DE102014015225A1 - Method for contrast-agent-based, multimodal fundus imaging - Google Patents

Abstract

The present invention relates to a method for contrast agent-based, multimodal fundus imaging. For this purpose, regions of interest of the eye in question are recorded at different times and / or under different conditions by means of imaging techniques, analyzed and stored for diagnosis and / or follow-up examinations. In the method according to the invention, after injection of a contrast agent with a first modality, an image (s) for displaying the fluorescence properties is recorded and abnormalities in certain regions that could indicate a pathological change are detected and registered. Subsequently, sectional images are taken at the coordinates of the detected abnormalities as a second modality and evaluated with respect to layer thicknesses and distances. The results are saved together with the recording time and their coordinates for diagnosis and / or follow-up examinations. The method proposed here is suitable for the diagnosis of age-related macular degeneration, as well as for the diagnosis of other diseases of the eye, such as diabetic retinopathy, Alzheimer's disease or other neurodegenerative diseases, depending on the respective recognition substances.

Description

The present invention relates to a method for contrast agent-based, multimodal fundus imaging. For this purpose, regions of interest of the eye in question are recorded at different times and / or under different conditions by means of imaging techniques, analyzed and stored for diagnosis and / or follow-up examinations.

In medicine, there are a variety of methods to represent the body, individual organs or tissues of humans. Since the different methods can each capture only one aspect of the anatomy or biochemistry of the human body, clinical diagnoses should be based on image information of various modalities.

According to the known state of the art, optical methods for imaging are used in ophthalmology in addition to ultrasound-based methods. In this case, it is useful to combine color or fluorescence imaging, which can be realized for example with the aid of OPMI devices, fundus cameras or laser ophthalmoscopes, with optical coherence tomography (OCT).

That's how it describes US 7,971,999 B2 a retinal examination method and apparatus based on two-dimensional images of the retina. For the widest possible examination and diagnosis of the retina of the eye, planar images with depth sectional images of the retina are combined here. For evaluation, these are displayed simultaneously or successively by means of one or a plurality of display units, such as monitors or displays. A disadvantage is that with the multimodal imaging method described here neither the detection of early, molecular changes nor the visualization of particularly small changes ("feeder vessels") is possible.

A solution for the automatic detection of age-related macular degeneration and other retinal abnormalities is described in US Pat US 2011/242306 A1 described. Retinal abnormalities are detected and analyzed based on one or more healthy areas from the data of a retinal scanner.

The US 7,593,559 B2 describes a method and system for co-registration of optical coherence tomographic volume scans (OCTs) with other clinical tests.

Both this method and that in the US 2011/242306 A1 described methods for the automatic detection of age-related macular degeneration, as well as do not allow the detection of molecular or cellular changes or very small "feeder vessel" and the "leading" of the subsequent OCT scan in the region thus identified (region-of-interest: ROI ).

None of the solutions known from the prior art describes the use of a contrast agent which uses various contrasting physical effects.

With the diagnostics known from the prior art, a precise classification of the different phases of a disease of age-related macular degeneration and thus also the early initiation of suitable therapeutic measures is not possible.

The object of the present invention is to develop a method for retinal imaging which is based on image data of various modalities and with which the diseases or the risk of a disease can be diagnosed at an early stage.

According to the invention, this object is achieved with the method for contrast agent-based, multimodal fundus imaging, based on image sets of the relevant eye; which were recorded at different points in time and / or under different conditions by means of imaging methods, achieved in that after injection of a contrast agent, for imaging molecular pathologies, cellular properties or vessels, an image is taken with the first modality for displaying the fluorescence properties that in In this first picture, abnormalities that may indicate a pathological change, it can be detected that the detected abnormalities or the affected region (region-of-interest: ROI) are registered, that as a second modality, sectional images at the coordinates of the detected abnormalities (ROI) be recorded that the sectional images of the second modality with regard to layer thicknesses and distances are evaluated and the results are stored together with the recording time and their coordinates for diagnoses and / or follow-up examinations.

Preferred developments and refinements are the subject of the dependent claims.

Although the method proposed herein for contrast agent-based, multimodal fundus imaging is described below for the diagnosis of age-related macular degeneration (AMD), it is basically also for the diagnosis of other diseases of the eye, such as diabetic retinopathy (DR) and Morbus Alzheimer's and other neurodegenerative diseases suitable. The prerequisite for this is that the corresponding recognition substances for the pathologies can be marked with a suitable contrast agent.

Biomarkers are measurable products of organisms that can be used as indicators for B. be used for environmental pollution or diseases.

The invention will be described in more detail below with reference to exemplary embodiments. To show:

1 : multimodal fundus imaging using a contrast agent with molecular, cellular or tissue-specific properties,

2 : multimodal fundus imaging using a contrast agent with high signal strengths and / or a long diagnostic window and

3 : Multimodal fundus imaging using a contrast agent with fluorescence and absorption or scattering properties.

The proposed method for contrast-based, multimodal fundus imaging is based on image sets of the subject eye of various modalities recorded at different times and / or under different conditions by means of imaging techniques. According to the invention, after injection of a contrast medium with a first modality, an image (s) for displaying the fluorescence properties is recorded, with this first modality abnormalities in certain regions (English: region-of-interest, abbreviated ROI) which could indicate a pathological change. detected and registered. Subsequently, sectional images are taken at the coordinates of the detected abnormalities as a second modality and evaluated with respect to layer thicknesses and distances. The results are saved together with the recording time and their coordinates for diagnosis and / or follow-up examinations.

The results are saved together with the recording time and their coordinates for diagnosis and / or follow-up examinations.

In some cases, it proves to be problematic that the specific and sensitive detection of disease-specific biomarkers in the "en face" image is often difficult because many pathologies, such as inflammation, neoplasia or neovascularization, in the early phase undetectable by standard methods are, because these can only represent morphological changes. This considerably complicates the determination of a region-of-interest for the subsequent analysis with the tomographic method.

Another difficulty is that multimodal information based on different imaging techniques is often not directly correlatable, e.g. As a fluorescence signal in the "en face" image usually is not directly associate with an OCT signal in the sectional view.

According to the invention, at least two images (sectional images) of different modalities are taken, these having to include at least partially equal areas.

Furthermore, in the proposed method an accuracy for the registration of the multimodal fundus imaging of <100 microns, preferably <50 microns required.

For imaging the fluorescence properties, optical imaging techniques are used, using fundus cameras, surgical microscopes, endoscopes, line scanners, or confocal laser scanners.

In contrast, both optical imaging techniques - such as microscopy and photoacoustic imaging - as well as X-ray, ultrasound, magnetic resonance, radioactive tracer-based methods are applicable to capture slices.

For the recording fluorescence images is of course crucial that the imaging process is tailored to the contrast agent used.

• • molekulare, zelluläre oder gewebespezifische Eigenschaften aufweisen oder,
• • eine hohe Signalstärken und/oder ein langes diagnostisches Fenster aufweisen, welche auch die Identifizierung von kleinen Veränderungen erlaubt oder
• • Fluoreszenzeigenschaften in Kombination mit Absorptions- bzw. Streueigenschaften aufweisen, welche den Einsatz als Kontrastmittel in der Bildgebung von Schnittbildern erlauben.

According to the invention, contrast agents are used which either:

• Have molecular, cellular or tissue-specific properties or
• • have a high signal strength and / or a long diagnostic window, which also allows the identification of small changes or
• • Have fluorescence properties in combination with absorption or scattering properties, which allow the use as a contrast agent in the imaging of sectional images.

• • dessen Fluoreszenzfarbstoff (Indocyanin Grün, Fluoreszein, Quantumdot) in eine mizellären Struktur oder ein viralen Vektor integriert ist (z. B. Solutol, Phospholipid-Polyethylen-Glycol, Polyglycerol-Sulfate) oder ohne „Hüllsubstanz” ist,
• • dessen Fluoreszenzfarbstoff an ein Antikörper, Antikörperfragment, Protein, Apatamer, DNA-Molekül oder RNA-Molekül gebunden ist oder selbst molekulare, zelluläre oder gewebespezifische Eigenschaften aufweist,
• • die über ein endogenes oder exogenen fluoreszierenden Molekül verfügen.

In particular, contrast agents are used here,

• • whose fluorescent dye (indocyanine green, fluorescein, quantum dot) is integrated into a micellar structure or a viral vector (eg solutol, phospholipid-polyethylene-glycol, polyglycerol sulfates) or without "shell substance",
• The fluorescent dye of which is bound to an antibody, antibody fragment, protein, apatamer, DNA molecule or RNA molecule or which itself has molecular, cellular or tissue-specific properties,
• • have an endogenous or exogenous fluorescent molecule.

According to a preferred embodiment, a fluorescent dye is used which has an excitation wavelength between 750 and 1100 nm, preferably between 750 and 800 nm.

For the analysis and evaluation of the contrast agent-based, multimodal fundus images, a computer is used which should display the images as well as the results on a display. Preferably, the computer is integrated into the device for fundus imaging and also realizes the registration algorithms, wherein the type of registration algorithm used may depend on the image modality (s) used.

• – Algorithmen zur Extraktion von Low-Level-Merkmalen, wie z. B.
• – Farbe
• – Form
• – Textur
• – Orientierung
• – Gradientenverteilung (Histogram of Oriented Gradients)
• – Algorithmen zur Extraktion von Kontextmerkmalen
• – Algorithmen zur Inferenz in graphischen Modellen, z. B.
• – GraphCut
• – Belief Propagation in unterschiedlichen Ausprägungen
• – Mean Field Inferenz
• – Gibbs sampling
• – Statistischer Klassifikator, z. B.
• – Nearest Neighbor
• – Support Vector Machine
• – Random Forests
• – Boosting (AdaBoost, GentleBoost).

In the context of image processing and evaluation, for example, the following algorithms known from the prior art can be used:

• - Algorithms for the extraction of low-level features, such. B.
• - Colour
• - Shape
• - texture
• - Orientation
• - Gradient Distribution (Histogram of Oriented Gradients)
• - Algorithms for the extraction of context features
• - Algorithms for inference in graphical models, eg. B.
• - GraphCut
• - Belief propagation in different forms
• - Mean Field Inference
• - Gibbs sampling
• - Statistical classifier, e.g. B.
• - Nearest Neighbor
• - Support Vector Machine
• - Random Forests
• - Boosting (AdaBoost, GentleBoost).

• • „Block-matching via cross-correlation”;
• • „Key point matching with robust outlier rejection”;
• • „Optimization with gradient descent methods”;
• • „Optimization with variational methods” oder
• • „Vessel segmentation, matching via cross-correlation”.

For the registration of detected abnormalities (ROI) known algorithms are used, these being dependent on the image modalities used. Thus, rigid and / or non-rigid approaches can be used in combination with any distance measures, such as:

• • "Block-matching via cross-correlation";
• • "Key point matching with robust outlier rejection";
• • "Optimization with gradient descent methods";
• • "Optimization with variational methods" or
• • "Vessel segmentation, matching via cross-correlation".

The lists documented here, both the contrast agents and the registration concerning are merely exemplary and not complete.

The following exemplary embodiments describe the use of the method according to the invention with reference to an eye which is suffering from age-related macular degeneration (AMD) or at least has an increased risk of such a disease.

The term macular degeneration is a group of diseases of the eye that affect the point of sharpest vision (macula lutea) of the retina and associated with a gradual loss of function of the tissues located there. By far the most common form of macular degeneration is age-related macular degeneration (AMD).

• • Drusenbildung,
• • frühe entzündliche Prozesse,
• • Expression vom Vascular Endothelial Growth Factor (VEGF),
• • Bildung von ersten „Feeder Vessel” (FV) und
• • retinalen Einblutungen.

Age-related macular degeneration can be diagnosed by the following features:

• • drusen formation,
• • early inflammatory processes,
• Expression of Vascular Endothelial Growth Factor (VEGF),
• • Formation of first "Feeder Vessel" (FV) and
• • retinal bleeding.

Drusen are deposits of extracellular material below the retina. They occur in all age groups, but increase in size and number with increasing age. They are considered as an early form of age-related macular degeneration. Druze does not cause any visual impairment per se, but may cause color and contrast sensitivity.

Vascular endothelial growth factor (VEGF) is an important signaling molecule that is effective in both vasculogenesis and angiogenesis. Vascular neoformations are used for the indication of wet macular degeneration.

Forming so-called feeding vessels or "feeder vessel" (FV) may also be an indication of a wet macular degeneration. Special forms of these feeding vessels are For example, so-called hairpin vessels or "hair pins" or so-called pearl necklace vessels or "Pearl Strings".

According to a first embodiment of the method according to the invention, after injection of a contrast agent with molecular, cellular or tissue-specific properties with the first modality, the fluorescence properties are shown. In this first modality, abnormalities (ROI) that could indicate a pathological change are detected and registered. Subsequently, with the second modality, sectional images are taken at the coordinates of the detected conspicuousnesses (ROI) and evaluated with respect to layer thicknesses and distances. The results are saved together with the recording time and their coordinates for diagnosis and / or follow-up examinations.

In this case, it is particularly advantageous if, in the first modality, two images are taken, one immediately after injection and another after exposure to the contrast agent, and subtracted from each other to display the fluorescence properties.

This shows the 1 multimodal fundus imaging using a contrast agent with molecular, cellular or tissue-specific properties.

This first embodiment shows the functionality of the method according to the invention using the example of the detection of pathological changes in the retina with the aid of a specific contrast agent. Pathological changes in the retina include, for example, inflammation, choroidal neovascularization or neoplasia, as well as atrophic areas.

The two images above show images of the first images taken using a fundus camera or laser scanner. Since the left image was taken immediately after injection, it shows only contrast medium, which still flows nonspecifically through the vessels comparable to a conventional angiography.

The right image, taken after the specific enrichment of the contrast agent, shows residues of the contrast agent in the vessels as well as specifically bound contrast agent. In order to display the fluorescence properties of interest, both images are subtracted from one another using algorithms and parameters which are shown in the resultant image below. In this resulting image of the first modality, an abnormality (ROI) that could indicate a pathological change was detected and registered.

By means of an image analysis, the regions (region-of-interest) are then identified with elevated fluorescence signals, wherein the signal height should be at least a factor 2 (optimally greater than a factor of 3) than the background signal. Optionally, additional classifiers for feature extraction, such as morphological peculiarities, can be applied.

The next picture shows as a second modality a sectional image at the coordinates of the detected conspicuousness (ROI), in which retinal layers were selected and their thickness measured. As a cross section, OCT scans in the form of B-scans or volume scans are possible.

The retinal layer thickness measured in the ROI is compared with the retinal layer thickness outside the ROI, ie healthy tissue. As a result, a therapeutic intervention, such. B. a drug or laser therapy can be derived.

Another possibility is to determine the penetration depth d of so-called "feeder vessel" or other pathological changes into the retinal tissue and to derive a therapeutic intervention.

The results documenting a pathological change are stored in a computer together with the time of acquisition and its coordinates for diagnoses and / or follow-up examinations. Follow-up examinations serve both to control the progression of the disease or to determine the efficacy of a therapeutic intervention.

According to a second embodiment of the method according to the invention, after injection of a contrast agent with high signal strengths and / or a long diagnostic window, a first modality for displaying the fluorescence properties is recorded, in which even very small abnormalities which could indicate a pathological change are detected and registered by feature extraction ,

Here, too, it is particularly advantageous if, in the first modality, two images are taken, one immediately after injection and another after exposure to the contrast agent, and are subtracted from each other to display the fluorescence properties using appropriate algorithms and parameters.

Due to the increased fluorescence signals of the contrast agent used, even very small, early pathological changes in morphology, such as "hair pin", "feeder vessel" or "pearl string" structures, are clearly visible.

For feature extraction, known methods of image processing or algorithms for extraction of low-level features are used.

Subsequently, the second imaging modality acquires sectional images at the coordinates of the detected conspicuousnesses (ROI), evaluates them with regard to layer thicknesses and distances and stores the results together with the acquisition time and their coordinates for diagnoses and / or follow-up examinations.

This shows the 2 multimodal fundus imaging using a contrast agent with high signal strengths and / or a long diagnostic window.

This second embodiment also shows the functionality of the method according to the invention using the example of the detection of age-related macular degeneration (AMD).

The top picture shows contrast medium, which still flows unspecifically through the vessels comparable to a conventional angiography as well as specifically bound contrast agent.

With this first modality for displaying the fluorescence properties, the very slight conspicuousness in the form of a so-called "pearl string" was detected in a region of interest (ROI).

The image below shows the image of the first modality in which the detected abnormalities are analyzed and registered in the form of a so-called "pearl string".

The next picture shows as a second modality a sectional image at the coordinates of the detected conspicuousness (ROI), in which retinal layer thicknesses were selected and measured. As a cross-sectional image, OCT scans in the form of B-scan or volume scans are possible.

The results documenting a pathological change are stored in a computer together with the time of acquisition and its coordinates for diagnoses and / or follow-up examinations. Follow-up examinations serve both to control the progression of the disease or to determine the efficacy of a therapeutic intervention.

According to a third embodiment of the method according to the invention, an image for displaying the fluorescence properties is recorded after injection of a contrast agent with fluorescence and absorption or scattering properties with the first modality.

With this first modality, abnormalities (ROI) that could indicate a pathological change are detected. On a registration of the detected ROI can be omitted in this embodiment.

Following this, sectional images are taken and evaluated as a second modality by selecting retinal layers and measuring their distances.

The contrast agent has contrast-altering properties for both imaging methods. Thus, in this embodiment, the pathology is also visualized directly in the sectional images of the second modality by the contrast agent. It is thereby possible to visualize pathology, such as CNV, inflammation or neoplasia, with 2 different imaging modalities and to take advantage of the diagnostic advantages of the particular modality.

While fluorescence imaging has a high "field of views" at high sensitivity, enabling the detection of pathologies in the periphery as well, optical coherence tomography realizes sectional images of the retina and allows the reconstruction of 3d data sets.

The results are also stored in this embodiment together with the recording time and their coordinates for diagnoses and / or follow-up examinations.

This shows the 3 multimodal fundus imaging using a contrast agent with fluorescence and absorption or scattering properties. The contrast agent is thus suitable as a contrast agent for both modalities.

The top image shows the image of the first image taken using a fundus camera or laser scanner. To display the fluorescence properties, the imaging in this modality is carried out after enrichment of the contrast agent, so that abnormalities (ROI), which could indicate a pathological change, can be detected.

The image below shows a cross-sectional image in which the pathologies are directly visualized by the contrast agent used.

The results documenting a pathological change are stored in a computer together with the time of admission for diagnoses and / or follow-up examinations. Follow-up examinations serve both to control the progression of the disease or to determine the efficacy of a therapeutic intervention.

With the solution according to the invention, a method for fundus imaging is provided which is based on various modalities of the eye in question and with which diseases or the risk of a disease can be diagnosed early on. The metrological effort is low, since recourse is made to known methods and / or devices.

The particular effect of the method is the fact that a specific fluorescence signal is used in conjunction with a corresponding image processing to detect a pathological or vital condition.

With the aid of a second imaging modality, for example based on OCT, ultrasound or photoacoustics, the abnormalities (ROI) detected on the basis of a first modality are examined in more detail in the form of sectional images.

• • spezifische Erkennung von Pathologien oder vitaler Parameter auf molekularer/zellulärer Ebene oder
• • Detektion von kleinen Gefäßen durch hohe Signalstärken des Kontrastmittels in Verbindung mit geeigneten optische Modalitäten. oder
• • Fluoreszenz- und Absorptions- bzw. Streueigenschaften, welche auch den Einsatz als Kontrastmittel in der Bildgebung von Schnittbildern erlaubt.

The method makes use of the following properties of the contrast agent:

• • specific detection of pathologies or vital parameters at the molecular / cellular level or
• • Detection of small vessels by high signal strengths of the contrast medium in conjunction with suitable optical modalities. or
• • Fluorescence and absorption or scattering properties, which also allows the use as a contrast agent in the imaging of sectional images.

For visualization, all imaging modalities can be used after appropriate labeling.

The combination of data from different imaging modalities provides additional information for the early detection of various diseases. It may be advantageous to combine the projection imaging with tomographic methods.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 7971999 B2 [0004]
• US 2011/242306 A1 [0005, 0007]
• US 7593559 B2 [0006]

Claims (13)

Method for contrast-based, multimodal fundus imaging based on image sets of the relevant eye; which were recorded at different times and / or under different conditions by means of imaging methods, characterized in that after injection of a contrast agent with a first modality a picture (s) is taken to show the fluorescence properties that with this first modality abnormalities in certain regions ( abbr. ROI) that could indicate a pathological change, it can be detected that the detected abnormalities are registered, that as a second modality sectional images are taken at the coordinates of the detected abnormalities, that the sectional images of the second modality be evaluated in terms of layer thicknesses and distances and the results are stored together with the recording time and their coordinates for diagnoses and / or follow-up examinations. A method according to claim 1, characterized in that at least 2 images (sectional images) of different modalities are included, at least partially include the same areas. A method according to claim 1, characterized in that the registration of the multimodal fundus imaging with an accuracy of <100 microns, preferably <50 microns. A method according to claim 1, characterized in that for the representation of fluorescence properties, optical imaging techniques are used, with fundus cameras, surgical microscopes, endoscopes, line scanners or confocal laser scanner are used. Method according to Claim 1, characterized in that both optical methods - including microscopy - and photoacoustic methods and also X-ray radiation, ultrasound, magnetic fields, radioactive radiation or else the method based on the invention can be used to record a sectional image. A method according to claim 1, characterized in that a contrast agent is used, the fluorescent dye is integrated into a micellar structure or a viral vector or other transport system or "carrier" molecule. A method according to claim 1, characterized in that a contrast agent is used, the fluorescent dye is bound to an antibody, antibody fragment, protein, DNA molecule or RNA molecule or even has molecular, cellular or tissue-specific properties A method according to claim 1, characterized in that a contrast agent with an endogenous or exogenous fluorescent molecule is used. A method according to claim 1, characterized in that the contrast agent includes a fluorescent dye whose excitation wavelength is between 750 and 1100 nm, preferably between 750 and 800 nm. A method according to claims 1 to 9, characterized in that after injection of a contrast agent having molecular, cellular or tissue-specific properties, an image is taken with a first modality, that with this first modality abnormalities that could indicate a pathological change are detected, that the detected abnormalities and the ROI are registered, that with the second modality sectional images are taken at the coordinates of the detected abnormalities, that the sectional images of the second modality are evaluated in terms of layer thicknesses and distances and the results together with the recording time and their coordinates for diagnoses and / or follow-up examinations are saved. A method according to claims 1 to 9, characterized in that after injection of a contrast agent with high signal strengths and / or a long diagnostic window with a first modality images are recorded for displaying the fluorescence properties, that in this first modality even very minor abnormalities on a pathological changes are detected, it can be detected that the detected abnormalities are registered, that with the second modality sectional images are taken at the coordinates of the detected abnormalities, the sectional images of the second modality are evaluated in terms of layer thicknesses and distances and the results together with the recording time and their coordinates are saved for diagnosis and / or follow-up examinations. Process according to claims 10 and 11, characterized in that in the first modality two images are taken, one immediately after injection and another after accumulation of the contrast agent and are subtracted from each other to display the fluorescence properties. Process according to claims 1 to 9, characterized in that after injection of a suitable for both modalities contrast agent with fluorescence and absorption or Scattering properties are recorded with a first modality images for displaying the fluorescence properties are detected in the abnormalities that could indicate a pathological change, detected that are recorded with the second modality sectional images in which also abnormalities that could indicate a pathological change detected and the results are stored together with the time of admission for diagnoses and / or follow-up examinations.

Images