for scanning the point-field beam across the sample in a first direction (e.g., the horizontal x direction) and a second sub-scanner Yscn for scanning the point-field beam across the sample in an intersecting second direction (e.g., the vertical y direction). If the scanning beam is a line field beam (e.g., line field OCT) and can sample an entire line portion of the sample at a time, only one scanner may be required to scan the line field beam across the sample to span the desired FOV.If the scanning beam is a full-field beam (eg, full-field OCT), a scanner may not be required and the full-field light beam may be illuminated across the entire desired FOV at once.

[0046] Regardless of the type of beam used, light scattered from the sample (e.g., sample light) is collected. In this example, scattered light returning from the sample is collected into the same optical fiber Fbr1 used to route light for illumination. A reference beam, derived from the same light source LtSrc1, travels along a separate path, which in this case includes optical fiber Fbr2 and a retroreflector RR1 with an adjustable optical delay. As will be appreciated by those skilled in the art, a transmissive reference path can also be used, with an adjustable delay located in either the sample or the reference arm of the interferometer. The collected sample light is combined with the reference beam, for example, in a fiber coupler Cplr1, to form optical interference within an OCT photodetector Dtctr1 (e.g., a photodetector array, digital camera, etc.). While one fiber port is shown reaching detector Dtctr1, those skilled in the art will appreciate that various interferometer designs can be used for balanced or unbalanced detection of the interference signal. The output from detector Dtctr1 is fed to a processor (e.g., an internal or external computing device) Cmp1, which converts the observed interference into sample depth information. The depth information may be stored in a memory associated with the processor Cmp1 and / or displayed on a display (e.g., computer / electronic display / screen) Scn1. The processing and storage functions may be localized within the OCT device, or the functions may be offloaded to (e.g., executed on) an external processor (e.g., an external computer system) to which the collected data is transferred. An example of a computing device (or computer system) is shown in Figure 14. This unit may be dedicated to data processing or may perform other tasks that are quite general and not dedicated to the OCT device.The processor (computing device) Cmp1 may include, for example, a field programmable gate array (FPGA), a digital signal processor (DSP), an application specific integrated circuit (ASIC), a graphics processing unit (GPU), a system on a chip (SoC), a central processing unit (CPU), a general purpose graphics processing unit (GPGPU), or combinations thereof, which may perform some or all of the processing steps in a serial and / or parallel manner with one or more host processors and / or one or more external computing devices.

[0047] The sample and reference arms in an interferometer can be constructed with bulk optics, fiber optics, or hybrid bulk optics systems and can have different architectures, such as Michelson, Mach-Zehnder, or common-path designs, as known to those skilled in the art. Light beam, as used herein, should be interpreted as any carefully directed optical path. Instead of mechanically scanning the beam, a light field can illuminate a one-dimensional or two-dimensional area of ​​the retina to generate OCT data (e.g., U.S. Pat. No. 9,332,902; D. Hillmann et al., "Holoscopy-holographic optical coherence tomography," Optics Letters, Vol. 36(13), p. 2290, 2011; Y. Nakamura et al., "High-Speed ​​three dimensional human retinal imaging by line field spectral domain optical coherence tomography," Optics Express, 2011). Express, 15(12), p. 7103, 2007; Blazkiewicz et al., "Signal-to-noise ratio study of full-field Fourier-domain optical coherence tomography," Applied Optics, 44(36), p. 7722, 2005. In time-domain systems, the reference arm must have an adjustable optical delay to create interference. Balanced detection systems are typically used in TD-OCT and SS-OCT systems, while a spectrometer is used at the detection port for SD-OCT systems. The invention described herein is applicable to both types of OCT systems.Various aspects of the present invention may be applied to any type of OCT system or other types of ophthalmic diagnostic systems and / or multiple ophthalmic diagnostic systems, including, but not limited to, fundus imaging systems, visual field testing devices, and scanning laser polarimeters.

[0048] In Fourier-domain optical coherence tomography (FD-OCT), each measurement is a real-valued spectrally controlled interferogram (Sj(k)). Real-valued spectral data typically undergoes several post-processing steps, including background subtraction, dispersion correction, etc. A Fourier transform of the processed interferogram yields a complex OCT signal output Aj(z) = |Aj|eiφ. The absolute value of this complex OCT signal, |Aj|, ​​reveals the scattering intensity at different path lengths and, therefore, the scattering profile with respect to depth (z-direction) within the sample. Similarly, the phase φj can also be extracted from the complex OCT signal. The scattering profile with respect to depth is called an axial scan (A-scan). A collection of A-scans measured at adjacent locations within the sample produces a cross-sectional image (tomogram or B-scan) of the sample. A collection of B-scans collected at different lateral locations on the sample constitutes a data volume or cube. For a particular data volume, the fast axis refers to the scanning direction along one B-scan, and the slow axis refers to the axis along which multiple B-scans are collected. The term "cluster scan" may refer to a unit or block of data generated by repeated acquisition at the same (or substantially the same) location (or region) to analyze motion contrast, which may be used to identify blood flow. A cluster scan can consist of multiple A-scans or B-scans collected at approximately the same location on the sample at a relatively short time interval. Because the scans in a cluster scan are of the same region, stationary structures remain relatively unchanged between scans in the cluster scan, while motion contrast between scans that meet predetermined criteria may be identified as blood flow.

[0049] Various methods for generating B-scans are known in the art, including, but not limited to, along the horizontal or x-direction, along the vertical or y-direction, along the x and y diagonals, or in a circular or spiral pattern. B-scans can be in the xz dimension, but can also be any cross-sectional image including the z-dimension. An exemplary OCT B-scan image of a normal retina of a human eye is shown in FIG. 11. An OCT B-scan of the retina provides a view of the structure of the retinal tissue. For illustrative purposes, FIG. 11 identifies the various normal retinal layers and layer boundaries. The identified retinal boundary layers include (from top to bottom) the inner limiting membrane (ILM) layer 1, the retinal nerve fiber layer (RNFL or NFL) layer 2, the ganglion cell layer (GCL) layer 3, the inner plexiform layer (IPL) layer 4, the inner nuclear layer (INL) layer 5, the outer plexiform layer (OPL) layer 6, the outer nuclear layer (ONL) layer 7, the junction between the outer segments (OS) and inner segments (IS) of photoreceptors (indicated by reference number layer 8), the external limiting membrane (ELM or OLM) layer 9, the retinal pigment epithelium (RPE) layer 10, and the Bruch's membrane (BM) layer 11.

[0050] In OCT angiography or functional OCT, analysis algorithms may be applied to OCT data collected at different times (e.g., cluster scans) at the same or nearly the same sample location on the sample to analyze motion or flow (see, e.g., U.S. Patent Application Publication Nos. 2005 / 0171438, 2012 / 0307014, 2010 / 0027857, 2012 / 0277579, and U.S. Patent No. 6,549,801, all of which are incorporated by reference in their entireties). OCT systems may use any one of a number of OCT angiography processing algorithms (e.g., motion contrast algorithms) to identify blood flow. For example, motion contrast algorithms can be applied to intensity information derived from the image data (intensity-based algorithms), phase information from the image data (phase-based algorithms), or complex image data (complex-based algorithms). An en face image is a 2D projection of the 3D OCT data (e.g., by averaging the intensity of each individual A-scan, whereby each A-scan defines a pixel in the 2D projection). Similarly, an en face vasculature image is an image displaying motion contrast signals in which the data dimension corresponding to depth (e.g., the z-direction along the A-scan) is displayed as a single representative value (e.g., a pixel in the 2D projection image), typically by summing or integrating all or isolated portions of the data (see, e.g., U.S. Pat. No. 7,301,644, incorporated herein by reference in its entirety). OCT systems that provide angiography capabilities may be referred to as OCT angiography (OCTA) systems.

[0051] FIG. 12 shows an example of an en face vasculature image. After processing the data and highlighting motion contrast using any of the motion contrast methods known in the art, an en face (e.g., front view) image of the vasculature may be generated by summing pixel ranges corresponding to a tissue depth from the surface of the retinal internal limiting membrane (ILM). FIG. 13 shows an exemplary B-scan of a vasculature (OCTA) image. As shown, structural information may be less clear because blood flow traverses multiple retinal layers, obscuring them more than in a structural OCT B-scan such as that shown in FIG. 11. Nevertheless, OCTA provides a noninvasive technique for imaging the retinal and choroidal microvasculature, which may be important for diagnosing and / or monitoring various pathologies. For example, OCTA may be used to identify diabetic retinopathy by identifying microaneurysms, neovascular complexes, and quantifying the foveal avascular zone and nonperfused areas. Furthermore, OCTA has been shown to show good agreement with fluorescein angiography (FA), a more traditional but less invasive technique that requires the injection of dye to observe vascular flow in the retina. Furthermore, in dry age-related macular degeneration (AMD), OCTA has been used to monitor the overall decrease in choriocapillaris flow. Similarly, in exudative AMD, OCTA can provide qualitative and quantitative analysis of choroidal neovascular membranes. OCTA has also been used to study vascular obstruction, for example, to assess nonperfused areas and the integrity of the superficial and deep plexuses.

[0052] Computing Devices / Systems FIG. 14 illustrates an exemplary computer system (or computing device). In some embodiments, one or more computer systems may provide functionality described or illustrated herein and / or perform one or more steps of one or more methods described or illustrated herein. The computer system may take any suitable physical form. For example, the computer system may be an embedded computer system, a system-on-chip (SOC), or a single-board computer system (SBC) (e.g., a computer-on-module (COM) or system-on-module (SOM)), a desktop computer system, a laptop or notebook computer system, a mesh of computer systems, a mobile phone, a personal digital assistant (PDA), a server, a tablet computer system, an augmented / virtual reality device, or a combination of two or more of these. Where appropriate, the computer system may reside in a cloud, which may include one or more cloud components within one or more networks.

[0053] In some embodiments, the computer system may include a processor Cpnt1, a memory Cpnt2, a storage Cpnt3, an input / output (I / O) interface Cpnt4, a communication interface Cpnt5, and a bus Cpnt6. The computer system may also optionally include a display Cpnt7, such as a computer monitor or screen.

[0054] The processor Cpnt1 includes hardware for executing instructions, such as those that constitute a computer program. For example, the processor Cpnt1 may be a central processing unit (CPU) or a general-purpose computing-on-graphics processing unit (GPGPU). The processor Cpnt1 may read (or fetch) instructions from an internal register, an internal cache, memory Cpnt2, or storage Cpnt3, decode and execute the instructions, and write one or more results to the internal register, the internal cache, memory Cpnt2, or storage Cpnt3. In particular embodiments, the processor Cpnt1 may include one or more internal caches for data, instructions, or addresses. The processor Cpnt1 may include one or more instruction caches and one or more data caches, for example, to hold data tables. Instructions in the instruction caches may be copies of instructions in memory Cpnt2 or storage Cpnt3, and the instruction caches may speed up retrieval of these instructions by the processor Cpnt1. Processor Cpnt1 may include any suitable number of internal registers and may include one or more arithmetic logic units (ALUs). Processor Cpnt1 may be a multi-core processor or may include one or more processors Cpnt1. Although this disclosure describes and illustrates a particular processor, this disclosure contemplates any suitable processor.

[0055] Memory Cpnt2 may include a main memory that stores instructions for processor Cpnt1 to execute or hold intermediate data during processing. For example, a computer system may load instructions or data (e.g., a data table) from storage Cpnt3 or from other sources (e.g., another computer system) into memory Cpnt2. Processor Cpnt1 may load instructions and data from memory Cpnt2 into one or more internal registers or internal caches. To execute instructions, processor Cpnt1 may read and decode instructions from the internal registers or internal caches. During or after execution of an instruction, processor Cpnt1 may write one or more results (which may be intermediate or final results) to an internal register, internal cache, memory Cpnt2, or storage Cpnt3. Bus Cpnt6 may include one or more memory buses (each of which may include an ADDRESS bus and a DATA bus) and may couple processor Cpnt1 to memory Cpnt2 and / or storage Cpnt3. Optionally, one or more memory management units (MMUs) facilitate data transfer between the processor Cpnt1 and the memory Cpnt2. The memory Cpnt2 (which may be a high-speed volatile memory) may include random access memory (RAM), such as dynamic RAM (DRAM) or static RAM (SRAM). The storage Cpnt3 may include long-term or high-capacity storage for data or instructions. The storage Cpnt3 may be internal or external to the computer system and may include one or more of a disk drive (e.g., a hard disk drive (HDD) or a solid-state drive (SSD)), flash memory, ROM, EPROM, optical disk, magneto-optical disk, magnetic tape, a universal serial bus (USB)-accessible drive, or other types of non-volatile memory.

[0056] The I / O interface Cpnt4 may be software, hardware, or a combination of both, and may include one or more interfaces (e.g., serial or parallel communication ports) for communicating with I / O devices, which may enable communication with a human (e.g., a user). For example, the I / O devices may include a keyboard, keypad, microphone, monitor, mouse, printer, scanner, speaker, still camera, stylus, table, touch screen, trackball, video camera, other suitable I / O device, or a combination of two or more thereof.

[0057] The communication interface Cpnt5 may provide a network interface for communicating with other systems or networks. The communication interface Cpnt5 may include a Bluetooth interface or other types of packet-based communication. For example, the communication interface Cpnt5 may include a network interface controller (NIC) and / or a wireless NIC or wireless adapter for communication with a wireless network. The communication interface Cpnt5 may provide communication with a Wi-Fi network, an ad hoc network, a personal area network (PAN), a wireless PAN (e.g., Bluetooth WPAN), a local area network (LAN), a wide area network (WAN), a metropolitan area network (MAN), a cellular network (e.g., a Global System for Mobile Communications (GSM) network), the Internet, or a combination of two or more thereof.

[0058] Bus Cpnt6 may provide a communication link between the above-mentioned components of the computing system. For example, bus Cpnt6 may include an Accelerated Graphics Port (AGP) or other graphics bus, an Enhanced Industry Standard Architecture (EISA) bus, a Front Side Bus (FSB), a HyperTransport (HT) interconnect, an Industry Standard Architecture (ISA) bus, an InfiniBand bus, a low-pin-count (LPC) bus, a memory bus, a MicroChannel Architecture (MCA) bus, a Peripheral Component Interconnect (PCI) bus, a PCI-Express (PCIe) bus, a Serial Advanced Technology Attachment (SATA) bus, a Video Electronics Standards Association local (VLB) bus, or any other suitable bus, or a combination of two or more thereof.

[0059] Although this disclosure describes and illustrates a particular computer system having a particular number of particular components in a particular arrangement, this disclosure contemplates any suitable computer system having any suitable number of any suitable components in any suitable arrangement.

[0060] As used herein, a computer-readable non-transitory storage medium may include one or more semiconductor-based or other integrated circuits (ICs) (e.g., field programmable gate arrays (FPGAs) or application-specific ICs (ASICs)), hard disk drives (HDDs), hybrid hard drives (HHDs), optical disks, optical disk drives (ODDs), magneto-optical disks, magneto-optical drives, floppy diskettes, floppy disk drives (FDDs), magnetic tapes, solid-state drives (SSDs), RAM-drives, SECURE DIGITAL cards or drives, or any other suitable computer-readable non-transitory storage medium, or any suitable combination of two or more thereof, where appropriate. A computer-readable non-transitory storage medium may be volatile, non-volatile, or a combination of volatile and non-volatile, where appropriate.

[0061] While the present invention has been described in conjunction with several specific embodiments, as will be apparent to those skilled in the art in light of the foregoing description, many other alternatives, modifications, and variations will be apparent. Accordingly, the invention as described herein is intended to embrace all such alternatives, modifications, applications, and variations that may fall within the spirit and scope of the appended claims.

Claims

1. 1. A method for monitoring a pathology of an eye (E) of a patient, comprising: An optical coherence tomography (OCT) system collecting an OCT scan of the eye (711); a processor (Cmp1) designating a region of interest (hereinafter referred to as ROI) of the macula within the OCT scan; the processor (Cmp1) determining a representative macular thickness measurement from the collected OCT scans that is characteristic of the overall thickness of the macular ROI; The processor (Cmp1) determines (61) a patient-personalized baseline thickness for the macular ROI; defining (64) an upper specification limit based on the patient-personalized baseline thickness by the processor (Cmp1) or in a user-adjustable manner; the processor (Cmp1) defining (65) a lower specification limit based on the patient-personalized baseline thickness; the processor (Cmp1) responding to the representative macular thickness measurement being equal to or greater than the upper specification limit by issuing an electronic signal (721) indicating the need for medical care; and the processor (Cmp1) adjusts at least one of the patient-personalized baseline thickness, the upper specification limit, and the lower specification limit based on the representative macular thickness measurement in response to the representative macular thickness measurement being below the lower specification limit.

2. 2. The method of claim 1, wherein the representative macular thickness measurement is based on a plurality of individual macular thickness measurements within the macular ROI, and the representative macular thickness measurement is determined as an average of all individual macular thickness measurements within the macular ROI, the highest individual macular thickness measurement within the ROI, or an average of two or more of the highest individual macular thickness measurements within the ROI.

3. 3. The method of claim 1 or 2, wherein the patient-personalized baseline thickness is based on an average of the lowest previous representative macular thickness measurements of a predetermined number of macular ROIs determined according to a healthcare professional's scheduled macular thickness testing interval.

4. 4. The method of claim 3, wherein the lowest prior representative macular thickness measurement is extracted from stable periods only, the condition being age-related macular degeneration (hereinafter AMD) in the eye, and a stable period being defined as one or more of a dry AMD period during which individual macular thickness measurements of a macular ROI did not change by more than 5%, or a period during which no medication was injected into the eye.

5. at least one of the upper specification limit and the lower specification limit is defined as an offset from the patient-personalized baseline thickness, the offset being based on a population statistical analysis of macular thickness measurements from corresponding macular ROIs in a general population of test eyes taken during a stable period, the condition being age-related macular degeneration (hereinafter AMD) in the eye, the stable period being defined as a dry AMD period, the dry AMD period being a period during which the individual macular thickness measurements in the test eye did not change by more than 5% or the test eye was not injected with a medication; and / or 3. The method of claim 1 or 2, wherein the patient-personalized baseline thickness is user-adjustable in fixed-size intervals within a predetermined range, and wherein the user-adjusted patient-personalized baseline overwrites a previously determined patient-personalized baseline thickness.

6. 3. The method of claim 1 or 2, wherein in response to the representative macular thickness measurement being at or below the lower specification limit, the patient-personalized baseline thickness is adjusted to the average of the current representative macular thickness measurement and one or more previous macular thickness measurements for the eye that are at or below the lower specification limit.

7. the patient-personalized baseline thickness is adjusted if a current representative macular thickness measurement that is at or below the lower specification limit is the third or subsequent consecutive representative macular thickness measurement for the eye that is at or below the lower specification limit; and / or 3. The method of claim 1, wherein at least one of the upper specification limit and the lower specification limit is adjusted independently of the patient-personalized baseline thickness.

8. 3. The method of claim 1, wherein at least one of the patient-personalized baseline thickness, the upper specification limit, and the lower specification limit is automatically adjusted by a preset increment within a predetermined range.

9. 3. The method of claim 1, wherein at least one of the upper specification limit and the lower specification limit is automatically adjusted by incorporating values ​​of the representative macular thickness measurements into a recalculation of at least one of the upper specification limit and the lower specification limit.

10. 3. The method of claim 1 or 2, wherein multiple ROIs of the macula are designated, each ROI having an individual patient-personalized baseline thickness independent of each other.

11. the plurality of ROIs of the macula have different individual upper and lower specification limits; and / or The method of claim 10 , wherein the upper and lower offsets of a selected one of the macular ROIs are set as the upper and lower offsets of all of the macular ROIs.

12. The method of claim 10 , wherein the multiple ROIs of the macula are concentric with one another.

13. each of the plurality of macular ROIs having an individual upper and lower specification limit based on a corresponding upper and lower offset from an individual patient-personalized baseline thickness; The method of claim 12 , wherein the upper and lower offsets of a most central ROI are set as the upper and lower offsets of all the macular ROIs.

14. at least one of the upper specification limit, the lower specification limit, and the patient personalized baseline thickness is remotely adjustable by an authorized user in response to receiving an electronic message via a telecommunications network; and / or 3. The method of claim 1 or 2, wherein the OCT scan of the eye is collected using a self-adapting optical coherence tomography system.

15. An optical coherence tomography (OCT) system, comprising: a light source (LtSrc1) for generating a light beam; a beam splitter (Cplr1) having a beam splitting surface for directing a first portion of the light to the reference arm and a second portion of the light to the sample arm; an optical system for directing light in the sample arm to one or more locations on the sample; a detector (Dtctr1) for receiving light returning from the sample arm and the reference arm and generating a signal in response to that light; 3. An OCT system, characterized in that it comprises a processor (Cmp1) configured to carry out the method according to claim 1 or 2.

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