Apparatus for photodynamic diagnosis

A device for "in vivo" diagnosis by means of a photosensibilisator light-induced reaction or a reaction caused by intrinsic fluorescence in biological tissue, having an illumination system, which is provided with at least one light source having a lamp system which generates incoherent light in a wavelength range of at least 380 to 680 nm, a light delivering unit which directs the light of said illumination system at the therapy and/or to-be-diagnosed tissue area, and an imaging, image-recording and image-transmitting unit which images the light coming from said tissue area in a proximal image plane. The device is distinguished in that the net spectral transmittance in the light delivering unit and in the image-generating unit of the device are selected in such a manner that, on the one hand, practically no light with a wavelength of .lambda. from the range utilized for excitation, which by nature has relatively high intensity, "reaches" via the image-generating unit of the device into the proximal image plane, whereas light with a wavelength of .lambda. from the range in which fluorescence occurs can reach the proximal image plane only if it comes from the illuminated tissue are and not from the illumination system.

DESCRIPTION
 1. Technical Field
 The present invention relates to a device for "in vivo diagnosis" by means
 of an intrinsic or foreign photosensibilisator light-induced reaction in
 biological tissue.
 2. State of the Art
 The method of diagnosis performed with a device of this type is also
 referred to in medicine as photodynamic diagnosis (PDD) or as fluorescence
 diagnosis. Moreover, using photosensibilisators for photodynamic therapy
 (PDT) is also known. With regard to this see WO 93/20810 to which,
 moreover, reference is explicitly made for the explanation of all terms
 and process steps not explained more closely herein.
 Furthermore, it has been proposed to perform endoscopic photodynamic
 diagnosis and therapy using a device which utilizes a Krypton ion laser
 with a wavelength of approximately 410 nm and power of more than 200 mWatt
 as the light source. The light of this laser is guided via a quartz light
 conductor having a small numerical aperture through an endoscope to the
 to-be-irradiated sites of the human body.
 In order to trigger a light-induced reaction in biological systems, the
 patient is given a photosensibilisator, which either has a hematoporphyrin
 basic structure such as the substance photofrin and photosan-3, or delta
 amino levulinic acid (ALA), recently in use in urology and dermatology, in
 a concentration of few mg/kg body weight. The hematoporphyrin derivatives
 are dispensed intravenously, whereas delta amino levulinic acid can be
 applied locally, i.e. it is injected as a solution, by way of
 illustration, into the urinary bladder. These substances accumulate in
 tumor tissues in double to ten-fold concentrations. This selective
 accumulation in tumor tissue represents a decisive basis for photodynamic
 diagnosis and photodynamic therapy.
 For diagnosis, the to-be-examined tissue is irradiated endoscopically with
 violet light, in known devices practically solely laser light,
 approximately 2-12 hours following dispensing the photosensibilisator
 (ALA). The porphyrin derivatives, high concentrations of which are present
 in the tumor tissue, are excited by this light and subsequently have a
 typical red fluorescence, by means of which the tumor can be localized.
 In addition to fluorescence, due to the accumulation of the
 photosensibilisator in the tissue, so-called autofluorescence of the
 tissue may be triggered due to so-called fluorophorene, i.e. intrinsic
 fluorescence substances.
 In photodynamic therapy, irradiation is conducted with red light, because
 this light with a wavelength of more than 630 nm penetrates the tissue to
 a depth of about 5 mm contrary to light with shorter wavelengths, which
 penetrates strikingly less deep. Despite the use of this optimum
 wavelength, the indication for use of photodynamic therapy is presently
 limited to flat, surface carcinoma.
 It can be assumed the biological course of the light-induced reaction is as
 follows:
 The photosensiblisator stored in the tissue is excited by the absorption of
 a light quantum with a defined energy content emitted by the respective
 light source. If violet light is irradiated within the scope of the
 photodynamic diagnosis, fluorescence radiation is emitted upon returning
 to the initial state.
 If photodynamic therapy occurs in conjunction with radiation using red
 laser light of higher power density, there is a transition from the
 excited state to a metastabilized intermediate state, from which the
 energy which is released by the return to the initial state is transmitted
 to the molecular oxygen, which absorbs this energy forming excited
 singulet oxygen. This aggressive singulet oxygen destroys the cell
 structures in the concerned tissue by means of photooxidation. This
 cellular damage in conjunction with the simultaneous collapse of the tumor
 vessel system leads to complete destruction of the tumor (phototoxic
 effect).
 However, this procedure has certain problems depending on the
 photosensibilators employed. If photofrin and photosan-3 are used as
 photosensibilisators for photodynamic diagnosis, technologically very
 complicated devices have to be employed for fluorescence detection,
 because due to the interfering intrinsic-fluorescence, the fluorescence of
 the tumor tissue can only be suitably detected with the aid of very
 complicated, computer-supported image processing technology and highly
 sensitive cameras with low-light amplifiers.
 If delta amino levulinic acid is utilized, the induced fluorescence is
 strong enough that it can be visibly recognized. However, the fluorescence
 obtained with the delta amino levulinic acid does not yield an optimum
 quality endoscopic image for recording for the diagnosis. The use of a
 quartz light conductor with a small numerical aperture, such as is
 employed for light transmission of a laser beam, permits only very poor
 illumination of the image.
 Employing an additional light conductor, which could improve illumination,
 reduces the lumen available for the other channels in the endoscope to
 such an extent that it drastically decreases the possibility of utilizing
 other endoscopic instruments.
 Above all, when using known devices, the additional light introduced into
 the endoscope may superimpose the, even with delta amino levulinic acid,
 relatively weak fluorescence image.
 Moreover, the aforedescribed processes for the diagnosis and therapy
 require different light sources, and in particular laser sources, which,
 on the one hand, increases costs and, on the other hand, makes handling
 the endoscopic system more difficult.
 Similar problems arise when conducting photodynamic diagnosis using a
 microscope and, in particular using a surgical microscopic.
 SUMMARY OF THE INVENTION
 The object of the present invention is to improve a device for diagnosis by
 means of an intrinsic or foreign photosensibilisator light-induced
 reaction or a reaction caused by intrinsic fluorescence in biological
 tissue in such a manner that the induced fluorescence can be detected with
 a strong contrast while at the same time there being sufficient
 illumination, preferably not using lasers, for observing the tissue area.
 The solutions of the object of the present invention are based on the
 following fundamental concept:
 The net transmittance in the light delivering part and in the
 image-generating part of the invented device are selected in such a manner
 that, on the one hand, practically no light with a wavelength of .lambda.
 from the range used for excitation, which by nature has relatively high
 intensity, "reaches" via the image-generating part of the device into the
 proximal image plane, whereas light with a wavelength of .lambda. from the
 range in which fluorescence occurs can only reach the proximal image plane
 if it comes from the illuminated area of tissue and not from the
 illumination system. On the other hand, the net transmittance of the light
 delivering part and of the image-generating part of the device ensures
 that the illuminated area of tissue is so strongly illuminated with light
 of a wavelength which lies neither in the range of the excitation spectrum
 nor in the range of the fluorescence spectrum, that the examining
 individual can perceive, due to this wavelength range of the directly
 reflected light, details of the illuminated area of tissue independent of
 the fluorescence radiation.
 In other words, an element of the present invention is that the image of
 the tissue area illuminated with excited light is simultaneously generated
 by means of fluorescence light and reflected illumination light, with the
 two portions contributing to image generation are of such a nature with
 regard to wavelength and with regard to their intensity that they do not
 "interfere" with each other.
 The invented device for diagnosis by means of a light-induced reaction in
 biological tissue by means of an intrinsic or foreign photosensibilisator
 respectively by means of intrinsic fluorescence is provided with an
 illumination system having at least one light source, a light delivering
 unit which directs the light of the illumination system at the
 to-be-diagnosed area of tissue and an imaging unit which images the light
 coming from the tissue in a proximal image plane. Devices for diagnosis of
 corporal tissue having the aforementioned features are commonly known and
 are used, by way of illustration, in endoscopy or microscopy.
 An element of the present invention is that, a wide band light source is
 employed, in a manner, as such, known outside photodynamic diagnosis,
 which emits incoherent light in a wavelength range of at least 380 to 660
 nm, preferably from 370 to 780 nm. This wide band light source may possess
 a different spectral distribution than that of conventional light sources
 used in endoscopy. However, if the light source is also utilized for
 conventional examination of the area examined with photodynamic diagnosis
 as well, it is preferable if the light source is a conventional high-power
 light source like those used in medical endoscopy. The power input of the
 light source is preferably at least 300 watt.
 When using "wide band" light sources, in the past the problem arose that
 the light reflected at the to-be-examined area of tissue superimposes the
 fluorescence light. For this reason, an element of the present invention
 is that not only the net transmittance Ti.sub.1 (.lambda.) of the light
 delivering unit is adapted to the fluorescence excitation spectrum of the
 photosensibilisator and the net transmittance Ti.sub.b (.lambda.) of the
 imaging unit to the fluorescence spectrum of the photosensibilisators.
 Alternatively an element of the present invention is that, the net
 transmittance of the entire system comprising the light delivering unit
 and the imaging unit, yielded by the multiplication of net transmittance
 Ti.sub.l (.lambda.) and Ti.sub.b (.lambda.), has a spectral transmittance
 of more than 5% only in a range of a maximum of 50 nm and is otherwise
 less than 5%. In this range of a maximum of 50 nm, the net transmittance
 of the entire system may attain values of 10% and more.
 In the alternative, the net spectral transmittance Ti.sub.l (.lambda.) of
 the light delivering unit has, in addition to a first pass region, which
 is adapted to that of the fluorescence excitation spectrum of the
 photosensibilisator respectively of the tissue, also a second pass region,
 the wavelengths of which lie between the wavelengths of the fluorescence
 excitation spectrum and the wavelengths of the fluorescence spectrum. The
 net spectral transmittance Ti.sub.b (.lambda.) of the imaging unit has, in
 addition to a first pass region, which is adapted to the fluorescence
 spectrum of the photosensibilisator respectively of the tissue, also a
 second pass region which lies in the same wavelength range as that of the
 second pass region of the light delivering unit. The net transmittance of
 the entire system comprising the light delivering unit and the imaging
 unit has a spectral transmittance of more than 5%, which preferably may be
 10% and more, only in the second pass region and is otherwise less than 5%
 in the above wavelength range.
 As a result of this design of the spectral pass regions of the light
 delivering unit and of the imaging unit, the fluorescence light can be
 perceived clearly and with a strong contrast on the image generated by the
 illumination light by way of illustration of the surroundings of a tumor.
 It is preferred if the first and the second pass regions of the imaging
 unit are approximately complementary, yielding a strong contrast between
 the fluorescence image and the illuminated background image, which
 contrast can be enhanced by an alternating representation of both images
 on a monitor.
 Furthermore, it is preferred if the intensity of the illumination light and
 the filters are selected in such a manner that the power input of the
 light with wavelengths from the second range arriving on the proximal
 image plane is 10% (and less)up to approximately 100% of the cumulated
 power of the light in the first pass region of the imaging unit.
 In order to adapt the different photosensibilisators and/or different
 diagnostic conditions or in order to convert the invented device to a
 therapeutic procedure, it is furthermore preferred if the transmission
 properties of the light transmitting unit and of the imaging unit can be
 adjusted by means of one or multiple optical elements.
 It is preferred if the setting occurs in such a manner that the intensity
 of the induced fluorescence light lies in the same magnitude as the
 overall intensity of the reflected part of the light of the illumination
 system. Especially advantageous is if the setting occurs in such a manner
 that both intensities are approximately the same.
 In any case, the invented device has the advantage that in order to conduct
 photodynamic diagnosis while at the same time illuminating the observed
 field and for preliminary and/or follow-up visual observation of the
 examined area, it suffices to employ a single light source. Furthermore,
 the photodynamic therapy can be performed with the invented device without
 changing the light source, i.e. with a single light source. In this event,
 as previously mentioned, the transmission properties of the light
 delivering unit are adapted to the absorption spectrum of the
 photosensibilisator.
 The optical elements employed for adjusting the transmission properties of
 the light delivering unit and of the imaging unit are preferably filter
 systems which can be placed in the illumination beam path and in the
 examination beam path. The illumination beam path refers to the beam path
 of the lamp of the light source to the light delivering unit, via this
 unit and from this unit to the area of tissue to be diagnosed. The optical
 elements and, in particular, the filter systems can principally be
 disposed in any site of this beam path. However, especially preferred is
 the arrangement between the illumination system and the light delivering
 unit, by way of illustration a light-conducting fiber bundle. (Without a
 filter system, the net transmittance is assumed 100%.)
 Accordingly, the observation beam path refers to the beam path from the
 illuminated area of tissue to the imaging unit and from there to the
 proximal image plane. (Without a filter system the net transmittance is
 also assumed 100%.
 If the invented device is integrated in an endoscope, the image plane can
 be located in the endoscope both in the region of the distal end, by way
 of illustration when using a distally disposed video chip, as well as in
 the region of the proximal end. In the latter case, the imaging unit has,
 in addition to a lens as an imaging unit, for example, a relay lens system
 or a flexible fiber bundle as the image transmitting unit. If a relay lens
 system or a fiber bundle are employed as the image transmitting unit, the
 filter systems placed in the observation beam path are preferably disposed
 between the "last surface" of the relay lens system respectively of the
 exit surface of the fiber bundle and the proximal image plane.
 If the invented device is integrated in a surgical microscope, a component
 of the imaging unit is the microscope lens system downstream of which, by
 way of illustration a video recorder can be disposed as the image
 recording unit.
 As previously explained, an element of the present invention is that the
 illumination light reflected by the to-be-diagnosed area of tissue and its
 surrounding area does not superimpose the fluorescence light. In order to
 realize this inventive fundamental concept, it is preferred if the
 respective filter systems to be placed in the illumination beam path and
 in the observation beam path have practically opposite filter
 characteristics. In the case of a device designed according to claim 2,
 the opposite design of the filter characteristic relates, of course, only
 to the characteristic of the first pass region, but not to the
 characteristic of the second pass region.
 The curves, showing the transmission of the two opposite filters in
 dependence on the wavelength, intersect, in the embodiment according to
 claim 1 preferably with a transmission of the individual systems which is
 less than 50%.
 In another embodiment of the present invention, the filter placed in the
 illumination beam path is provided with at least two separate filters of
 which one filter is a thermostable interference filter and the other
 filter a thermostable heat protection filter (neutral filter).
 In the following, the properties of these filters are explained under the
 precondition that delta amino levulinic acid is employed as the
 photosensibilisator. If another photosensiblisator is employed, the filter
 properties have to be adapted accordingly:
 If delta amino levulinic acid (ALA) is used, it is preferable if the
 transmission of the illumination beam path by means of a short pass filter
 is at least 50% in the range between 380 and 430 nm. In an especially
 preferred embodiment, transmission between 370 and 440 nm is at least 70%
 and preferably 95%.
 If the wavelength is 445.+-.4 nm respectively 447.+-.2 nm, transmission
 reaches 50%. In the event of greater wavelengths, transmission is much
 smaller and usually lies below 1%.
 In a preferred embodiment of the present invention, transmission lies below
 1% in the wave length range between 460 and 600 nm as well as in the
 wavelength range between 720, preferably 660 nm, and 780 nm. In the
 wavelength range in which mainly fluorescence light is excited, thus in
 the case of delta amino levulinic acid in the wavelength range between 600
 and 720, preferably 660 nm, transmission is less than 0.1%.
 These characteristic, of the filter system yields a light distribution of
 the illumination light which ensures that in the wavelength range in which
 mainly fluorescence light occurs, practically no "non-fluorescence light"
 is radiated back by the tissue area to be examined.
 Accordingly, the filter in the observation beam path (long pass filter) has
 the following characteristic:
 T.sub.l (.lambda.=370-430 nm)&lt;0.1%
 T.sub.l (.lambda.=453.+-.2 nm)=50%
 T.sub.i (.lambda.=500-1100 nm)=95%, preferably 98-99%
 The tolerance for the wavelengths of the two filters, at which the
 respective transmission is 50%, is preferably .+-.2 nm. This design of the
 filter ensures that the net transmission of the entire system is only in
 the range between 430 and 460 nm greater than 5%. The maximum value
 reached in this range should preferably not be more than 15%.
 The use of optical elements and, in particular, of filters for influencing
 the radiation beam path transmission characteristic has the advantage
 that, by way of illustration, normal white-light illumination and
 observation can occur by swinging out the filter so that the examining
 person, thus by way of illustration a physician, can also assess the
 tissue area examined using fluorescence diagnosis, i.a. according to
 color. Color is, by way of illustration in the field of ophthalmology, an
 essential assessment criteria.
 The thermostable heat protection filter (neutral filter) also employed in a
 preferred embodiment of the present invention, can have the following
 characteristic:
 T.sub.l (.lambda.=370-440 nm)&gt;95%
 T.sub.l (.lambda.=440-700 nm).apprxeq.90%
 T.sub.l (.lambda.=700 nm)=50%,
 T.sub.l (.lambda.=720-1100 nm)&lt;1%,
 The use of a thermostable heat protection filter has the advantage that the
 interference filter is not heated by infrared light during diagnosis. This
 heating could, under circumstances, alter the filter characteristic and
 reduce the sensitivity of a camera recording element as well as destroy
 the light transmitting unit due to the high intensity.
 In any case, it is preferable if the individual filters are only placed
 upon need in the respective beam paths, with their removal from the beam
 path, under circumstances, being permitted or prevented by a monitoring
 signal.
 As filters, commercially available filters provided, in accordance with the
 invention, with the "almost stepped-shaped" characteristic, thus by way of
 illustration known interference filters, can be provided the carrier
 material of which is quartz.
 As the light source, known light sources can be employed as well, in
 particular, light sources known from endoscopy, which emit wide band in
 the mentioned wavelength range. A light source of this type, which emits
 light in sufficient intensity, is by way of illustration a gas discharge
 lamp and, in particular a xenon gas discharge high pressure lamp. Should
 in an individual case, the light output of the light source not suffice, a
 "pulsed" light source, such as a flash device or a laser, can be employed
 in addition to a "continuously operating" light source. Especially in the
 alternative solution set forth in claim 2, the light with a wavelength
 .lambda. in the first pass region can be generated with a laser, which may
 be a pulsed or a continuous wave laser. The light with wavelengths from
 the second pass region can then come from a more or less wide band "white
 light source".
 Commercially available light conductors having at least one fiber which
 advantageously possesses a numerical aperture of more than 0.45 can be
 employed as the light transmitting units, especially in endoscopic uses,
 because efficient light conduction to the to-be-diagnosed area then
 becomes possible. Fibers of this type have, by way of illustration, a core
 of quartz and an encasing of a thermostable material.
 In the event a light conducting fiber is employed, it is preferable if the
 light source, i.e. by way of illustration the gas discharge lamp, has a
 focal spot with a diameter of less than 2 mm, which is generated by an
 elliptical reflector, which has a numerical aperture for a light emergence
 of more than 0.45. In this case, highly efficient coupling between the
 illumination system and the light transmitting unit, thus the fiber light
 conductor is obtained.
 Furthermore, a gas discharge lamp, whose focal spot is focused on a
 diameter of less than 2 mm by means of a parabolic reflector and a focus
 unit, can also be used. The focus unit is in this case preferably a lens
 system which has at least one element having an aspherical surface.
 In another preferred embodiment of the present invention, the illumination
 system, thus the light source and optical elements connected upstream of
 the light source, such as filters, etc., is designed in such a manner that
 the excitation wavelengths are provided variable according to the
 respective, utilized photosensibilisator and the respective tissue to be
 diagnosed. This variability can either occur by corresponding influencing
 of the light source or by means of filters connected upstream, such as,
 e.g. graded filters or prisms.
 In this manner, different areas of tissue can be selectively excited to
 fluorescence.
 The invented device permits both visual observation of fluorescence and
 recording the fluorescence image with an image recorder, such as a video
 camera or the like.
 This video camera respectively unit is disposed in the image plane of the
 imaging unit. In the event of distal disposal of the video unit, it is
 disposed in the image plane of the lens of the endoscope. In the event of
 proximal disposal of the video unit, it is disposed in the image plane of
 the image transmitting unit, thus of the relay lens system or of the fiber
 bundle. Alternatively, the video unit can be designed in such a manner
 that it records the eyepiece image. If a microscope is employed as the
 imaging unit, the video unit is disposed in such a manner that it records
 the eyepiece image of the surgical microscope.
 The video unit can, in particular (at least), be provided with a CCD
 recorder. In this event, the gas discharge lamp may be a periodically
 operating flash discharge lamp which is triggered by a control and
 evaluation unit in such a manner that the flash exposure occurs solely in
 the light integration phase of the CCD recorder(s). In this way, highly
 effective illumination of the area to be examined is attained while
 reducing the application of light energy on the illumination system and on
 the surroundings, thereby also decreasing the heat respectively thermal
 load on the components.
 If visual observation of the area to be examined should occur
 simultaneously or the light power input should be increased
 simultaneously, it is advantageous if, in addition, a continuously
 operating light source is provided.
 In order to control the video signal, it is furthermore preferable if the
 video unit is provided with a variable exposure setting; in this way,
 video image superimposition can be prevented and a well-contrasted image
 is always obtained permitting good detection of the fluorescence
 radiation.
 An invented device, which possesses the aforedescribed features, permits
 visual observation of the fluorescence image by means of the naked eye or
 by means of a video unit. However, a special advantage of the invented
 device is that the image generated by it permits largely automated
 evaluation:
 For this purpose the output signal from the video unit is applied to an
 image processing system. This image processing system can execute a number
 of manipulations in the image delivered by the video unit:
 Color images can, by way of illustration, be recorded via the RGB (red,
 yellow, blue) input channels and transformed into the HSI color space:
 (H=Hue)
 (S=Saturation)
 (I=Intensity)
 In the HSI space, the "fluorescence radiation", by way of illustration,
 caused by the tumors stands out due to HSI separation.
 Furthermore, the image processing system can electronically fade out a hue
 range in the depicted color image to enhance the contrast between
 different areas. If the image processing system conducts RGB recording,
 the, by way of illustration, in addition blue and/or green channel can be
 switched on and off. This method has the advantage that switching off the
 blue and/or green channels lets the fluorescence image emerge particularly
 clearly.
 This clear emergence is intensified by the image processing system fading
 the faded out color channel shutterlike into the color image, by way of
 illustration, represented on a monitor, yielding the viewer a "striking"
 representation, which particularly simplifies detection of tumors.
 An examination procedure can occur approximately as follows:
 First the tissue area is examined visually. In other words, a physician
 observes the area illuminated with "white" light with the eyepiece of an
 endoscope respectively of a microscope or on a monitor. In order to switch
 to photodynamic diagnosis, a short pass filter and, if need be, the
 thermostable heat protection filter is swung into the illumination beam
 path by means of a foot switch or a switch on the video camera.
 Simultaneously, the green channel and/or the blue channel are periodically
 switched off. In this way, the physician sees on the monitor once only the
 fluorescence image (or the "normal" image) and then the superimposition of
 the fluorescence image with the "normal" image, which is generated by the
 light from a small area in which the transmission of the entire system is
 not equal to 0, thus either the overlapping region or the second pass
 region. Reversely, the background image (blue channel) can also be
 periodically superimposed with the fluorescence image.
 Furthermore, the imaging processing system can calculate the fluorescence
 contrast value at individual points of the image for the maximum
 fluorescence wavelength for determining possible tumors. If delta amino
 levulinic acid (ALA) is employed as the photosensibilisator, the contrast
 relationship of the wavelength of 630 nm to the intensity in the range of
 maximum 50 nm can be calculated, in which range the entire system has a
 spectral transmittance of more than 5%:
 By comparing the images recorded with and without fluorescence excitation,
 in the easiest case subtraction of the images, the image processing unit
 can determine the intensity of the fluorescence radiation and can
 calculate the contrast, thereby permitting exact localization of possible
 tumors.
 The invented device can be utilized for a great variety of medical
 examinations:
 In addition to the especially preferred use in endoscopic applications, the
 invented device can also be employed in combination with a surgical
 microscope, by way of illustration, in neurosurgery, colposcopy of
 ophthalmology.
 However, in any event, a device is yielded which possesses, in particular,
 the following advantages due to the joint observation of the illumination
 light reflected at the tissue simultaneously or alternating with the
 fluorescence light:
 Orientation also of fluorescence negative tissue is possible.
 The orientation realized according to the present invention has the
 advantage over solely white light illumination, in particular, if ALA is
 employed as the photosensibilisator that there is a strong emphasis of the
 vessel structure and clear visibility is yielded even if there is diffuse
 bleeding into the rinsing fluid.
 The threshold value function of the blue light suppresses the non-specific
 red fluorescence of the normal tissue.
 Above all, however, the detection of real fluorescence positive areas by
 means of color contrast is possible and not by means of intensity
 contrast, as would be the case if the illumination light were totally
 blocked. This simplifies, in particular, image processing!
 The color contrast obtained according to the present invention, contrary to
 intensity contrast, is independent of the observation distance and of the
 observation angle, thereby reducing the possibility of error
 substantially. Moreover, complex image processing procedures are obviated
 so that in the event of automated detection simple image processing
 procedures can be used.

DESCRIPTION OF PREFERRED EMBODIMENTS
 FIG. 1 shows schematically the design of an invented device for endoscopic
 uses. Reference number 1 stands for an endoscope which is provided in a
 known manner with a light conductor connection 2, a rod-shaped part 3,
 which can be introduced into a (not depicted) human body and an eyepiece
 4.
 The light conductor connection 2 is connected via a light conductor cable 5
 to a light source 6 which, by way of illustration, may be provided with a
 xenon discharge lamp. A light conductor 21 in the endoscope 1, which
 conductor is composed for instance of a fiber bundle, guides the light
 from the source 6 coupled into the light conductor connection 2 to the
 distal end 11 of the endoscope 1. The light leaving the distal end 11
 illuminates the to-be-examined tissue area 7.
 The light coming from the tissue area 7 enters an objective 31, only
 schematically depicted, is guided via an image transmitter 32 to the
 proximal end 12 of the endoscope 1.
 In the shown preferred embodiment, the image transmitter 32 is provided
 with a multiplicity of relay lens systems of which each executes a 1:1
 image and is composed of so-called rod lens systems. Alternatively, the
 image transmitter 32 can be provided with a fiber imaging system.
 The image of the tissue area 7 generated in the proximal image plane 13 can
 be observed through the eyepiece 4 with the eye. Alternatively or in
 addition to observation with the eye, the image can be recorded with a
 video camera 8 via a beam splitter. In the alternative shown in FIG. 1,
 the video camera 8 is directly attached to the eyepiece 4.
 In as far as the design is described in the preceding, it is known from, by
 way of illustration, an endoscope provided with a video camera from Karl
 Storz GmbH & Co, Tuttlingen, Germany. For the details of the design,
 reference is made to this manufacturer's known endoscopes.
 For conducting so-called photodynamic diagnoses, the device shown in FIG. 1
 is improved to such an extent that filter systems can be placed in the
 illumination beam path and in the observation beam path.
 For this purpose, in the preferred embodiment shown in FIG. 1, a filter
 system 9, to which the light conductor cable 5 is flanged, is attached to
 the light emergence connection 61 of light source 6. The filter system 9
 is provided with a thermostable interference filter 91 and a thermostable
 heat protection filter 92, which is essentially supposed to reduce the
 thermal load of the interference filter 91. A filter 93 is also placed
 before the video camera 8 or the eye, with which the image is to be
 visually evaluated.
 The exposure setting of the video camera 8 and the light emitted by the
 light source 6 is controlled by a control and evaluation unit 10. By way
 of illustration, the control and evaluation unit 10 can synchronize a
 flash-light source with the light integration phase of a CCD chip in the
 video camera 8. Furthermore, the control and evaluation unit 10 regulates
 the light power input emitted by the light source 6 and/or the exposure
 setting of the video camera.
 Furthermore, the output signal of the video camera 8 is applied to the
 control and evaluation unit 10. The evaluation unit can, in particular, be
 provided with an image processing system which processes the output signal
 of the video camera further in the manner described in the introduction
 and represents the image-processed output signal on a monitor. Of course,
 the output signal emitted directly by the video camera and/or the
 image-processed output signal can also be stored, e.g. by means of a video
 recorder and/or stored in an image data bank or further processed in
 another manner by means of electronic data processing.
 If a photosensibilisator is used, reflected illumination light as well as
 fluorescence light, caused by the light-induced reaction of the
 photosensibilisator in biological systems, is emitted by the tissue area
 7. In order to be able to detect the, compared to the reflected light,
 small amount of fluorescence light and, in particular, to separate it from
 "non-fluorescence light" in subsequent image processing, a suitably
 selected transmission characteristic of the illumination beam path and
 observation beam path is required. Filters 91 and 93 placed in the beam
 path serve to set the transmission characteristic during the photodynamic
 diagnosis. As the filters, by way of illustration, can be removed by being
 swung out of the beam paths, normal observation of the tissue area 7 is
 also possible without, by way of illustration, leading to color
 distortion.
 In the following, the characteristics of filters 91 and 93 for the first
 preferred embodiment of the present invention are described with reference
 to FIG. 2 for the event that delta amino levulinic acid is employed as the
 photosensiblisator. If other photosensibilisators are utilized, the filter
 characteristic has to be adapted accordingly.
 In FIG. 2a, the bold curve represents the transmission (in percent) of
 filter 91 as the function of the wavelength (in nm), thus the so-called
 net transmittance T.sub.i (.lambda.), whereas the thin curve represents
 the net transmittance T.sub.i (.lambda.) of filter 93. Furthermore, the
 fluorescence spectrum is plotted in FIG. 2a.
 FIG. 2a shows the net transmission of filter 91 at wavelengths smaller than
 approximately 440 nm is greater than 90%. At wavelengths greater than
 approximately 460 nm, transmission is less than 1%. At about 455 nm,
 transmission is 50%. Furthermore, in the preferred embodiment of an
 interference filter 91, shown in FIG. 2a, transmission occurs in the range
 between 600 and 660 nm, preferably however 720 to 780 nm, in which the
 fluorescence light occurs more intensively, is especially low and, in
 particular, less than 0.1%, preferably 0.01%. Thus, filter 91 is a short
 pass filter.
 Filter 93 has an almost opposite characteristic:
 At wavelengths between 370 and 430 nm, transmission T.sub.l (.lambda.) is
 less than 0.1% preferably even at least one magnitude less than 0.1%. At a
 wavelength of 445 nm, the transmission is 50%. At the wavelengths between
 500 and 1100, the transmission is almost 99% or more.
 The transmission curves of filters 91 and 93 intersect in the shown
 preferred embodiment approximately at transmission values of more than
 60%. However, the curves may, and in particular preferably at weak
 fluorescence, also intersect at transmission values of 25 to 30%.
 FIG. 2b shows the transmission characteristic of the entire system yielded
 by the multiplication of the curves of the individual filters 91 and 93.
 As can be seen, transmission lies above 1% only in the range between 440
 and 460 nm and attains a maximum value of approximately 50%.
 In the aforedescribed alternative, in which the curves intersect at
 transmission values from 25 to 30%, the maximum value is approximately
 12.5%. This means that only a small part of the illumination light
 reflected at the tissue area 7 "reaches" the proximal image plane 13. The
 fluorescence light generally emitted at wavelengths .lambda. between 500
 and 780 nm usually between 600 and 660 nm, reaches the image plane 13
 unimpeded, because it has to pass only the long pass filter 93 but not the
 short pass filter 91.
 Although this still permits visual observation of the tissue area 7, the
 fluorescence part of the determined light can be reliably separated from
 the reflected, short-wave light.
 The FIGS. 3a and 3b show the corresponding curves of the second preferred
 embodiment of the present invention in which filter 91 placed in the
 illumination beam path as well as filter 93 placed in the observation beam
 path have a second pass region at approximately 490 nm.+-.10 nm.
 The wavelengths given in the preceding relate to the use of delta amino
 levulinic acid as the photosensibilator. If other photosensibilisators or
 if intrinsic fluorescence is utilized, the wavelengths, at which the
 individual filters change their transmission characteristics, have to be
 adapted accordingly. However, unaltered remains essentially the property
 that both complementary filter curves intersect at a net transmittance of
 approximately 50% or less than 50% or that there is a second pass region.
 Also unaltered remains that the entire system differs distinctly from zero
 and, in particular, is greater than 1% only in a small range, usually 50
 nm if need be however more or less.
 If the invented device is to be employed for therapy, the filter system 9
 has to be provided with an additional filter which has no short pass
 characteristic but rather an intermediate pass to long pass
 characteristic.
 The preceding description of preferred embodiments, which relates to the
 use of delta amino levulinic acid as the photosensibilisator, does not
 limit the scope or spirit of the overall inventive concept described in
 the claims or in the specification.