Department of Ophthalmology
University of Helsinki
Helsinki, Finland
Digital Photography in the Diagnosis and Follow-up of Ocular Diseases
by
Jukka M. Saari
Academic Dissertation
To be publicly discussed, by permission of the Medical Faculty of the University of
Helsinki, in the Auditorium 2 of Biomedicum Helsinki, Haartmaninkatu 8, Helsinki on
November 30th, 2007 at 12 o’clock noon.
From the Department of Ophthalmology, University of Helsinki, Helsinki, Finland, and
the Department of Ophthalmology, University of Turku, Turku, Finland
Supervised by:
Professor Tero Kivelä, MD, FEBO Professor K. Matti Saari, MD, FEBO
Department of Ophthalmology Department of Ophthalmology
Helsinki University Central Hospital University of Turku
Helsinki, Finland Turku, Finland
Reviewed by:
Docent Eero Aarnisalo, MD Docent Markku Teräsvirta, MD, FEBO
Department of Ophthalmology Department of Ophthalmology
Satakunta Central Hospital Kuopio University Central Hospital
Pori, Finland Kuopio, Finland
Opponent:
Professor Hannu Uusitalo, MD
Department of Ophthalmology
University of Tampere
Tampere, Finland
Yliopistopaino 2007, Helsinki
ISBN 978-952-92-3034-1
ISBN 978-952-10-4374-1 (PDF version, available at http://ethesis.helsinki.fi)
To my parents
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ABBREVIATIONS
AMD Age-related macular degeneration
CCD Charge-coupled device
CI Confidence interval
CNV Choroidal neovascularization
COMS Collaborative Ocular Melanoma Study
CT Computed tomography
DR Diabetic retinopathy
ETDRS Early Treatment Diabetic Retinopathy Study
FAG Fluorescein angiography
HLA Human leukocyte antigen
ICD International classification of diseases
ICG Indocyanine green
IOP Intraocular pressure
IR Infrared
IRMA Intraretinal microvascular abnormalities
IRT Infrared transillumination
LBD Largest basal diameter
MA Microaneurysm
MRI Magnetic resonance imaging
NPDR Non-proliferative diabetic retinopathy
OCT Optical coherence tomography
PAD Pathologic-anatomical diagnosis
PAL Phase alternating line
PC Personal computer
PDR Proliferative diabetic retinopathy
RNFL Retinal nerve fiber layer
RPE Retinal pigment epithelium
SLO Scanning laser ophthascope
TRC Topcon retinal camera
UV Ultraviolet
VKH Vogt-Koyanagi-Harada
WHO World Health Organization
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LIST OF ORIGINAL PUBLICATIONS
This dissertation is based on the following original publications, which will be referred
to in the text by their Roman numerals I-V.
I Saari JM, Summanen P, Kivelä T, Saari KM. Sensitivity and specificity of
digital retinal images in grading diabetic retinopathy. Acta Ophthalmol Scand
2004; 82: 126-130.
II Saari JM, Kivelä T, Summanen P, Nummelin K, Saari KM. Digital imaging in
differential diagnosis of small choroidal melanoma. Graefes Arch Clin Exp
Ophthalmol. 2006; 244: 1581-1590.
III Saari JM, Nummelin K. Digital infrared transillumination imaging of iris. J
Ophthalmic Photogr 2005; 27(1): 20-24.
IV Saari JM, Nummelin K. Iris atrophy, serous detachment of the ciliary body and
ocular hypotony in chronic phase of Vogt-Koyanagi-Harada disease. Eur J
Ophthalmol 2005; 15: 277-283.
V Saari JM, Kivelä T, Summanen P, Nummelin K, Saari KM. Infrared
transillumination imaging and fluorescein angiography of iris nevus and
melanoma. J Ophthalmic Photogr 2007; 29(1): 17-20
The original publications have been reproduced with the permission of the copyright
holders.
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TABLE OF CONTENTS
ABBREVIATONS ………………………………………………………………………… 4
LIST OF ORIGINAL PUBLICATIONS………………………………………………… 5
TABLE OF CONTENTS…………………………………………………………………..6
ABSTRACT………………………………………………………………………………... 9
1. INTRODUCTION……………………………………………………………………... 11
2. REVIEW OF LITERATURE……………………………………………………….... 13
2.1 Photographic and digital imaging methods in ophthalmology……………….. 13
2.1.1 Photography of the anterior segment of the eye................................................... 13
2.1.2 Slit-lamp photography.......................................................................................... 13
2.1.3 Transpupillary transillumination photography of the eye……………………… 14
2.1.4 Transcleral transillumination photography of the iris………………………….. 14
2.1.5 Infrared photography of the iris………………………………………………… 15
2.1.6 Infrared transillumination stereophotography of the ciliary body and iris……... 16
2.1.7 Photography of the ocular fundus………………………………………………. 17
2.1.8 Monochromatic fundus photography……………………………………………19
2.1.8.1 Red-free light photography………………………………………………….. 19
2.1.8.2 Red light photography………………………………………………………. 22
2.1.9 Infrared photography of the ocular fundus……………………………………... 22
2.1.10 Fluorescein angiography……………………………………………………….. 23
2.1.10.1 Fluorescein angiography of the ocular fundus……………………………… 25
2.1.10.2 Fluorescein angiography of the iris…………………………………………..25
2.1.10.3 Anterior segment fluorescein angiography in corneal diseases……………...26
2.1.11 Digital imaging of the eye……………………………………………………… 27
2.1.12 Indocyanine green angiography…………………………………………………28
2.1.13 Scanning laser ophthalmoscopy………………………………………………... 29
2.1.14 Optical coherence tomography…………………………………………………. 30
2.1.14.1 OCT retinal imaging………………………………………………………… 31
2.1.14.2 OCT anterior segment imaging……………………………………………… 32
2.2 Teleophthalmology………………………………………………………………. 33
2.3 Grading of diabetic retinopathy………………………………………………… 34
2.4 Melanocytic tumours of the uvea……………………………………………….. 37
2.4.1 Choroidal nevus and melanoma…………………………………………………38
2.4.2 Nevus and melanoma of the iris…………………………………………………39
2.5 Vogt-Koyanagi-Harada disease………………………………………………….40
3. AIMS OF THE PRESENT STUDY…………………………………………………...43
4. MATERIALS AND METHODS………………………………………………………45
4.1 Subjects (I – V) …………………………………………………………………...45
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4.2 Diagnostic criteria (I, II, IV, V) ………………………………………………… 47
4.2.1 Diabetes (I) …………………………………………………………………….. 47
4.2.2 Grading of diabetic retinopathy (I) …………………………………………….. 47
4.2.3 Uveal melanoma (II, V) ………………………………………………………... 49
4.2.3.1 Choroidal melanoma (II) …………………………………………………….49
4.2.3.2 Iris melanoma (V) …………………………………………………………… 50
4.2.4 Uveal nevus (II, V) …………………………………………………………….. 50
4.2.4.1 Choroidal nevus (II) ………………………………………………………….50
4.2.4.2 Iris nevus (V) …………………………………………………………………51
4.2.5 Vogt-Koyanagi-Harad disease (IV) ……………………………………………. 51
4.3 Classification of iris colour (III, V) …………………………………………….. 53
4.4 Imaging methods (I – V) …………………………………………………………54
4.4.1 Digital retinal imaging (I, II, IV) ………………………………………………. 54
4.4.1.1 Digital retinal imaging in screening for DR (I) …………………………….. 54
4.4.1.2 Digital retinal imaging of choroidal melanocytic tumours (I) ……………… 55
4.4.1.3 Digital retinal imaging of the Vogt-Koyanagi-Harada patient (IV) ……….. 55
4.4.2 Colour photography of the anterior eye (III, IV, V) …………………………… 55
4.4.3 Digital transpupillary transillumination imaging of the iris (IV) ……………… 55
4.4.4 Infrared transillumination imaging of the iris and ciliary body (III, IV, V) ……56
4.4.4.1 Infrared transillumination stereophotography of the iris and ciliary
body (V) ………………………………………………………………………56
4.4.4.2 Digital infrared transillumination imaging of the iris and cialiary body
(III, IV, V) …………………………………………………………………… 56
4.4.5 Fluorescein angiography (II, IV, V) …………………………………………… 57
4.4.5.1 Fluorescein angiography of the fundus (II, IV) ……………………………... 57
4.4.5.2 Fluorescein angiography of the iris (V) …………………………………….. 59
4.5 Subtraction method to evaluate growth of choroidal melanocytic tumours
(II) ………………………………………………………………………………… 59
4.6 Data collection, enrolment and experimental protocol (I, II, V)……………… 60
4.6.1 Experimental protocol and grading of diabetic retinopathy (I) ………………... 60
4.6.2 Eligibility criteria, enrolment and experimental protocol of small choroidal
melanoma study (II) …………………………………………………………… 60
4.6.3 Evaluation of the usefulness of the subtraction method (II) …………………… 62
4.6.4 Data analysis of IRT and FAG findings of iris melanocytic tumours (V) …….. 62
4.7 Statistical methods (I, II, III, V) ………………………………………………... 63
5. RESULTS………………………………………………………………………………. 65
5.1 Sensitivity and specificity of digital retinal images in grading diabetic
retinopathy (I)……………………………………………………………………. 65
5.2 Digital imaging in differential diagnosis of small choroidal melanoma (II)…. 67
5.3 Digital infrared transillumination imaging of normal iris (III)………………. 72
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5.4 Iris atrophy, serous detachment of the ciliary body and ocular hypotony
in chronic phase of VKH disease (IV)…………………………………………... 73
5.5 Infrared transillumination imaging and fluorescein angiography of iris
nevus and melanoma (V)………………………………………………………… 75
5.5.1 Infrared transillumination imaging)……………………………………………. 75
5.5.2 Fluorescein angiographic findings)…………………………………………….. 76
6. DISCUSSION)………………………………………………………………………..... 77
6.1 Sensitivity and speficifity of digital retinal images in grading diabetic
retinopathy (I)……………………………………………………………………. 77
6.1.1 Digital red-free and colour imaging in grading diabetic retinopathy (I) …………. 77
6.1.2 The effect of the size of the imaging field in grading diabetic retinopathy (I) …... 79
6.1.3 The role of screeners in grading diabetic retinopathy…………………………….. 79
6.1.4 Screening of diabetic retinopathy…………………………………………………. 79
6.2 Digital imaging in differential diagnosis of small choroidal melanoma (II)…. 80
6.2.1 Comparative use of digital colour, red-free light and red light imaging………….. 80
6.2.2 Subtraction method………………………………………………………………...82
6.2.3 Epidemiological aspects of choroidal melanoma………………………………..... 82
6.3 Digital infrared transillumination imaging of the iris (III, IV, V)…………..... 83
6.4 Infrared transillumination findings of the iris and ciliary body in
chronic phase of Vogt-Koyanagi Harada disease (IV)………………………… 90
6.5 Infrared transillumination imaging and fluorescein angiography in
differential diagnosis of iris nevus and melanoma (V) ………………………... 93
6.6 Teleophthalmology and future directions ……………………………………... 95
7. SUMMARY AND CONCLUSIONS…………………………………………………. 97
8. ACKNOWLEDGEMENTS…………………………………………………………… 101
9. REFERENCES………………………………………………………………………… 103
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ABSTRACT
Purpose: The aim of the present study was to develop and test new digital imaging
equipment and methods for diagnosis and follow-up of ocular diseases.
Methods: The whole material comprised 398 subjects (469 examined eyes), including
241 patients with melanocytic choroidal tumours, 56 patients with melanocytic iris
tumours, 42 patients with diabetes, a 52-year old patient with chronic phase of VKH
disease, a 30-year old patient with an old blunt eye injury, and 57 normal healthy
subjects. Digital 50° (Topcon TRC 50 IA) and 45° (Canon CR6-45NM) fundus
cameras, a new handheld digital colour videocamera for eye examinations (MediTell), a
new subtraction method using the Topcon Image Net Program (Topcon corporation,
Tokyo, Japan), a new method for digital IRT imaging of the iris we developed, and
Zeiss photoslitlamp with a digital camera body were used for digital imaging.
Results: Digital 50° red-free imaging had a sensitivity of 97.7% and two-field 45° and
50° colour imaging a sensitivity of 88.9-94%. The specificity of the digital 45°-50°
imaging modalities was 98.9-100% versus the reference standard and ungradeable
images that were 1.2-1.6%. By using the handheld digital colour video camera only, the
optic disc and central fundus located inside 20° from the fovea could be recorded with a
sensitivity of 6.9% for detection of at least mild NPDR when compared with the
reference standard.
Comparative use of digital colour, red-free, and red light imaging showed 85.7%
sensitivity, 99% specificity, and 98.2 % exact agreement versus the reference standard
in differentiation of small choroidal melanoma from pseudomelanoma. The new
subtraction method showed growth in four of 94 melanocytic tumours (4.3%) during a
mean ±SD follow-up of 23 ± 11 months.
The new digital IRT imaging of the iris showed the sphincter muscle and radial
contraction folds of Schwalbe in the pupillary zone and radial structural folds of
Schwalbe and circular contraction furrows in the ciliary zone of the iris.
The 52-year-old patient with a chronic phase of VKH disease showed extensive
atrophy and occasional pigment clumps in the iris stroma, detachment of the ciliary
body with severe ocular hypotony, and shallow retinal detachment of the posterior pole
in both eyes.
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Infrared transillumination imaging and fluorescein angiographic findings of the iris
showed that IR translucence (p=0.53), complete masking of fluorescence (p=0.69),
presence of disorganized vessels (p=0.32), and fluorescein leakage (p=1.0) at the site of
the lesion did not differentiate an iris nevus from a melanoma.
Conclusions: Digital 50° red-free and two-field 50° or 45° colour imaging were
suitable for DR screening, whereas the handheld digital video camera did not fulfill the
needs of DR screening. Comparative use of digital colour, red-free and red light
imaging was a suitable method in the differentiation of small choroidal melanoma from
different pseudomelanomas. The subtraction method may reveal early growth of the
melanocytic choroidal tumours.
Digital IRT imaging may be used to study changes of the stroma and posterior
surface of the iris in various diseases of the uvea. It contributed to the revealment of iris
atrophy and serous detachment of the ciliary body with ocular hypotony together with
the shallow retinal detachment of the posterior pole as new findings of the chronic
phase of VKH disease. Infrared translucence and angiographic findings are useful in
differential diagnosis of melanocytic iris tumours, but they cannot be used to determine
if the lesion is benign or malignant.
Key words: choroid, diabetic retinopathy, digital imaging, infrared transillumination,
melanoma, nevus, ocular fundus, photography, Vogt-Koyanagi-Harada disease
Introduction
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1. INTRODUCTION
A photographic image requires light reflected from a target. The eye is in the very
surface of the body and the anterior segment of the eye is thus ready for photographic
imaging. The eye itself is a physiological “camera” of the body with a clear optic media.
Since the invention of the ophthalmoscope by Helmholtz in 1851, the unique possibility
of studying the ocular fundus in vivo has existed.101 The fundus can be photographed,
because it reflects a significant fraction of the light incident on it. The reflected light
forms an exact real image of the fundus, which can be documented on photographs. By
using monochromatic light of different wavelengths, different layers of the retina can be
photographed. The IR light penetrates the sclera and the iris, and it can be used for IR
transillumination photography of the iris and ciliary body.
Ophthalmic photography is an important part of the documentation of different
pathological conditions of the eye. The advantages of it include reliable detection and
accurate recording of different lesions and the possibility to compare the changes with
previous appearances. The colour slides and film-based photographs, however, are
difficult to manipulate, store, and transmit across telephone lines to other clinicians.
They are relatively expensive and evaluation of these images is delayed by the film
development.
The development of digital imaging technology during the course of the last ten years
has made it possible to switch to ophthalmic digital imaging. The advantages of it are
immediate observation of the recordings, replacement of a faulty image with a new one,
immediate assessment for treatment, an enlarged image of the lesion on a computer
Introduction
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monitor screen, no expenses for film developing, convenient storage of the images, easy
comparison of follow-up pictures, and faster data transfer through telemedicine. The
present investigation was initiated to develop and evaluate digital imaging methods for
the examination of eye diseases.
Review of Literature
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2. REVIEW OF LITERATURE
2.1 Photographic and digital imaging methods in ophthalmology
2.1.1 Photography of the anterior segment of the eye
The anterior segment of the eye is readily accessible for minute and delicate
examination. Straightforward photography of the external eye is useful in maintaining a
permanent record and in the assessment of small changes of a lesion. Photography of
the anterior segment of the eye was introduced by Drüner in 1900.56 Stereoscopic
cameras were brought into use by Lentz in 1924 and Drüner in 1927.57,139 Colour
photography of the anterior eye was started by Morax in 1929 and Redway in
1930.160,179 A useful instrument for the photography of the anterior segment of the eye
consisted of a simple camera mounted on standard ophthalmic equipment with a chin
and forehead-rest to immobilize the patient’s head.
2.1.2 Slit-lamp photography
Gullstrand developed the slit-lamp in 1911 and combined it with a corneal
microscope.93,94 In this system focal illumination of extreme accuracy and mobility was
combined with a binocular microscope giving an erect image with a full stereoscopic
effect. Goldmann added a joystick control for fine simultaneous adjustments of the slit-
lamp and the microscope.92 The system provided magnifications approaching those of
histology and therefore the technique was termed biomicroscopy.
The first photographic recordings of slit-lamp views were restricted to one plane and
were often not satisfactory.230 Photography of the anterior segment requires a camera
with a good depth of focus. Sysi incorporated a minute camera in one objective of the
Review of Literature
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biomicroscope.226 This allowed a high degree of accuracy in focusing. By using a
complicated apparatus Goldmann obtained pictures of a sharp optical section through
the cornea and the lens.91 Littmann’s anterior segment camera had a focal depth of
1:46.142
2.1.3 Transpupillary transillumination photography of the eye
If white light enters the eye in a parallel beam, the pupil appears luminous due to the
emerging rays of the fundus glow and it reveals lenticular opacities as well as atrophies,
and other defects of the pigment epithelium of the iris.55,72 Transpupillary
transillumination photographs may be taken by employing a camera with its focus at the
lens plane.144
2.1.4 Transcleral transillumination photography of the iris
Donaldson lead a bright light from a 600 watt-second electronic flash into the eye
through the conjunctiva and sclera by using a light pipe made of Pyrex glass. For
photographing iris translucency he used a stereoscopic anterior-segment camera and
colour film (Kodachrome II).53 Defects in the pigment epithelium showing translucency
of the iris were reported in albinism, diabetes mellitus, pigmentary glaucoma, the use of
miotics in open-angle glaucoma, pseudoexfoliation, and uveitis.54
For iris translucency photography Repo et al. lead the light from a diaprojector and
flashlight into the eye by using optical fiber with two branches at its proximal root. The
probe of the optical fiber was placed on the temporal portion of the eye as posteriorly as
possible. The photographs were recorded by using an anterior segment camera
(Topcon), attached to a biomicroscope, using black-and-white film (ASA 400).181,182,183
Review of Literature
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They reported peripheral iris transluminance in 45% of the patients with
pseudoexfoliation syndrome and capsular glaucoma and in 18% of the eyes in the
control group.183 They observed generalised transluminance of the iris in 42-45% of the
eyes of 62 unselected patients with carotid transient ischemic attacks.182 Abnormal iris
transluminance occurred also in patients with type 2 diabetes after 10 years of follow-
up, especially in those patients with severe retinopathy.239
2.1.5 Infrared photography of the iris
The range of wavelengths of the visible spectrum is from 400 nm at the blue end to 700
nm at the red end.35,40 The human eye is markedly less sensitive to light above 700 nm
wavelength, but intense light can be detected up to 780 nm, and will be perceived as red
light. The wavelength of the IR radiation is between 780 nm and 1 mm. Infrared
radiation cannot be seen like visible light. In ophthalmological literature the term IR
“light” is commonly used instead of IR radiation and we do so in this study as well. In
the same way we use here IR “transillumination” instead of IR transradiation. The
subdivisions of the IR region can vary depending on the publication. The International
Commission on Illumination (CIE) divides the IR spectrum into IR-A (780 - 1400 nm),
IR-B (1400 – 3000 nm) and IR-C (3 µm – 1 mm). IR-A is often called near-IR and IR-B
short-wavelength IR. The IR-C section has been divided sometimes as mid-wavelength
IR (3 – 8 µm), long-wavelength IR (8 – 15 µm) and far IR (15 - 1000 µm). The area of
IR-A and IR-B is sometimes referred to as reflected IR, and IR-C as thermal IR. The IR
rays used in ophthalmic photography and digital imaging are near-IR waves, which a
human being cannot feel.
Review of Literature
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Robert W. Wood published in 1910 the first IR photograph taken on experimental film
that required very long exposure time. In 1933, Dekking first published a paper on the
use of IR light in ophthalmology.45 IR photographs were taken on black and white IR
film. The IR photographs could be taken in an illuminated room when the visible light
was filtered by using a Kodak Wratten 25A filter in front of the film.71 A black room
was needed for the IR photography if a Kodak Wratten 87, 88A, or 89A filter was fitted
in front of the illuminating light.71 Due to the difference in the wave length between the
visible light and the IR light, the focusing distance of IR photography was greater than
by using the visible light. Thus the focusing was more difficult in IR photography than
in typical photography. Usually IR photography only revealed the superficial layer of
the iris and not the sharp definition of the structures. Because IR light passes easily
through the cornea, sclera, and pigment epithelium, it could be used for evaluation of
the anterior surface of the iris, presence of synechiae and the contour and size of the
pupil through the opacified cornea.71,110,150
An infrared TV camera could be used for IR photography of the iris.152 Better focusing,
the possibility of following dynamic changes of the iris and pupil and bigger primary
enlargement were benefits of this method. The equipment, however, was expensive and
resulted in a rather low sensitivity.152
2.1.6 Infrared transillumination stereophotography of the ciliary body and iris
In 1976, Saari and Nieminen described an analog IRT stereo technique for studying
deeper layers of the iris and the ciliary body.196 The photographs showed that the iris
was rather dense in children, well developed in adults and somewhat atrophic in the
elderly. On the posterior surface of the iris the radial contraction folds and the structural
Review of Literature
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folds of Schwalbe and circular contraction folds were seen; they were delicate in
children and more pronounced in adults and the elderly.199 IRT stereophotography was
used to show atrophic areas, foreign bodies, and cysts of the iris and ciliary body.196 It
showed different types of atrophic changes of the iris in Fuchs’ heterochromic cyclitis,
rheumatic iridocyclitis, and in sarcoid uveitis.121,197,200
Wilson measured the lens diameter during accommodation in a young female carrier of
ocular albinism by using retroillumination IR video photography and pixel unit
measurements. 248 He disproved the theory that the lens diameter increases in
accommodation. Roberts succeeded by using a standard digital camera modified to
detect visible and IR light, and a halogen fiberoptic light source placed against the
inferior eyelid, to demonstrate the presence of bilateral iris and ciliary body cysts in a
50-year old woman.185
2.1.7 Photography of the ocular fundus
The ophthalmoscope was introduced by Helmholtz in 1851.101 After its introduction
many improvements have been incorporated into the ophthalmoscope and innumerable
such modifications have been made by ophthalmologists and instrument makers.
Dennett introduced the electric ophthalmoscope in 1885.49 Gullstrand was the first to
construct the reflexless indirect ophthalmoscope in 1911.93
The first photograph of the human retina was taken by Jackman and Webster in 1886.
However, Nordenson in 1925 was the pioneer to develop successful photography of the
ocular fundus.165 The Nordenson camera (Zeiss) was a modification of Gullstrands
reflexless indirect ophthalmoscope, and all subsequent instruments are based on the
Review of Literature
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same general principles. The use of electronic and xenon arc flashes resulted in bright
illumination of the ocular fundus during photography.12,95 In 1955 Littman introduced a
new Zeiss fundus camera which was in general use for the next 20-25 years until the
new Japanese wide-angle cameras came into common use.143
Fundus cameras are often described by the angle of view. An angle of 30 degrees,
considered the normal angle of view, creates a film image magnified by a factor of 2.5.
A narrow-angle fundus camera has an angle of view of 20 degrees or less. Wide-angle
fundus cameras were introduced in the 1970s. They image between 45 and 140 degrees
and provide proportionately less retinal magnification.232
Both mydriatic and nonmydriatic fundus cameras require pupil dilation. Usually fundus
photography is done after pharmacologic pupil dilatation. Nonmydriatic fundus cameras
are used in a darkened room providing the natural pupil dilation. An IR light is then
used to preview the retina on a video monitor. Once the monitor’s image is focused and
aligned, a flash is fired, and the image is exposed. The nonmydriatic fundus camera was
pioneered by Canon in the late 1970s, and by the mid-1980s, Canon, Kowa, and Topcon
were marketing various models. Stereo fundus photography or any type of ocular
angiography cannot be performed with nonmydriatic cameras, as these techniques
require multiple flashes.232
Stereoscopic photography of the fundus is an old invention.153,231 Stereoscopy could
easily be attained if the camera was moved appropriately between exposures or by using
a stereo-camera fitted with appropriate prismatic devices.27,135,149,153,231
Review of Literature
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The early photographs were taken on monochrome black and white film. Mann, Von
Bahr, and Hansell and Beeson succeeded in colour photography of the eyeground by
using the Zeiss Nordenson fundus camera and Kodachrome colour film.12,95,149 Colour
photography was generally more informative than the black and white photographs
taken with white light. Photographs of the ocular fundus had a detailed exactness that
could not be equaled by any written word or free-hand reproduction.149
2.1.8 Monochromatic fundus photography
Monochromatic fundus photography is performed with the use of a narrow-band
spectral illumination of various wavelengths. Lesions on different anatomical layers in
the ocular fundus can be seen with an increased contrast when using appropriate
monochromatic illumination. The shorter waves of the spectrum allow visualization of
changes in the nerve fibre layer and sharp contours of the retinal vessels. Increasing the
wavelength of illumination increases the light penetration into the fundal layers.47,79
2.1.8.1 Red-free light photography
In 1913, Vogt was the first to observe the retina in red-free light.238 He gave a detailed
description of the RNFL. In 1956, Behrendt and Wilson introduced red-free light
photography of the ocular fundus.17 They used interference filters and black and white
film. They noticed that the RNFL was invisible in red light, but its visibility was
increased in green-blue and blue light from 549 to 477 nm though it began to disappear
at 431 nm. Blue light does not penetrate beyond the RNFL, but it is reflected from this
layer of the retina. With blue light the deeper retina is more or less invisible except for
locations where the RNFL is destroyed, which enhances the contrast between normal
Review of Literature
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and degenerated areas of RNFL.16 Several later authors confirmed the usefulness of
monochromatic red-free light photography in the visualization of the RNFL.47,79,157,234
Table 1 Percent transmittance of Kodak Wratten filters No 58 (green), 25 (red) and 87
(visibly opaque for infrared photography)62
Wavelength Percent transmittance____________________________________(nm) No 58 No 25 No 87
460 - - - 70 0.23 - - 80 1.38 - - 90 4.90 - - 500 17.7 - - 10 38.8 - - 20 52.2 - - 30 53.6 - - 40 47.6 - - 60 27.8 - - 80 9.0 - - 90 3.5 12.6 - 600 1.5 50.0 - 10 0.41 75.0 - 20 - 82.6 - 40 - 86.7 - 60 - 88.2 - 80 - 89.0 - 90 - 89.3 - 700 0.53 89.5 - 20 - 40 0.8 60 12.3 80 33.2 800 56.9 20 68.0 40 76.3 60 79.5 80 80.7 900 81.9 20 82.7 40 83.4 60 84.0 80 84.6 1000 85.3 40 86.6 80 88.1 1100 88.5
In 1972, Hoyt and Newman were the first to suggest that red-free light photography
might be useful for studying structural changes of RNFL in glaucoma in 1972.107 At
Review of Literature
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first the RNFL was photographed on black and white film usually through a Kodak
Wratten green filter No. 58 (540 nm, Table 1) using the 30° picture angle of a Zeiss
fundus camera.1 Later on a wide-angle fundus camera with its blue interference filter
(495 nm) could be used to photograph RNFL in glaucoma.2 The wide picture angle
allowed observation of the entire RNFL defect in a single picture. In older patients with
nuclear sclerosis the blue light was scattered in the anterior eye and better photographs
were achieved with longer wave-lengths (Kodak Wratten No 58, Table 1). Hemoglobin
transmits spectral red while it absorbs the green and blue-violet end of the spectrum.
Blood appears black in red-free light and the retinal vessels are sharply outlined against
a bright background.47,79,100
2.1.8.2 Red light photography
Red light photography, using a Kodak Wratten filter No 25 (Table 1) or 29, is useful for
examination of the deeper layers of the retina and choroid. Wavelengths above 580 nm
cause reduction in contrast of retinal vessels and a large increase in light penetration. It
shows the retinal arteries as light bands and the retinal veins dark.79 At 650 nm, the
largest arteries are barely visible, while the large veins can still be observed. At 600 –
650 nm it allows intense visualization of the choroidal pigment.47,79 In healing
toxoplasmic retinochoroiditis it revealed spotted accumulation of choroidal pigment at
the edges of the lesion, whereas only slight pigmentation was seen in colour
photographs.201 Red light photography revealed heavy pigmentation at the edges of an
old scar.202 With this method the choroidal vessels may be outlined as light bands
through the RPE. In choroideremia the red light photography clearly revealed the
choroidal vessels that were relatively obscured in red-free light photography.79
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In juvenile haemorrhagic maculopathy red light photography revealed depigmentation
of the RPE overlaying the choroidal lesion, and clearly demonstrated the subsequent
pigment-ring lesion and proliferation of pigment epithelium at the borders of an old
lesion, RPE degeneration in the center of it, and pigment epithelial atrophy around the
lesion.194 Red light photography is valuable in showing pigmentary changes of the
earlier stages of AMD.
2.1.9 Infrared photography of the ocular fundus
Kugelberg photographed the ocular fundus with IR rays by using the Nordenson fundus
camera.136 The filter used was Kodak Wratten 25 (Table 1) and the plates were Eastman
IR plates 1-R. Kodak Wratten filter No 25 was used over the camera lens because IR-
sensitive film and plate materials are also blue and violet sensitive.62 The pictures
showed poor contrast and details were difficult to obtain. The retinal blood vessels were
not sharply defined and normal retinal light reflexes were absent.
The IR colour photography of the ocular fundus by means of Ektachrome-IR-aerofilm
8843 was superior to IR black-and-white film because it permitted choroidal changes,
especially the choroidal tumours, to become clearly prominent.129 Kodak Ektachrome
IR colour film has three emulsion layers sensitized respectively to peak in the green, red
and infrared with a combined sensitivity spectrum of 350 to 900 nm. A yellow filter is
used on the camera to withhold the blue to which each of these layers is also sensitive.
Upon processing the resulting colour display is a modified “false-colour” rendition of
the subject (Table 2).
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Table 2. The resulting colour display of infrared colour photography of the ocular
fundus.35,40
Subject Colour
Healthy retina yellow-red
-retinal vessels pale shadows
-haemorrhages pale shadows
-exudates pale shadows
Arterial occlusion (post) cyan blue
Coloboma blue
Melanotic lesion of fundus
-retinal layer red-brown
-choroidal layer dark blue
-sclera reddish
The modified IR colour photography of the ocular fundus was popular during the first
half of the 1970s, but since then is rarely used due to difficulties in acquiring IR colour
film.
2.1.10 Fluorescein angiography
Fluorescein dye was synthesized by Adolf von Baeyer in 1871.10 Fluorescein staining
found early use in the diagnosis of various corneal disorders.28 Ehrlich revealed that
fluorescein passes through the blood-aqueous barrier and can be traced in the aqueous
humour after a subcutaneous injection in rabbits.65 Already in the early decades of the
20th century the first attempts to use fluorescein for in vivo staining of the blood vessels
of the iris and of the ocular fundus occurred.105,125 When Novotny and Alvis reported in
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1960 and 1961 that retinal vessels could be photographed after an intravenous
fluorescein injection, FAG became an important method of examination in
ophthalmology.166,167
Sodium fluorescein (C20H10Na2) is a highly watersoluble organic molecule with a
molecular weight of 376.27.164 Excitation of fluorescein occurs when it is exposed to
blue wavelengths between 465 and 490 nm, resulting in the emission of yellow-green
frequencies (520 to 530 nm).186 In the bloodstream of the ocular fundus fluorescein is
excited by a wavelength of 465 nm to the maximum excitation wavelength of 500nm,
and emits a wavelength of 525 nm.46 In practice, light energy necessary for excitation is
projected into the globe by using a blue excitation filter. The emitted light energy is
documented by using a green emission filter in front of the camera.
After intravenous injection, the fluorescein is equally distributed within 3 to 5 minutes
throughout the blood. Only 60% to 80% of sodium fluorescein is bound to plasma
proteins, particularly to albumin.22 The free dye passes readily across the capillaries and
enters the tissues. Normal retinal capillaries and RPE do not leak fluorescein whereas
loss of their integrity permits leakage of free fluorescein into the neurosensory retina.
New vessels in the retina and iris leak profusely. Most of the fluorescein is eliminated
from the bloodstream within one hour, predominantly by the kidneys.186
FAG is an excellent tool for studying the retinal circulation but it has limitations with
regard to the choroidal circulation. The blue-green fluorescein excitation wavelengths
are absorbed and scattered by RPE and macular xanthophyll, producing the “black
macula” seen in FAG. The free fluorescein leaks rapidly out of the fenestrated
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choriocapillaris, producing the diffuse background fluorescence that obscures
visualization of the deeper choroidal vessels.
2.1.10.1 Fluorescein angiography of the ocular fundus
In 1959, MacLean and Maumenee studied the human fundus by angioscopy after
intravenous injection of fluorescein.145 The development of FAG of the ocular fundus
created a revolution in the understanding and treatment of posterior segment disease.167
The classic description of “The pathogenesis of disciform detachment of the
neuroepithelium” by Gass in 1967, his stereoscopic atlas of macular diseases and its
subsequent revisions set new standards in fundus diagnosis.86,88 Several textbooks on
FAG of the ocular fundus by using film-based images for analysis of fundus disorders
gave basis for clinical research, teaching, and patient care for diabetic retinopathy,
branch vein occlusion, AMD and other retinal and choroidal
diseases.4,33,148,170,188,191,206,217,246,249 The Finnish ophthalmologists also contributed to the
FAG studies on the ocular fundus.111,113,114,137,138,173,194,195,201,235 Already in 1978 dozens
of books and thousands of articles had been written about FAG, and the technique had
become standardised and routine.103 All medical-retinal specialists and later on nearly
every ophthalmologist were able to interpret film-based FAG images as a guide for
treatment. Different applications of laser treatment have been based almost entirely on
the results of this examination technique.147
2.1.10.2 Fluorescein angiography of the iris
In 1968, Jensen and Lundbaek were the first to use fluorescein photography of the
iris.120 By using a modified fundus camera on patients with diabetes they found
fluorescein leakage from the pupillary border. This finding was corroborated by
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Baggesen in 196911 by using a modified slit-lamp camera developed by Bruun – Jensen
for iris angiography.25 Raitta and Vannas used a slit-lamp camera for iris
angiography.174 They observed vasodilatation and neovascularization of the iris after a
central retinal vein thrombosis. Vannas modified a Zeiss Opton slit-lamp for iris
angiography.233 He observed vascular proliferation and fluorescein leakage in the iris of
patients with pseudoexfoliation and capsular glaucoma. For stereoangiographies the
equipment was equipped with the necessary angle adjustment device.
In 1974, Helve and Nieminen developed the technique for simultaneous bilateral FAG
of the anterior eye.102 By using this method Saari et al. observed an ischaemic sector,
narrow radial vessels, neovascularization, and fluorescein leakage in the iris of patients
with Fuchs’s heterochromic cyclitis.198
2.1.10.3 Anterior segment fluorescein angiography in corneal diseases
The first report concerning FAG of the limbal vasculature came from Mitsui et al., who
demonstrated the vascular patterns of normal and inflamed limbus and of progressive
and regressive pannus.156 FAG of the anterior segment was used to study the corneal
vascularization in trachoma, herpes simplex keratitis, lipid keratopathy and unsuccessful
penetrating graft, and in rosacea keratitis.63,133 Saari studied the vascular changes in
inflammatory diseases of the cornea by means of anterior segment FAG.193 He observed
that simple avascular central and marginal corneal ulcers stained with fluorescein in the
late phase of angiography, progressive pannus with pronounced fluorescein leakage
occurred in chronic corneal ulcer, disciform keratitis, Mooren’s ulcer, and complicated
acute keratoconus whereas in sclerokeratouveitis and in gutter associated with
rheumatoid arthritis the corneal vessels showed less leakage.193
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2.1.11 Digital imaging of the eye
The CCD, an image sensor containing an array of light sensitive capacitors, was
invented in 1969. The CCD measures the amount of light on a certain surface area and
turns that information into electrical current.70 The signal in the current is put through
analog-to-digital conversion and thus the unique original analog image becomes a
perfectly reproducible digital image. The size of the active area, signal-to-noise ratio,
contrast resolution and spatial resolution are characteristics that are common to all
CCDs.70 The size of the active area determines how large the original image can be.
This can be modified by creating a smaller or larger array of capacitors. The signal-to-
noise ratio is a measurement of the relationship between meaningful information and
meaningless background information.204 Imperfections in the image capture system can
never be completely eliminated. The contrast resolution signifies the capability of the
system to measure different intensities of light. It can be modified e.g. by allowing the
capacitors more time to receive signals. Spatial resolution is the distance between points
of measurements and can be modified by increasing the number of capacitors in a given
area.232 Most optical systems can be modified to create a digital record by adding a
charge-coupled system and a computer to store the record.
The development of ophthalmic video digitizing systems began in the early 1980s. PAR
Microsystems (Atlanta, GA), produced in 1983, was the first marketable ophthalmic
imaging system (IS-2000) with the video images digitized to a 512 x 512 pixel
resolution.203 There were 24 ribbon cables with more than twelve hundred connections
for just the video capture and memory boards. By using this equipment the image
sharpening took 2-3 minutes and image registration took over 5 minutes. The cost of the
basic system was 150 000 US$ and the disks approximately 400 US$ each.203
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In 1987, Topcon purchased the PAR Microsystems and released the product under the
IMAGEnet name.203 In 1990, they integrated the Kodak Megaplus (Model 1.4) high
resolution video camera into their use. In 1995 Topcon brought to ophthalmic
photography the Microsoft Windowsbased software, transferring the images onto
computer networks.203
A Zeiss-adapted fundus camera using a Kodak (Rocherster, NY) digital camera was
introduced in 1988. Later Zeiss models used the Kodak DCS-100 and DCS-200 camera
digital backs.203
In ophthalmology, digital images began to supplant film in FAG during the 1990s.232
Technical development of better and cheaper electronic cameras, computers, imaging
programs, and scanners have created more opportunities for the use of digital imaging
techniques in ophthalmology.211 Currently ICG angiography and OCT are digital
imaging methods that are widely available.251
2.1.12 Indocyanine green angiography
The choroidal circulation can be studied by ICG angiography which utilizes near-IR
light wavelengths and ICG dye. Near-IR light is less absorbed than visible light by the
RPE and the macular xanthophyll. Approximately 98% of ICG dye is bound to plasma
proteins and therefore it does not leak from the choriocapillaris as sodium fluorescein
dye typically does.32 ICG is considered non-toxic. It is removed from the blood stream
by the liver within the first minutes following intravenous injection.247 ICG dye absorbs
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light in the near-IR region of the spectrum (maximum absorption at 790-805 nm). ICG
fluoresces in the near-IR region with the maximum emission occurring at 835 nm.78
The first succesfull choroidal ICG-absorption angiograms after injection of the dye into
the carotid artery of a monkey or human patients showed the choroidal veins.42,130 The
first successful choroidal ICG-absorption angiography in humans by using intravenous
injection of ICG dye and IR sensitive black and white film was reported by Flower and
Hochheimer in 1972.77 With this method the largest choroidal veins could be visualized
but the choroidal arteries and choriocapillaris could not be seen. By ICG-fluorescence
angiography both the choroidal arteries and veins could be photographed.76 On the
photographic prints the vessels appeared white and the background black.
The early clinical ICG-fluorescence angiography studies were only performed in a few
European countries.34,38,112,193 The poor sensitivity of IR film and lack of commercially
available equipment prevented widespread use of film-based ICG angiography.20
The use of improved and commercially available digital high-speed video angiography
equipment increased the interest in ICG angiography.251,252 ICG angiography was used
to study the normal choroidal circulation.75 It was especially needed for the new
treatments of AMD associated CNV, particularly occult forms, and location of feeder
vessels that carry blood to CNV membranes.82,180,251
2.1.13 Scanning laser ophthalmoscopy
In the SLO a narrow 1 mm beam of a low power laser traverses the optical axis to a
single 10 µm point of the fundus and the image is generated by scanning the retina in a
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raster fashion. The reflected light is recorded by a photodiode and the digitised image is
stored in a PC linked to a monitor.30,241, 251 Observation at a variety of wavelengths,
including the IR, is possible by changing the laser and detector.30 By using SLO the
patient can tolerate the procedure well because it does not involve bright flashes, the IR
wavelengths of the SLO can penetrate media opacities and the imaging enables better
resolution as compared to conventional cameras.30,251
In the confocal SLO a small pinhole is moved in front of the photodiode on a conjugate
plane to the retina to select light reflected from different focal planes in the retina and
reveal three dimensional aspects of structures.240 Rodenstock (Rodenstock, Ottobrunn,
Germany) provided facilities for confocal imaging, FAG and ICG angiography.
In high-speed angiography the acquisition rate is higher than one image per second, the
maximum rate at which the Xenon flash lamp in most early fundus cameras could be
fired during FAG.251 Commercially available SLO permits ICG angiography image
acquisition at rates up to 16 images per second. The main clinical application of high-
speed ICG angiography has been in identification of CNV feeder vessels.251
2.1.14 Optical coherence tomography
In 1991, Huang et al. described a new technique, OCT, for ophthalmic structural
imaging.109 OCT performs high-resolution, micron-scale, cross-sectional, or
tomographic imaging of the internal microstructure in biological tissues by measuring
the echo time delay and intensity of backscattered or backreflected light.84,99,109 OCT
enables real-time in situ imaging of the tissue structure with a resolution of 1 to 15 μm,
which is one to two orders of magnitude finer than such imaging technologies as
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ultrasound, magnetic resonance, or computer tomography. OCT can be performed
without physical contact to the eye, thereby minimizing patient discomfort during
examination.84
2.1.14.1 OCT retinal imaging
OCT has had its largest clinical impact in ophthalmology for retinal imaging. The
instrument design for OCT retinal imaging is similar to a fundus camera. A high-power
objective lens is used so that the retina is relay imaged onto an image plane inside the
instrument. A video camera enables real-time viewing of the retinal image. A standard
instrument has an ~30 degree field of view. OCT imaging can be performed at different
locations of the fundus by controlling the OCT scanning beam with a computer.207
OCT imaging of the retina is performed with IR light at an ~800 nm wavelength. The
image is displayed using a false colour or gray scale map that corresponds to detected
backscattered light levels ranging between 4x10-10 to 10-6 of the incident light.84
OCT enables cross-sectional images of the retina with micrometer-scale resolution. It
can discriminate the cross-sectional morphologic features of the fovea and optic disc,
the layered structure of the retina, such as the nerve fibre layer, ganglion cell layer, or
photoreceptors, and normal anatomic variations in retinal and retinal nerve fibre layer
thickness with 10 μm depth resolution.99 OCT was used to study different macular
diseases, including macular oedema, macular holes, central serous chorioretinopathy,
AMD and CNV, and epiretinal membranes. OCT has been used for monitoring of
glaucoma and macular oedema in diabetic retinopathy.207
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2.1.14.2 OCT anterior segment imaging
In 1994, Izatt et al. first demonstrated OCT imaging of the anterior eye.117 The axial
image resolution was 10 μm and it was first performed with IR light at an ~ 800 nm
wavelength. The image spanned a transverse dimension of 21 mm, thus allowing cross-
sectional imaging of the entire anterior chamber. It showed the curvature of the anterior
and posterior surfaces of the cornea, the depth of the anterior chamber, and a cross-
section of the iris. The iris scattered light strongly, so deeper structures were
shadowed.117
The instrument design for OCT anterior eye imaging was similar to a slit-lamp
biomicroscope. The OCT beam can be positioned and scanned under operator control so
that it generates real-time cross-sectional images of selected structures in the anterior
eye. For imaging the anterior segment, a large depth of field is required, thus the
focused spot size of the OCT beam must be large. As a result, the OCT image resolution
in the transverse direction is usually coarse. Therefore imaging of the anterior eye was
later on typically performed using 1310 nm wavelengths.172 Longer wavelengths are
scattered less and they enable deeper image penetration depths into the anterior
segment. Since these wavelengths are not visible to the operator using conventional
video cameras, a visible aiming beam is used to guide the positioning of the OCT
beam.84
The rapid popularization of corneal refractive surgery spurred investigators to apply
OCT to corneal imaging.108,131 They used high-speed imaging at 1300 nm wavelength
for corneal and anterior segment OCT. They studied the cornea after LASIK operation,
differential diagnosis of keratoconus and post-LASIK keratectasia, anterior chamber
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width and other biometric parameters, surgical results after trabeculectomy and deep
sclerectomy, and some ocular pathologies of the anterior eye.108
2.2 Teleophthalmology
Telemedicine ie. the transfer of electronic medical data from one location to the other
has existed since at least the 1960s when the National Aeronautics and Space
Administration of the United States was forced to develop methods to follow the health
of astronauts in space from the ground. In one of the earliest telemedicine projects
resulting from this pioneering work the National Aeronautics and Space Administration
collaborated with Indian Health Service of the United States government to send a
mobile health unit into the midst of the Papago tribe in Arizona USA.83 Two-way
television, radio and remote telemetry was linked to an Indian Health Service hospital
and the mobile health unit could be transported to remote areas of the reservation. The
definitive benefit of telemedicine is to bring medical services to isolated, geographically
dispersed, and physically confined persons unable to reach a physician within
reasonable time or distance.14 Technological advancements in high-resolution digital
imaging, computers, and communication networks are constantly advancing the
opportunities and improving the quality of telemedical consultations.39 Having medical
images in a digital form advances modularity which helps in the creation of
standardised tools for magnifying, analyzing, enhancing, archiving, transferring and
printing copies of the images.255
In ophthalmology diagnoses of glaucoma, diabetic retinopathy, and diseases of the
anterior segment are often based on images.254 This provides opportunities to apply
telemedicine in ophthalmology. Engagement in an efficient teleophthalmological
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program requires that the examination results be converted into a digital form and that
ophthalmoscopy and other analog examination methods be replaced or fitted with a
system that enables the examiner to capture a digital record.30,218 Telemedicine has been
used successfully in the creation of cost-effective screening methods and programs for
ophthalmological diseases.140,169
2.3 Grading of diabetic retinopathy
In 1856, Jaeger was the first to describe diabetic macular changes in the form of
yellowish spots and extravasations of the retina.118 The meaning of these findings was
controversial until it was confirmed histopathologically that diabetes was linked to
macular oedema.163 The first case of proliferative retinopathy was reported by Manz in
1876.151 When insulin treatment for diabetes became standard, the numbers of advanced
cases of DR grew quickly. Retinal photocoagulation was discovered by Meyer-
Schwickerath in 1949 and further developed in the 1950s and 1960s as a method to
prevent diabetic neovascularization.44 Simultaneously the development of FAG in the
early 1960s made new information available on the pathological processes of DR. The
Airlie House Symposium of 1968 set the stage for important developments like
photocoagulation of wide areas of the retina, defined the relevant clinical questions of
the era and created the basis for the Airlie House classification of DR.15
A number of multicenter studies such as the Diabetic Retinopathy Study and the
ETDRS report No. 10 took up the challenge of developing the standarised classification
of retinopathy suggested by the Airlie House symposium.50,61 These important
multicenter studies verified the meaningfulness of various retinal characteristics that had
been suggested to be related to diabetes.
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Fig. 1. Seven standard fields of the modified Airlie House classification (shown for a right eye). Field 1
is centered on the optic disc and field 2 on the macula. Field 3 is temporal to the center of macula. Fields
4 to 7 are tangential to horizontal lines passing through the upper and lower poles of the disc and to a
vertical line passing through its center.
The ETDRS report No. 10 established a grading procedure in which nonsimultaneous
stereoscopic pairs of seven standard fields (Fig. 1) of the retina were taken with a 30º
fundus cameras.61 Certain characteristics were graded only if they appeared in the
photographic field containing the optic disc: new vessels on or within 1 disc diameter of
the disc, dilated tips of new vessels of the disc, fibrous proliferation on or within 1 disc
diameter of the disc, plane of proliferation on or within 1 disc diameter of the disc and
papillary swelling. Characteristics that were only graded in the macular field were the
hard exudates and exudate rings, posterior vitreous detachment, retinal thickening
including the size of the thickened area and maximum thickness of the thickened area,
cystoid spaces, and clinically significant macular oedema. Other characteristics were
included when occurring in any of the photographic fields in some cases discluding the
fields 1 and or 2: microaneurysms; haemorrhages; drusen; hard exudates; soft exudates;
intraretinal microvascular abnormalities; venous abnormalities such as venous beading,
narrowing, loops, duplication, sheathing or perivenous exudates; arterial abnormalities
such as arteriolar narrowing or arteriolar sheathing; arteriovenous nicking; new vessels
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elsewhere than in the retina; dilated tips of new vessels elsewhere; fibrous proliferations
elsewhere; plane of proliferation elsewhere; preretinal haemorrhage; vitreous
haemorrhage; retinal elevation or scars of prior photocoagulation. A fourth group of
nondiabetic abnormalities were also graded when noticed: questionable abnormality,
asteroid hyalosis, central vein occlusion, branch vein occlusion, central artery occlusion,
branch artery occlusion, disciform macular degeneration, chorioretinal scar not
including photocoagulation scars, choroidal nevus, subretinal fibrous tissue, coloboma
or other or questionable abnormalities.
The grades for each feature could be converted into descriptive terms of the feature:
absent, questionable, definitely present, moderate, severe and very severe. These grades
were further summarised by noting the maximum grade for a feature in any
photographic field and the number of non-overlapping fields in which the characteristic
was present.61
The results of the ETDRS study suggested that variability in the grading process was
the smallest when grading new vessels and fibrous proliferations elsewhere than in the
retina, haemorrhages, microaneurysms, hard exudates, retinal thickening and clinically
significant macular oedema with substantial interobserver agreement.61 The study went
on to divide characteristics of retinopathy into groups according to their severity and
suggest a scale of progression of DR.43
The grading of DR is important in relation to screening for DR. WHO set the criteria for
a screenable disease in 1971: the disorder that should be screened is well defined,
knowledge is available about the prevalence and the progression of the disorder,
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effective treatment modalities exist, simple and safe screening methods are available
and the screening programme is cost effective.250 Diabetic retinopathy fulfills these
criteria and recommendations for starting screening programs were published in various
parts of Europe.122
Alternatives to the ETDRS grading protocol were devised due to the impracticality of
the original protocol in relation to its use on a large scale and the development of new
cameras with a greater than 30º photographic field. Experimenting with different
numbers and sizes of photographic fields showed that enlarging the screened area of the
retina resulted in significantly more neovascularization discovered.244 Retinal
photography has the methodological advantage of creating a document for repeated
evaluations and comparisons during follow-ups. Digital photography of the retina adds
the possibility of sending the photographs through a network to a remote location in
which experts can quickly analyse the photographs. This enables a screening
programme to reach parts of the population that were previously left unscreened.
2.4 Melanocytic tumours of the uvea
Uveal melanoma arises from neuroectodermal melanocytes within the choroid, ciliary
body or iris.6 In1905, De Schweinitz suggested that melanomas of the eye may be nevi
that have turned malignant, currently this is the opinion of most ophthalmologists.208
Uveal melanoma is the most common primary malignant neoplasm of the eye in
Caucasian adults and uveal nevus is the most common benign tumour.6,7 Uveal nevi
are usually asymptomatic whereas uveal melanomas tend to grow, invade, metastasise
to the liver and other tissues, and cause death.
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2.4.1 Choroidal nevus and melanoma
The typical melanocytic choroidal nevus is a small gray to brown tumour usually with a
bland surface appearance. The tumour may exhibit surface alterations such as drusen
and retinal pigment epithelial clumping and typically has a basal diameter smaller than
5 mm and thickness of 1 mm or less.6,7
Diagnosis and management of small choroidal melanoma remains under heavy
discussion.221 A number of benign and malignant lesions can simulate the
ophthalmoscopic appearance of choroidal melanoma.36,216 Careful repeated observations
are recommended as a method to document growth, the primary differentiating feature
of a small choroidal melanoma from a choroidal nevus. Features that have had an
association with the risk of tumour growth include the presence of drusen, orange
pigment, subretinal fluid, retinal pigment epithelium changes, juxtapapillary location
and symptoms.8,26,37,85,155,214 Malignant melanomas may occasionally be only 2 or 3 mm
in diameter showing clinical similarity to benign choroidal nevus.155, 212 Studies on
tumour doubling times have indicated that metastasis from choroidal melanoma can
occur early in the course of the disease, when the tumour is about 3 mm in basal
diameter and 1.5 mm in thickness.68
Many of the pseudomelanomas of the ocular fundus may be differentiated from
malignant melanomas on the basis of their clinical appearance, fluorescein angiographic
features, and ultrasound characteristics, but some lesions may present diagnostic
difficulty.212,213 FAG alone is not a reliable method for differentiation between choroidal
nevus and small choroidal melanoma and between neoplasms and simulating lesions of
the ocular fundus.29,87,154 In a prospective study on 51 patients with histologically
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confirmed choroidal melanomas FAG was diagnostic for melanoma in 63%, equivocal
in 6%, and nondiagnostic in 30% of all the cases.29
2.4.2 Nevus and melanoma of the iris
The typical melanocytic tumour of the iris appears as a localised melanotic stromal
lesion and may involve any portion of the iris. Typically the diameter is 3 mm or less
and thickness is 0.5 mm or less.6,7
A correlation exists between light iris colour and iris melanomas.128,187 In Finland one
out of every 20 uveal melanomas is a primary melanoma of the iris.175 Uveal melanoma
of the iris has less potential to metastasise and kill the host than melanoma of the
choroid or ciliary body due to early detection and treatment of melanomas of the
iris.6,124 Patients with malignant melanoma of the iris are on average ten to 20 years
younger than those with a similar tumour of the choroid or the ciliary body.225
Melanoma of the iris is equally probable to occur in either eye but bilateral tumours are
almost unknown. The neoplasm is more likely to occur in the lower half of the iris.
In the management of melanocytic lesions of the iris it is normal to start with periodic
observation to observe the possible enlargement of the mass.228 These tumours may ring
the iris, distort the pupil, undergo necrosis, cause secondary iritis, and increase
intraocular pressure when there is extensive angle involvement.89 They may involve
focal ectropion or pupillary peaking. If pronounced growth is noted, complete excision,
usually by a sector iridectomy is suggested.
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Fluorescein leakage has been observed at the site of iris melanomas and a number of
studies have reported disorganised leaking vessels in iris melanomas.13,31,41,48 Other
studies dispute the presence of disorganised vessels as an important characteristic in the
differential diagnosis between benign and malignant iris tumours.89,132 Neither
transpupillary nor diascleral transillumination, by using white light, has been helpful in
diagnosing iris tumours, since the pigment epithelium of the iris forms a barrier to the
transmission of visible light.7
2.5 Vogt-Koyanagi-Harada disease
Vogt in 1906 and Koyanagi in 1929 reported cases with symptoms of bilateral
nontraumatic chronic iridocyclitis associated with poliosis, alopecia, vitiligo and
dysacusis.134,237 In 1926, Harada described a variation of this syndrome consisting of
bilateral posterior uveitis with an exudative retinal detachment and pleocytosis of the
cerebrospinal fluid.96 The connection between these two forms of the disease was
suggested by Babel in 1932.9 In current literature the disease is generally known as
VKH syndrome but is sometimes referred to with other names such as
uveomeningitis.168
VKH disease generally occurs in people with a dark pigmentation such as orientals,
american indians, hispanics and blacks.81 Currently it is thought to be caused by a
T-lymphocyte mediated autoimmune reaction targeting melanocytes.90 Shindo et al.
suggested an association with HLA alleles DRB1*05 and DRB1*10.219
The American Uveitis Society established the criteria for VKH syndrome in 1978 as
follows: The presence of at least three of the following findings: bilateral iridocyclitis,
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posterior uveitis with exudative retinal detachment or sunset glow fundus, central
nervous system involvement and dermatologic manifestations such as alopecia, vitiligo
or poliosis in the absence of previous ocular trauma or surgery.80 The criteria were
revised at the First International Workshop on VKH disease in 1999, with allowance for
the different ocular findings present in the early and late stages of the disease.177
The progress of VKH disease is generally divided into four stages, a prodromal stage
consisting mainly of auditory or neurologic symptoms, an acute uveitic stage, a chronic
phase characterised by the variable development of depigmentation, and a
chronic-recurrent phase with iridocyclitis.177 An early administration of high-dose
corticosteroid treatment generally turns VKH disease quiescent but does not stop the
development of chronic-recurrent uveitis in all cases.116,189
Review of Literature
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Aims of the Present Study
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3. AIMS OF THE PRESENT STUDY
The purpose of our study was to:
1. Test the sensitivity and specificity of digital retinal images in grading DR.
2. Evaluate comparative use of digital colour, red-free, and red light imaging in the
differential diagnosis of choroidal nevus and melanoma.
3. Develop and assess digital IRT imaging of the iris.
4. Describe the changes of the iris and ciliary body in the chronic phase of VKH
disease by using digital IRT imaging.
5. Evaluate IRT imaging and FAG findings in differential diagnosis of iris nevus
and melanoma.
Aims of the Present Study
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Materials and Methods
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4. MATERIALS AND METHODS
4.1 Subjects (I – V)
Altogether the material comprised 398 subjects including 154 men and 244 women with
ages ranging between 12 and 93 years. The total number of eyes examined was 469
(Table 3).
In the study on the sensitivity and specificity of digital retinal images in grading DR (I)
we included 70 subjects, 37 men and 33 women, with an age range between 22 and 83
(mean 41.8 ± 19.1) years. Forty-two of the subjects, 28 men and 14 women were
patients with diabetes (79 examined eyes) aged between 23 and 83 (mean 53.2 ± 16.8
years). The mean duration of the disease was 19.8 ± 12.2 (range 1 – 44) years. Forty
patients had DR and 31 of them had been treated with photocoagulation (56 examined
eyes). The control group consisted of 28 healthy medical students (29 examined eyes)
with an age range between 22 and 31 (mean 24.7 ± 1.7) years.
For the study on digital imaging in differential diagnosis of small choroidal melanoma
(II) we re-evaluated the case records of 241 consecutive patients referred to the Turku
University Eye Clinic for suspected choroidal melanoma. Eighty three of the patients
were men and 158 women, with the ages ranging between 13 and 93 (mean 64 ± 14)
years. The entry criteria for the digital imaging study were digital colour, red-free and
red light imaging of the ocular fundus due to a suspected small choroidal melanoma. Of
the 241 patients, 110 (45.6%), 33 men and 77 women, with an age range between 15
and 91 (mean 66 ± 15) years, fulfilled the inclusion criteria for the digital imaging
study.
Materials and Methods
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Table 3. Number of examined subjects and eyes in different diagnostic groups
Original Diagnostic Number of Number of
publication group examined subjects examined eyes
I Diabetic 42 79 patients
Controls 28 29
Total 70 108
II Suspected 241 241 choroidal melanoma
III Normal 29 59 subjects and eyes
Blunt eye trauma 1 1
Total 30 60
IV VKH disease 1 2
V Melanocytic 56 58 tumours of iris
Total 398 469
To describe a new method for digital IRT imaging of the iris (III) we studied 30
subjects (60 examined eyes), 10 men and 20 women, with ages ranging between 22 and
30 (mean 24.3 ± 1.9) years. Twenty nine of them were healthy subjects with no known
general or eye diseases. One 30-year-old male student that was otherwise healthy had
suffered a blunt sport eye injury of the right eye at the age of 12. In biomicroscopic
examination all eyes were calm with no aqueous flare or cells, the irides showed normal
structure, and the ocular fundus was normal in all volunteers.
Materials and Methods
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To describe iris atrophy, serous detachment of the ciliary body, and ocular hypotony in
the chronic phase of VKH disease (IV) we did an ocular examination and follow-up
including digital IRT imaging of the iris and ciliary body in both eyes of a 52-year-old
woman with chronic phase of this disease.
To compare IRT imaging and FAG findings between iris nevus and melanoma (V) we
studied 56 patients, 24 men and 32 women, with an age range between 12 to 92 (mean
57) years. All of these patients had melanocytic tumours of the iris. Two patients had an
iris nevus in both eyes. Thus the material consisted of altogether 58 eyes with a
melanocytic tumour of the iris.
4.2 Diagnostic criteria (I – V)
4.2.1 Diabetes (I)
In the study on evaluation of digital fundus cameras for DR screening (I) there were 42
subjects with diabetes. Seventeen of them (40.5%) had type 1 diabetes and 25 (59.5%)
type 2 diabetes as defined by the American Diabetes Association.69
4.2.2 Grading of diabetic retinopathy (I)
The grading of DR used in this study was a modified version of the Diabetic
Retinopathy Study Report No. 8 and ETDRS Reports Nos. 7, 10 and 18 and comprised
nine diagnoses:43,50,60,61
(1) No DR. May include retinal haemorrhages, cotton wool spots and changes related to
branch vein occlusion, age-related macular degeneration, or other retinal diseases but no
MAs.
Materials and Methods
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(2) Minimal NPDR. MAs only (usually <3-5), no other changes typical of DR.
(3) Mild NPDR. MAs, mild retinal haemorrhages, hard exudates, cotton wool spots,
venous loops.
(4) Moderate NPDR. MAs, moderate retinal haemorrhages in four quadrants or severe
in one quadrant, mild IRMA in one to three quadrants or if mild IRMA in four
quadrants or if definite venous beading in one quadrant, then no other severe NPDR
changes.
(5) Severe NPDR (preproliferative). The 4-2-1 rule characterised by one of the
following: MAs and severe retinal haemorrhages in four quadrants (4/4), venous
beading in at least two quadrants (2/4), moderate to severe IRMA in at least one
quadrant; or the 2-1-4 rule characterised by at least two of the following: MAs and
severe retinal haemorrhages in at least two up to three quadrants (2-3/4), venous
beading in one quadrant (1/4), mild IRMA in all four quadrants (4/4).
(6) Proliferative DR. Definite new vessels in the retina or on the optic disk without
high-risk characteristics.
(7) High risk PDR. PDR with preretinal haemorrhage, fibrous tissue and other high risk
characteristics50
(8) Advanced diabetic eye disease. Advanced PDR including vitreous haemorrhages,
fibrous tissue, retinal detachment, rubeosis iridis.
(9) Ungradeable. Cannot grade due to inadequate digital imaging quality or obscuration
from vitreous haemorrhage or other abnormality.
Materials and Methods
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4.2.3 Uveal melanoma (II, V)
4.2.3.1 Choroidal melanoma (II)
All cases of suspected choroidal melanoma underwent a careful ophthalmological
examination, including ophthalmoscopy through a dilated pupil, photography or digital
imaging of the fundus, FAG of the fundus, and B scan ultrasonography of the suspected
lesion. The suspected choroidal melanoma appeared as a dark brown to a golden solid
tumour with prominent clumps of orange lipofuscin pigment on their surface and some
with visual symptoms and secondary nonrhegmatogenous retinal detachment.6,7
The diagnostic criteria to differentiate small choroidal melanoma from choroidal nevus
were similar to those reported by Shields et al. in 2004 by using the mnemonic
“TFSOM” (to find small ocular melanoma), where T = thickness greater than 2 mm, F =
subretinal fluid, S = symptoms, O = orange pigment and M = margin touching optic
disc.211 Choroidal melanosytic tumours that display none of these factors have a 3 %
risk of turning into melanoma at 5 years and most likely represent choroidal nevi.
Tumours that display one factor have a 38% risk of growth, and those with two or more
factors show growth in over 50% of cases.212 Presumed cases of choroidal melanoma
were referred to the Department of Ophthalmic Oncology at Helsinki University Eye
Clinic, which is the only ophthalmic oncology unit in Finland. An ophthalmic
oncologist confirmed the diagnosis of most cases of choroidal melanoma in our study.
The material of melanoma patients in the digital imaging study was limited to cases
with small choroidal melanoma. We used the COMS criteria for small-sized melanoma
with a 5-16 mm largest basal diameter and 1.0 – 2.5 mm height.220 All cases of medium-
sized and large-sized melanomas were excluded from the digital imaging study.
Materials and Methods
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Similarly, patients who had undergone treatment of the choroidal melanoma before
digital imaging of the lesion were excluded from the trial. Of the 241 patients, 110
patients (45.6%), 33 men and 77 women with ages ranging between 15 and 91 (mean 66
± 15) years, fulfilled the inclusion criteria for the digital imaging study (II).
4.2.3.2 Iris melanoma (V)
Only primary iris melanocytic tumours with more than 2/3 of the tumour occurring in
the iris were included in this study. All adenomas of the iris epithelium and melanomas
that arose in the ciliary body with secondary iris extension were excluded. Each patient
underwent a full ophthalmological examination. The follow-up period from the first to
the last ophthalmological examination varied between 1 month and 34 years (mean 6
years 11 months). The tumour was classified as a melanoma of the iris in five cases of
which four were histologically proved. The fifth melanoma patient, a 51-year old man,
had an elevated iris tumour that showed involvement of the chamber angle and growth
of the largest basal diameter from 7 mm to 10.6 mm during a 9-year follow-up, and the
tumour was clinically diagnosed as a melanoma of the iris by two ophthalmic
oncologists.
4.2.4 Uveal nevus (II,V)
Uveal nevi are benign lesions composed of atypical melanocytic cells that are benign by
histopathological criteria.7
4.2.4.1 Choroidal nevus (II)
Key features of benign choroidal nevus were gray to brown (melanotic) or tan
(amelanotic) choroidal mass usually 5 mm or less in diameter and 1 mm or less in
Materials and Methods
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thickness. Most uveal nevi were asymptomatic. They showed a bland surface
appearance with some drusen and retinal pigment epithelial alterations.7 They usually
did not show any enlargement when followed by fundus photography or digital imaging
by ultrasonography.
4.2.4.2 Iris nevus (V)
The iris nevus was a brown or fleshy iris mass usually 3 mm or less in diameter.7 In
this study in 53 eyes, the melanocytic tumour was diagnosed as an iris nevus that
appeared as a localised stromal lesion of the iris involving any portion of the iris from
the pupillary margin to the iris root. The diagnosis was based on histopathological
examination after sector iridectomy in four eyes, and in 49 eyes it was based on clinical
serial re-evaluation and the fact that the lesion did not show any growth when observed
carefully through the use of slit-lamp colour photographs during a mean follow-up of 7
years (V).
4.2.5 Vogt-Koyanagi-Harada disease (IV)
The diagnostic criteria of VKH disease used in this study were the same as reported by
the International Committee on VKH Disease Nomenclature.177 In complete VKH
disease criteria 1 to 5 must be present:
1. No history of penetrating ocular trauma or surgery preceding the initial onset of
uveitis.
2. No clinical or laboratory evidence suggestive of other ocular disease entities.
3. Bilateral ocular involvement (a or b must be met, depending on the stage of disease
when the patient is examinded)
a. Early manifestations of the disease.
Materials and Methods
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(1) Diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction,
or optic disk hyperemia), which may manifest as one of the following:
(a) Focal areas of subretinal fluid, or
(b) Bullous serous retinal detachments.
(2) With equivocal fundus findings; both of the following must be present:
(a) Focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage,
large placoid areas of hyperfluorescence, pooling within subretinal fluid, and optic
nerve head staining by FAG, and
(b) Diffuse choroidal thickening, without evidence of posterior scleritis by
ultrasonography.
b. Late manifestations of disease.
(1) History suggestive of prior presence of findings from 3a, and either both (2) and (3)
below, or multiple signs from (3):
(2) Ocular depigmentation (either of the following manifestations is sufficient):
(a) Sunset glow fundus, or
(b) Sugiura sign (perilimbal vitiligo)
(3) Other ocular signs:
(a) Nummular chorioretinal depigmented scars, or
(b) Retinal pigment epithelium clumping and/or migration, or
(c) Recurrent or chronic anterior uveitis
4. Neurological / auditory findings (may have resolved by time of examination).
a. Meningismus (malaise, fever, headache, nausea, abdominal pain, stiffness of the
neck and back, or a combination of these factors; headache alone is not sufficient to
meet definition of meningismus, however), or
b. Tinnitus, or
Materials and Methods
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c. Cerebrospinal fluid pleocytosis.
5. Integumentary finding (not preceding onset of central nervous system or ocular
disease).
a. Alopecia, or
b. Poliosis, or
c. Vitiligo.
4.3. Classification of iris colour (III, V)
The iris colour was assessed clinically and from colour photographs of both eyes. In the
study on digital IRT imaging of the iris (III) we used the five-grade classification of
Seddon et al. by using standard photographs for grading iris colour.209 In our study (III)
73.3% of eyes belonged to iris colour grade 1 of Seddon et al.209and only eight subjects
(16 eyes) showed more brown irides (Table 4).
Table 4. Classification of iris colour of 60 eyes according to standard photographs of
Seddon et al.208 (III)
Gender Classification of iris colour Total number of eyes
1 2 3 4 5
Males 16 2 2 - - 20
Females 28 2 - 6 4 40
Total 44 4 2 6 4 60
In the study on IRT imaging and FAG of iris nevus and melanoma (V) the iris colour
was graded as light when the iris was blue, gray, or green and as dark when it was hazel,
brown or dark brown. In that study (V) the iris colour was light in 56/58 eyes (96.6%)
and hazel in two eyes with an iris nevus (3.4%).
Materials and Methods
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4.4 Imaging methods (I-V)
4.4.1 Digital retinal imaging (I, II, IV)
All images were captured by a professional photographer at the Turku University Eye
Clinic. For all types of digital retinal imaging, the pupils were dilated with 0.5%
tropicamide and with 10% phenylephrine eyedrops.
4.4.1.1 Digital retinal imaging in screening for DR (I)
A Topcon TRC 50 IA fundus camera (Topcon Corporation, Tokyo, Japan) was used to
take two 50 º digital colour images (768x576 pixels) and one red-free, black and white
image (1320x1032 pixels) using the green filter supplied by the manufacturer. A Canon
CR6-45NM digital fundus camera (Canon Europe, Amstelveen, the Netherlands) was
used to take two 45 º digital colour images per eye (2160 x 1440 pixels). In the 45-50 º
images one field covered the temporal area, including the macula and disc, and the
second field covered the nasal area, including the disc. A commercial version of a new
handheld digital video camera for eye examination (MediTell, Medimaker Ltd, Ranua,
Finland) was used for digital colour imaging of the central parts of the ocular fundus
(768 x 576 pixels). Two single (still) images were taken using a white light flash for
illumination and stored on a PC. Captured JPEG images had a field area of about 20 º
and a resolution of 72 dpi.192
Digital retinal imaging was carried out on 108 eyes (generating a total of 427 images).
Of the 108 eyes, 106 underwent digital 50 º retinal colour imaging and 106 eyes
underwent red-free imaging (Topcon TRC 50 IA, 290 images); 104 eyes were imagined
under both of these imaging modalities. Digital 45 º retinal colour imaging (Canon
Materials and Methods
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CR6-45NM) was carried out on 29 eyes (54 images). The handheld digital colour video
camera (MediTell) was used for the imaging of 44 eyes (83 images).
4.4.1.2 Digital retinal imaging of choroidal melanocytic tumors (II)
A Topcon TRC 50 IA fundus camera (Topcon Corporation, Tokyo, Japan) was used to
take digital colour images (1360x1024 pixels), red-free black and white retinal images
(1320 x 1032 pixels), and red light black and white choroidal images (1320 x 1032
pixels) using the filters supplied by the manufacturer.
4.4.1.3 Digital retinal imaging of the Vogt-Koyanagi-Harada patient (IV)
A Topcon TRC 50 IA camera (Topcon Optical Co. Ltd., Japan) was used for digital 50º
colour (768 x 576 pixels), blue light, red-free, red light, and fluorescein angiography
imaging of the ocular fundus. The red-free light, monochrome, black and white images
(1320 x 1032 pixels) were taken using the green filter supplied by the manufacturer.
4.4.2 Colour photography of the anterior eye (III, IV, V)
Colour photographs of the iris were taken with a standard Zeiss stereo slit-lamp camera
(Carl Zeiss, Oberkochen, Germany) (V). Digital colour images of the anterior eye were
taken using the Zeiss photoslitlamp with a digital camera body (Kodak DCS-315) (III,
IV).
4.4.3 Digital transpupillary transillumination imaging of the iris (IV)
Digital transpupillary transillumination imaging of the iris using white light was done
using the Zeiss photo slitlamp digital camera body (Kodak DCS-315) (IV).
Materials and Methods
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4.4.4 Infrared transillumination imaging of the iris and ciliary body (III, IV, V)
For digital infrared transillumination imaging oxybuprocaine eye drops (Oftan Obucain,
Santen, Tampere, Finland) were instilled onto the eye for topical anaesthesia.
4.4.4.1 Infrared transillumination stereophotography of the iris (V)
A high-intensity light from an electronic flash unit was led through a Kodak Wratten
gelatine filter No. 87 (Eastman Kodak Company, Rochester, New York, USA) filtering
unwanted visible light and transmitting only the IR light (Fig. 2 and Table 1) via a
fibreglass optic through the lateral wall of the bulbus (Fig. 3 and 4). Stereoscopic pairs
of photographs were taken with a Zeiss cornea microscope on Kodak high speed IR
black and white film, which was sensitive to reflected radiation in the range of 700 to
900 nm.62
4.4.4.2 Digital infrared transillumination imaging of the iris and ciliary body (III,
IV, V)
The examination light from the incandescent lamp (Guerra 3746/Z 6V 30W) of the
Zeiss slitlamp was passed through a Kodak Wratten gelatine filter No. 87 transmitting
only IR light via a 190 cm long light fiber optic cable (Luxtec, West Boylston,
Massachusetts, USA) through the temporal eye wall. A Topcon retinal camera (TRC 50
IA, Topcon Corporation, Tokyo, Japan), with its indocyanine green angiography filters
in place, and focused on the iris, was used to capture the IRT images of the iris.
Materials and Methods
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Fig. 2. Transmittance curve for Kodak Wratten filter No. 87 used for infrared photography.62
4.4.5 Fluorescein angiography (II, IV, V)
For each FAG we used 0.043 ml/kg of 10% sodium fluorescein (Fluorescite 10%, Alcon
Inc, Forth Worth).
4.4.5.1 Fluorescein angiography of the fundus (II, IV)
For fundus FAG the pupils were dilated with 0.5% tropicamide and with 10%
phenylephrine eyedrops. A Topcon TRC 50 IA fundus camera (Topcon Corporation,
Tokyo, Japan) was used for digital FAG imaging of the fundus using the filters supplied
by the manufacturer.
Materials and Methods
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Fig. 3. IRT photography of the iris showing the illuminating probe on the lateral side of the bulbus
Fig. 4. IRT photography of the ciliary body and iris. Illuminating probe located posteriorly near equator
Materials and Methods
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4.4.5.2 Fluorescein angiography of the iris (V)
Fluorescein angiograms of the iris were taken of 44 eyes. In 24 eyes, the analog FAG
was done using the Zeiss biomicroscope in which a motor-driven Nikon camera (Nikon
Corporation, Kawasaki, Japan) was connected. We used a Baird Atomic interference
filter B4 (Baird Atomic, Cambridge, Massachusetts, USA) and as the barrier a Kodak
Wratten filter No. 15. In 20 eyes, a digital iris FAG was taken using the Topcon TRC 50
IA fundus camera connected to a Kodak Mega Plus digital black and white camera 1.4i
focused on the iris.
4.5 Subtraction method to evaluate growth of choroidal melanocytic tumours (II)
A pair of digital colour images from different dates was chosen and compared by using
a special built-in utility tool of the Topcon Image Net Program (Topcon Corporation,
Tokyo, Japan). This tool can be used to compare the location of the borders of the lesion
using the subtraction method. At least three points of correspondence were selected in
each image to find the relative scale. Each point was first marked on the left-side image
(taken earlier) and then on the right-side image (taken later after the the follow-up). For
maximum accuracy, the corresponding points should be as distant as possible to each
other. The border of the tumour area was drawn in the left-side image by using the
mouse whereupon the program draws the line to the corresponding anatomical location
of the fundus in the right-side image (line A). The possible growth is evident if the
lesion of the right-side image extends over the line A. The amount of growth of the
tumour is better visualised when the border of the tumour area of the right-side image is
also drawn by using the mouse, whereupon the program also draws the line to the
Materials and Methods
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corresponding anatomical location in the left-side image (line B). The area of growth is
between lines A and B.
4.6 Data collection, enrolment and experimental protocol (I, II, V)
4.6.1 Experimental protocol and grading of diabetic retiniopathy (I)
Each eye-camera combination was assigned a random code. The digital images and the
corresponding codes were sent in electronic form for assessment to three graders (A, B
and C). Thus there were altogether 1281 grading events. Two of the graders (B and C)
were ophthalmologists and one (A) was a bachelor of medicine with special training in
assessing images of DR. They were masked to all clinical and personal data of the
patients and to the grading of the other screeners.
All graders received written definitions of the stages of DR before the study began and
were asked to classify pathological findings according to this protocol. To begin with,
retinopathy of each eye was graded in a randomised and masked manner using digital
colour images and digital red-free images separately. Later we used the combined
results of the ophthalmological examination including the three-mirror lens funduscopy
and the digital colour and red-free black-and-white images of the ocular fundus as a
mixed gold standard reference against which the digital retinal colour and red-free
images were compared.
4.6.2 Eligibility criteria, enrolment and experimental protocol of small choroidal
melanoma study (II)
This study included all patients who had been referred to the Department of
Ophthalmology, Turku University Central Hospital from January 1, 1987 through
Materials and Methods
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December 31, 2003 due to a suspected choroidal melanoma. All cases with
conjunctival, iris and predominantly ciliary body tumours were excluded. The cases
were abstracted from the computerised patient file system of the Turku University
Central Hospital by using the international classification codes for the diagnosis: ICD-9
for the years 1987-1995 and ICD-10 after 1996. Since nearly all cases of suspected
choroidal melanoma in the Hospital District of Southwest Finland were referred to the
Department of Ophthalmology, Turku University Central Hospital, evaluation of the
hospital records alone gave population based figures from the incidence of choroidal
melanoma. The population in the Hospital District of Southwest Finland decreased from
469,765 in 1987 to 433,178 in 1991, and then increased to 452,444 in 2003; during the
study period the mean population was 450,468.
By using the social security numbers of the patients with suspected choroidal
melanoma, we collected all those cases that had undergone digital color, red-free and
red light imaging of the ocular fundus. A random code was assigned to each case. Based
on the digital images we determined the diagnosis for every case in a random manner
and masked for all clinical data of the patients. Later, we used the combined results of
the ophtahlmological examination and follow-up including the mydriatic three-mirror
lens funduscopy, the assessments of the digital colour, red-free and red light images,
FAG and B scan ultrasonograpgy images, and when available, the diagnosis of the
ophthalmic oncologist as a mixed gold reference standard against which the
comparative use of the digital retinal colour, red-free and red light images were
compared to determine the sensitivity and specificity of this diagnostic method for the
diagnosis of small choroidal melanoma and different pseudomelanomas.
Materials and Methods
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Visualisation of the lesion was graded in the digital images as follows: 1) the lesion was
not visualised because the examination light did not reach the lesion, or it transmitted it
without reflecting its contours; 2) the lesion was visualised; 3) the lesion was visualised
as darkly pigmented or black. We determined the distribution of different diagnostic
groups according to different combinations of grades of visualisation of the lesion when
digital colour, red-free and red light images were used.
4.6.3 Evaluation of the usefulness of the subtraction method (II)
To evaluate the usefulness of the subtraction method for demonstration of growth of the
melanocytic choroidal lesion (II), digital colour images of patients with coroidal nevus
and small choroidal melanoma were studied. The usefulness of the subtraction method
was graded as follows: 1) the subtraction method could not be used; 2) the method was
useful but did not show growth of the lesion; 3) the method was useful, showing growth
of the lesion.
4.6.4 Data analysis of infrared transillumination and fluorescein angiography
findings of iris melanocytic tumours (V)
According to the IRT, the tumour was graded as translucent, partially translucent, or
non-translucent to IR light. Fluorescein angiograms were divided into those in which
the tumour caused complete, incomplete or no masking of the iris vessels. The degree of
leakage from the tumour vessels was divided into four categories: none, early moderate,
late moderate, and late gross. The pattern of tumour vasculature was graded as normal
(geometric with vessels of small calibre) or disorganised (vessels of varying calibre)
(V).
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4.7 Statistical methods (I, II, III, V)
The statistical program used in this study was SAS® 8.2 system for Windows. All
p-values lower than 0.05 were considered statistically significant.
To assess the sensitivity and specificity of digital retinal images in grading DR (II) the
sensitivity and specificity of the findings for different digital imaging modalities were
calculated per eye. The results were given with 95% confidence intervals (95% CI). The
percentage of overcalls, undercalls, and exact agreement were examined. The chi-square
test was used to determine whether the sensitivity and specificity of different imaging
modalities differed between patients treated with photocoagulation and those not treated
with photocoagulation, and to determine whether the overcalls and undercalls differed
between colour and red-free imaging. Levels of agreement between different imaging
modalities were determined by weighed κ statistic with 95% CIs. Interpretation of κ has
been defined earlier.74
In the study on digital imaging in the differential diagnosis of small choroidal
melanoma (III) the mean annual incidence of choroidal melanoma per 100,000
population was calculated by using the corrected population statistics of the Hospital
District of Southwest Finland for the years 1987-2003.222 Sensitivity and specificity of
the findings for combined use of colour, red-free and red light images were calculated
per eye. The results were given with 95% exact confidence intervals (95% CI). The
percentage of overcalls, undercalls, and exact agreement were examined. Levels of
agreement between comparative use of colour, red-free and red light images and the
reference standard were determined by using a κ statistic with 95% CI. Interpretation of
κ-values has been defined earlier.74
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In the study on digital IRT imaging of the normal iris (IV), the effect of gender and of
the colour of the iris on the IRT findings was analysed by using the Fischer’s exact test.
To compare IRT imaging and FAG findings between iris nevus and melanoma (V)
the association between diagnosis and two ordinary scaled variables (infrared
transillumination and degree of masking in iris angiography) were analysed by an
extended Mantel-Haenszel mean score statistic.223 The relationships between the
outcome variable and other categorical variables were assessed using Fisher’s exact test.
All tests were two-tailed.
Results
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5. RESULTS
5.1 Sensitivity and specificity of digital retinal images in grading diabetic
retinopathy (I)
Digital 50° red-free imaging (Topcon TRC 50 IA) had a sensitivity of 97.7% (95%
CI 95.8 – 99.7), two-field 50° colour imaging (Topcon TRC 50 IA) a sensitivity
94.0% (95% CI 90.8 – 97.2), and two-field 45° colour imaging (Canon CR6 – 45
NM) a sensitivity of 88.9% (95% CI 82.0 – 95.8) for detection of at least mild NPDR
when compared with the reference standard. No statistically significant differences
appeared in the specificity between digital red-free (98.9%; 95%CI 96.7-100) and
colour imaging (99.0; 95%CI 96.9-100 for the Topcon TRC 50 IA and 100% for the
Canon CR6-45NM) for detection of at least mild NPDR when compared with the
reference standard.
Digital red-free imaging showed 98.1% and digital colour imaging 95.5% (Topcon
TRC 50 IA) and 89.3% (Canon CR6 – 45 NM) exact agreement for detection of at
least mild NPDR when compared with the reference standard. Digital red-free
imaging only showed 0.3% and digital colour imaging 2.6% (Topcon TRC 50 IA)
and 9.5% (Canon CR 6-45 NM) undercalls for detection of at least mild NPDR when
compared with the reference standard. In all imaging modalities and in all graders the
overcalls varied between 0% and 1.0%. Only 1.3% of digital red-free images and
1.2-1.6% of digital colour images (Topcon and Canon) were ungradeable. The
handheld digital colour video camera (MediTell) only showed 6.9%; 95%CI 2.3-
11.5 sensitivity for detection of at least mild NPDR when compared with the
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reference standard and ungradeable images represented 92.3%. A good intergrader
agreement existed between all three graders for all four imaging modalities.
Digital red-free imaging showed the best sensitivity, digital colour imaging with
Topcon TRC 50 IA the second best and with Canon CR 6-45 NM the third best
sensitivity for detection of different diagnostic groups of DR. Although the
differences in the sensitivity between these imaging modalities were not statistically
significant. In all these imaging modalities the sensitivity decreased with an increase
of the severity of DR. The sensitivity of the handheld digital colour video camera
was statistically significantly lower than those of the other digital imaging modalities
in all diagnostic groups. The specificity of digital colour and red-free imaging
modalities (Topcon and Canon) was excellent in all diagnostic groups of DR. The
specificity of the handheld digital video camera was low and showed a wide
confidence interval because the percentage of ungradeable images was over 90% in
all diagnostic groups of DR.
When comparing the Topcon TRC 50 IA digital colour and red-free imaging
modalities the three graders did altogether 318 gradings per eye for both imaging
modalities. Both imaging modalities showed a very good agreement between the
imaging modality and the reference standard. Digital colour imaging showed 41
undercalls and 30 overcalls, and digital red-free imaging 24 undercalls and 65
overcalls. These differences were statistically significant (p = 0.000082). The
differences were most pronounced when grading mild and moderate NPDR.
Microvascular changes including MAs and IRMA were more clearly visualised in
red-free images than in colour images. Direct comparison between digital colour and
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red-free imaging, however, showed a very good agreement in detecting and grading
DR (weighted kappa 0.84; 95%CI 0.80-0.88; grade “ungradeable” deleted; table not
shown).
Of the patients with DR, 31 had been treated with photocoagulation which made the
grading more difficult. No statistically significant differences, however, existed in
the sensitivity figures of different imaging modalities between the 56 eyes, which
had been treated with photocoagulation and 23 eyes without any photocoagulation
(p = 0.28).
5.2 Digital imaging in differential diagnosis of small choroidal melanoma (II)
From January 1, 1987 through December 31, 2003 altogether 241 patients were referred for
clinical evaluation because of an opthalmoscopically visible lesion suspected to be a
malignant melanoma of the choroid (Table 3). Of these, 61 (25.3%) were found to have
choroidal melanoma. The mean annual incidence of choroidal melanoma in Southwest
Finland was 0.80 per 100 000 population. Of the total number, 180 (74.7%) were diagnosed
as having various simulating lesions (Table 5). The most frequent pseudomelanomas were
choroidal melanotic and amelanotic nevi (64.7%), disciform lesions (5.4%), congenital
hypertrophy of retinal pigment epithelium (1.7%) cases, and circumscribed choroidal
haemangioma (1.3%) (Table 5).
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Table 5. Final diagnosis of 241 patients referred because of suspected choroidal melanoma.
RPE denotes retinal pigment epithelium
Diagnosis ___________Patients_________ Percent of total Number Age (mean ± SD)
Choroidal nevus 156 65 ± 14 64.7
Choroidal melanoma 61 60 ± 13 25.3
Disciform lesions 13 71 ± 11 5.4
Congenital hypertrophy of RPE 4 42 ± 24 1.7
Circumscribed choroidal 3 53 ± 8 1.3 haemangioma
Choroidal haemorrhage 2 80 ± 4 0.8
Retinochoroidal scar following 1 66 0.4 retinochoroiditis
Macroaneurysm and retinal 1 78 0.4 haemorrhage
Total 241 64 ± 14 100.0
Table 6. Patients who were eligible for the digital imaging study. RPE denotes retinal
pigment epithelium
Diagnosis ___________Patients_________ Percent of total Number Age (mean ± SD)
Melanotic choroidal nevus 72 66 ± 14 65.5
Amelanotic choroidal nevus 15 66 ± 15 13.6
Small choroidal melanoma 7 61 ± 22 6.4
Disciform lesions 11 76 ± 7 10.0
Congenital hypertrophy of RPE 3 32 ± 9 2.7
Choroidal haemorrhage 1 83 0.9
Macroaneurysm and retinal 1 78 0.9 haemorrhage
Total 110 66 ± 15 100.0
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Of the 110 patients who were eligible for the digital imaging study seven (6.4%) had small
choroidal melanoma (Table 6). The most frequent pseudomelanomas were melanotic
choroidal nevus (65.5%), amelanotic choroidal nevus (13,6%), disciform lesions (10%), and
congenital hypertrophy of the retinal pigment epithelium (2.7%) (Table 6).
Melanotic choroidal nevi were pigmented, flat, small (generally smaller than 3 to 7.5 mm at
the largest basal diameter) and mostly circular or oval lesions. Digital colour images showed
melanotic choroidal nevi as slate grey to moderately pigmented lesions in 63 (87.5%) of the
72 cases, and as heavily pigmented in nine cases (12.5%). Red-free images did not show the
melanotic choroidal nevus in 61 (85%) cases and only revealed it in 11 cases due to the rich
or intense pigmentation of the lesion (15%). Red light images revealed the melanotic
choroidal nevus as dark or black in most cases (97%), and as dark grey in the two smallest
(0.5 mm in largest basal diameter) melanotic choroidal nevi. The most popular grading
combination (82%) of a melanotic choroidal nevus in digital colour/red-free/red light images
was: the lesion was seen (2)/ lesion was not seen (1)/ lesion was seen as darkly pigmented as
black (3).
Amelanotic choroidal nevi were hypopigmented or completely nonpigmented solid lesions
replacing the normal choroid clinically. The lesions were typically circular or ovoid in basal
configuration. They appeared in the postequatorial choroid but in no case beneath the foveola.
The amelanotic areas showed early and late hyperfluorescence in fluorescein angiography.
Digital colour images revealed them as a yellowish light but some of the lesions had very
mild melanotic pigmentation along the margins or extending towards the center of the lesion.
Digital red-free images showed the lesion mostly as light areas but in three cases only due to
rich drusen-like changes overlying the lesion. Red light images revealed the lesion as light
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areas with only occasional small dark patches. In all amelanotic choroidal nevi the
combination of grades of visualization in digital colour/red-free/red light images was 2/2/2.
Seven patients had a small choroidal melanoma as a circumscribed, localised, and elevated
choroidal lesion. Six of these patients had visual symptoms due to melanotic choroidal
melanomas, which appeared in digital colour images as brown or grey lesions with clumps of
orange pigment on their surface in four patients, subretinal fluid in three, and marginal touch
of the optic disc in two patients. The tumours ranged from 5 to 14 mm at the largest basal
diameter (mean, 7.8 mm) and 1.0 to 2.4 mm in thickness (mean, 1.7 mm). Fluorescein
angiography in the tumour area of three patients showed pinpoint leaks that increased in size.
Red-free images revealed only three of the small melanotic choroidal melanomas. In all six
cases with the melanotic choroidal melanoma the lesion appeared in red light images as
darkly pigmented or black. In one of the seven patients with small choroidal melanoma,
colour images revealed amelanotic choroidal melanoma as a yellowish-white oval lesion with
some pigment clumps and 4.5 x 5.5 mm at basal diameter. The tumour was 2 mm in thickness
in B-scan ultrasonography examination. Both red-free and red light images revealed the lesion
as a light area with some black pigment clumps.
A disciform lesion was visualised in digital colour images as a yellowish-white choroidal
lesion with dark greenish ring of hyperpigmentation, or as a focal choroidal infiltrate. Red-
free images did not reveal the greenish pigment-ring lesion clearly, but showed the focal
choroidal infiltrate as a light grey or whitish area surrounded by a shallow disciform retinal
detachment. Disciform lesions were visualized in all 11 cases in digital colour and red-free
images. In six cases the disciform lesion was not clearly seen in red light images but in five
cases red light images showed degeneration of the pigment epithelium at the site of the lesion
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and in one of these cases the pigment-ring lesion as a black area. Congenital hypertrophy of
the retinal pigment epithelium appeared as a variably pigmented, well-delineated, flat lesion
in digital colour, red-free and red light images. A choroidal haemorrhage appeared in digital
colour images as localized dark red or brownish elevation, over which the retinal vessels
course. Red-free images showed the haemorrhage as black with grey or whitish patches due to
changes of the overlying retina. Red light images revealed grey and black areas in the well
delineated lesion. Absorption of the haemorrhage was seen during a follow-up of six months,
and a yellowish white atrophic scar was seen in colour images one year later.
Of the 110 eyes examined by comparative use of colour, red-free and red light imaging there
was exact agreement in 108 cases (98.2%; 95% CI 93.6 to 99.8) between the digital imaging
and the reference standard in assessment of diagnosis of cases referred due to suspected
choroidal melanoma. Digital imaging showed one undercall (0.9%) of a small (4.5 x 5.5 mm
at basal diameter and 2 mm in thickness) amelanotic choroidal melanoma as an amelanotic
choroidal nevus, and one overcall (0.9%) of a large (10 mm at largest basal diameter), heavily
pigmented peripheral melanotic choroidal nevus as a small choroidal melanoma. Digital
imaging showed 85.7% (95% CI 42.1 to 99.6) sensitivity and 99.0% (95% CI 94.7 to 99.9)
specificity in comparison with the reference standard for detection of small choroidal
melanoma from all choroidal tumors suspected to be choroidal melanoma (n = 110); and
85.7% (95% CI 42.1 to 99.6) sensitivity, 98.9% (95% CI 93.8 to 99.9) specificity, 1.1%
undercalls, and 97.9% (95% CI 92.5 to 99.7) exact agreement for detecting it from all
melanocytic choroidal tumors (n=94). Direct comparison between combined use of digital
colour, red-free and red light imaging and the reference standard showed excellent agreement
in detecting small choroidal melanoma from all suspected choroidal lesions (κ 0.847; 95% CI
0.639 to 1.0) and from all melanocytic choroidal tumors (κ 0.846; 95% CI 0.636 to 1.0).
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The usefulness of the subtraction method to reveal growth of the choroidal tumour was
evaluated in 94 cases including 78 with melanotic and 16 amelanotic choroidal tumors. In 60
cases the method could not be used because in 46 cases including 39 with melanotic nevi, 4
amelanotic nevi, and 3 melanomas the colour images of the lesion were only available from
one visit, and in 14 cases including 7 with melanotic nevi and 7 amelanotic nevi the lesion
was too diffusely bordered or peripheral. In 34 cases the subtraction method could be used
with the follow-up (time between the used earlier and later digital images) varying between 6
and 68 (mean 28 ± 19) months. In 30 cases, including 26 with melanotic nevi and 4
amelanotic nevi the subtraction method was useful but did not show growth of the lesion. Of
the seven cases with small choroidal melanomas the subtraction method could not be used in
three cases including two melanotic and one amelanotic choroidal melanoma, because the
patient was referred for treatment after the first visit. In four melanocytic choroidal tumours
the subtraction method revealed growth of the lesion during a retrospectively determined
minimum follow-up of 9 to 36 (mean 23 ± 11) months, and the diagnosis was reclassified as
choroidal melanoma.
5.3 Digital infrared transillumination imaging of normal iris (III)
In the normal iris digital IRT images showed the sphincter muscle as a dark circular band in
the pupillary zone of the iris in all eyes. The posterior surface of the iris showed the delicate
radial contraction folds of Schwalbe in the pupillary zone in 58 of the 60 examined normal
eyes (96.7%). The more prominent radial structural folds of Schwalbe were seen in the ciliary
zone in all eyes. The circular contraction furrows were seen in 55 eyes (91.7%). The anterior
iris stroma including the vessel layer and the anterior surface of the iris was poorly outlined.
In 14 eyes (23.3%) with translimbal or corneal illumination some parts of the collarette or
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radial iris vessels were seen as light bands. At the side of the illuminating probe a reflex of the
temporal equatorial border of the lens was outlined as a dark circular band in 56 eyes
(93.3 %), whereas in four eyes with translimbal or corneal illumination the equatorial border
of the lens was not discernible. Neither the gender nor the iris colour had any significant
effect on the visualisation of the iris structures and the reflex of the temporal equatorial border
of the lens with IRT imaging. If the illuminating probe was located posteriorly near the
equator, the ciliary body could also be visualised (Fig 4).
Biomicroscopy and digital colour images of the anterior eye clearly showed outlined
pigmented iris patches or iris nevi in 12 eyes (20%). These were not discernible in the infrared
transillumination images of six eyes, whereas more dense or thicker iris nevi were visualised
as dark areas in infrared transillumination images of six eyes. Infrared transillumination
images showed an iris cyst in one (1.7%) of the 60 examined normal eyes. In two eyes
(3.3%), including the right eye of the 30-year-old man with a history of a blunt eye injury 18
years earlier, the iris looked somewhat atrophic.
5.4 Iris atrophy, serous detachment of the ciliary body and ocular hypotony in
chronic phase of VKH disease (IV)
A 52-year-old woman, who had been treated for chronic bilateral uveitis with prednisolone
eye drops for two years, and operated on for complicated cataracts of both eyes one year
earlier, was referred to the Department of Ophthalmology, Turku University Central Hospital
on August 21, 2000. Visual acuity was 0.04 in the right eye and 0.6 in the left, the IOP was
0-1 mmHg in the right eye and 2-3 mmHg in the left. The iris was greyish in both eyes
showing 3+ aqueous flare and 1+ cells. Digital IRT imaging showed for both eyes small and
large patches of atrophy both in the pupillary and ciliary zones of the iris and gathering of
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pigment in the inner half of the ciliary zone, and detachment of the ciliary body. In both eyes
oedema of the optic disc and a pale fundus occurred. The macular area was oedematous,
showing chorioretinal folds. In the posterior pole between the superior and inferior temporal
vessels the sensory retina showed a shallow elevation. In the midperiphery, the fundus
showed mottled hyperpigmentation and small patches of depigmentation. Fluorescein
angiography showed chorioretinal folds in the posterior fundus, accumulation of fluorescein
in the subretinal space, some diffusely scattered dots of hyperfluorescence due to window
defects of retinal pigment epithelium, and diffuse fluorescence of the disc in the late phase.
Ultrasonography showed shallow serous detachment of the retina in the posterior pole.
Vitiligo in both forearms, upper arms, thighs, legs, and on the left wrist, sensoryneural
hearing-loss in the audiogram of both ears, pleocytosis in the cerebrospinal fluid, and the
HLA phenotypes confirmed the diagnosis of VKH disease.
The treatment was started using 80 mg prednisolone a day, topical prednisolone eye drops
every hour daily to both eyes and prednisolone ointment at night, plus scopolamin eye drops
twice daily. The eye condition did not respond to the prednisolone treatment. Cyclosporin A
with a daily dose of 250 mg (3 mg/kg) was added to the treatment and
continued for two years.
On May 16, 2002 corrected visual acuity was 0.6 in both eyes. There was 1+ aqueous flare
but no cells in both eyes. The IOP was 4 mmHg in the right eye and 5 mmHg in the left. The
iris was greyish blue in both eyes. Conventional transpupillary transillumination with white
light only showed minute patchy atrophy of the pigment epithelium in the pupillary zone.
Digital infrared transillumination imaging showed extensive atrophy of the iris stroma and
occasional small pigment clumps both in the pupillary and ciliary zones of the iris, and
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detachment of the ciliary body in both eyes. The treatment did not normalise bilateral shallow
retinal detachment of the posterior pole, serous detachment of the ciliary body, and severe
ocular hypotony.
5.5 Infrared transillumination imaging and fluorescein angiography of iris nevus
and melanoma (V)
5.5.1 Infrared transillumination imaging.
Infrared translucency (37% in iris nevi and 40% in iris melanomas) was not a differentiating
factor between an iris nevus and melanoma (p = 0.53). IRT images showed the iris nevi as
translucent and ill defined (8%), partly translucent with a lighter and darker area at the site of
the nevus (29%), or as black and mostly well delineated area not transmitting IR light (63%).
Table 7. Infrared transillumination and fluorescein angiographic findings in 58 consecutive
melanocytic iris tumours
Variable Categories Nevus Melanoma P-value (N = 53) (N = 5)
Infrared transillumination Translucent 4 (8%) 2 (40%) Partly translucent 14 (29%) 0 0.53 Opaque 31 (63%) 3 (60%) Not available 4
Masking in iris angiography None 7 (18%) 2 (40%) Incomplete 8 (20%) 0 0.69 Complete 24 (62%) 3 (60%) Not available 14
Filling pattern of tumour Normal 31 (79%) 3 (60%) Disorganised vessels 8 (21%) 2 (40%) 0.32 Not available 14
Fluorescein leakage from None 26 (67%) 3 (60%) tumour vessels Early moderate 5 (13%) 0 1.0 Late moderate 5 (13%) 0 Late gross 3 (8%) 2 (40%) Not available 14
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The iris melanoma was translucent to IR light in two cases, showing in IRT images as a light
area at the site of the tumour. In three cases the iris melanoma did not transmit IR light and it
appeared in IRT images as a black area, which extended in one case partly into the ciliary
body (Table 7).
5.5.2 Fluorescein angiographic findings
Complete masking of fluorescence (62% in iris nevi and 60% in iris melanomas, p = 0.69),
presence of disorganised vessels (21% in iris nevi and 40% in iris melanomas, p = 0.32), and
fluorescein leakage (34% in iris nevi and 40% in iris melanomas, p = 1.0) at the site of the
lesion did not differentiate an iris nevus froma a melanoma (Table 7).
Discussion
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6. DISCUSSION
6.1 Sensitivity and speficifity of digital retinal images in grading diabetic
retinopathy (I)
6.1.1 Digital red-free and colour imaging in grading diabetic retinopathy (I)
Red-free photographs showed well the superficial layers of the retina and retinal
vessels.47,79 We showed that digital red-free imaging had the best sensitivity (97,7 %;
95%CI 95.8-99.7) and specificity of 98,8%; 95%CI 96.7-100 for diagnosis of mild
NPDR. We observed that microvascular changes of DR, including MAs and IRMA,
were most clearly visualised with digital red-free imaging, which is in good agreement
with earlier observations based on red-free photographs and red-free black and white
images.100,104,243 Overcalls in the digital red-free imaging versus the reference standard
support earlier findings that red-free wide-field digital imaging was more sensitive for
DR screening than mydriatic ophthalmoscopy, the currently accepted screening method,
and more sensitive than the 35 mm colour slides.104,141
We showed that digital retinal colour imaging (Topcon TRC 50 IA and Canon CR6-
45NM) had a sensitivity of 88.9-94.0% and a specificity of 99.0-100% for diagnosis of
mild NPDR. Thus both digital colour and red-free retinal imaging surpass the criteria of
80% sensitivity and 95% specificity set for the acception of a screening method for
sight-threatening DR.24,227 Our results only showed 1.2-1.6% ungradeable digital retinal
colour images and 1.3% digital red-free images. These figures are lower
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than the 5% failure rate for any photographic method acceptance for screening of
DR.24,227 Kappa values showed very good agreement between colour and red-free
imaging.
We used single (still) images produced by a commercial version of the handheld digital
colour video camera (MediTell) in the grading of DR (I). The images were examined in
a multicenter study by three examiners in a randomised and masked manner. The
handheld digital video camera showed a sensitivity of 6.9% (95% CI 2.3 – 11.5) and
ungradeable images represented 92.3 % (I). The quality of the single (still) images of
the ocular fundus produced by the handheld video camera (MediTell) (I) was worse
than that of the continuous fundus colour videophotography. 192 Still images were
obscure and showed only occasionally haemorrhages and hard exudates, but could not
demonstrate MAs, IRMA or neovascularization. This can be explained by the fact that
although the pixel count reflecting the resolution of the system was better in MediTell
(768 x 576 pixels) than that of most basic video systems, it was only slightly more than
one-third of the digital Canon CR 6-45NM fundus camera (2160 x 1440 pixels).203
Furthermore, the imaging field of MediTell was about three disc diameters (15º) and
imaging was possible only at about 20º peripheral to the fovea. These attributes explain
the high percentage of ungradeable images and the low sensitivity of MediTell for
detection of at least mild NPDR. These figures do not reach the criteria for DR
screening.24,227 Similarly, in an earlier study, the handheld Nidek NM-100 fundus
camera was not suitable for diagnosis of DR.253 The MediTell camera should be further
developed by improving the focusing qualities, use of a head-rest, increasing the
imaging field, and by providing the possibility of red-free imaging.
Discussion
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6.1.2 The effect of the size of the imaging field in grading diabetic retinopathy (I)
The size of the imaging field had an effect on the sensitivity of the imaging modality.
The digital retinal colour and red-free imaging with the 50º field Topcon TRC 50 IA
camera showed the best sensitivity followed by the 45º field Canon CR6-45NM camera.
The sensitivity was significantly worse when using the 15º field MediTell camera which
made digital imaging possible at only about 20º from the central fundus but the poor
sensitivity and specificity reflected not only the size of the imaging field but also the
camera’s inferior picture quality. An earlier study reported that in photographic
screening a wide field is of benefit in detection of neovascularization.245 Two-field 45º
photography disclosed 77% of neovascularizations detected by two-field 60º
photography.244
6.1.3 The role of screeners in grading diabetic retinopathy
Ideally, screening of DR should be done by a dedicated ophthalmologist.184 We found
no significant differences in the sensitivity figures of different imaging modalities for
screening DR between the specially trained bachelor of medicine and the
ophthalmologists. Similarly, in two earlier studies the quality of the screening results
was not related to the medical specialty of the screeners.104,140 These results support the
suggestion that other health care providers can screen,provided that they are thoroughly
trained and may have a dedicated ophthalmologist as consultant.184
6.1.4 Screening of diabetic retinopathy
It is important to establish effective screening programs for detection of DR, which in
its early easily treatable form is asymptomatic and is a common cause of preventable
blindness.140,224 A general consensus exists concerning the cost-effectiveness of
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screening DR.21,119,140,224 Our results (I) showed that digital red-free and colour imaging
of the fundus provided sensitivity, specificity, and exact agreement good enough to be
recommended for screening of DR. They also support earlier findings that in
photographic screening a wide field is also of benefit in detection of PDR.224,242,244,245
Photography allows conservation of resources when a population is screened for DR
instead of forcing an ophthalmologist to check the eyes of every patient with a
biomicroscope, he can just examine photographs taken by a specially trained nurse.
Digital imaging allows immediate, magnified images that can easily be analysed,
enhanced, archived, printed or transferred to remote computers thus allowing
telemedicine and telecare of DR.140
6.2 Digital imaging in differential diagnosis of small choroidal melanoma (III)
6.2.1 Comparative use of digital colour, red-free light and red light imaging
Comparative use of digital colour, red-free, and red light imaging had a 85.7% (95% CI
42.1 - 99.6) sensitivity and 99.0% (95%CI 94.7 - 99.9) specificity for diagnosis of
choroidal melanoma. It surpasses the 80% sensitivity and 95% specificity levels
considered acceptable for a photography screening method for sight-threatening eye
disease.226 No (0%) ungradeable digital images occurred which is lower than the 5%
failure rate considered acceptable for any photographic method for screening of the eye
disease.226 We found a 98.2% (95% CI 93.6 - 99.8) exact agreement between the use of
digital images and the reference standard in differentiation of small choroidal melanoma
from pseudomelanomas. Direct comparison between the use of digital images and the
reference standard showed excellent agreement in detecting choroidal melanoma from
suspect choroidal lesions (κ 0.847; 95%CI 0.639 - 1.0).
Discussion
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The clinical diagnosis of choroidal melanoma by an ophthalmic oncologist is accurate
in over 98% of instances when the tumour size is medium or large, and the COMS
misdiagnosis rate of 0.48% for medium and large-sized choroidal melanomas is the
lowest ever reported.36 Digital colour images may be regarded as a surrogate for
ophthalmic physical examination by fundus biomicroscopy. Together with the red-free
retinal imaging and the red light choroidal imaging it yielded a high diagnostic accuracy
including 85.7% sensitivity, 99.0% specificity, and 98.2% exact agreement versus
reference standard in diagnosing small choroidal melanoma and different
pseudomelanomas.
We found that one undercall and one overcall in the use of digital imaging versus
reference standard in the diagnosis of choroidal nevus and melanoma indicates that by
using digital images only it is difficult to differentiate between a suspicious choroidal
nevus and a small choroidal melanoma always correctly. Standard clinical information,
including demographic data, medical history, presenting symptoms, mydriatic contact
lens funduscopy, comparative use of digital colour, red-free, and red light imaging,
FAG, B scan ultrasonography and if needed, ICG angiography, and orbital CT scan and
MRI yield a higher diagnostic accuracy than the digital colour, red-free, and red light
imaging alone. Digital non-stereo imaging of the ocular fundus only gives
two-dimensional images of the lesion. Ultrasonography is a particularly useful clinical
method giving accurate measures of the thickness of the lesion. In addition, scanning
laser ophthalmoscopical ICG angiography, OCT, and diagnostic transvitreal fine-needle
aspiration biopsy may have value for special questions in the evaluation of small
choroidal tumours in departments of ophthalmic oncology.3,5,161 Digital images can be
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delivered for diagnostic purposes not only via the image net to different departments of
the same eye center but can be transmitted by electronic mail via the Internet to distant
experts of ocular oncology for second opinion of the fundus lesion.
6.2.2 Subtraction method
Suspicious choroidal nevi require follow-up to detect growth and to clinically verify the
diagnosis of choroidal melanoma.26 When growth is documented, treatment is generally
recommended although documented growth is not an unequivocal indicator of
melanoma for small melanocytic tumours.5,66,146 We described a new subtraction
method to demonstrate early growth of the melanotic choroidal tumour (III). Four
melanocytic choroidal tumours (4.3 % of all 94 melanocytic choroidal tumors, and 11.8
% of those studied by subtraction method) showed growth during a minimum follow-up
of 9 to 36 (mean 23 ± 11) months. This finding is in good agreement with an earlier
study showing growth in 4.5% of choroidal nevi, 14.2% of suspicious nevi, 50.1% of
dormant melanomas, and 86.1% of active melanomas during 5 years of follow-up.8
Because there were also 5.8 to 16% metastatic and death rates for patients with growing
small choroidal melanomas during a 5-year follow-up, a need for early diagnosis and
treatment of those tumours exists.26,51,67,68 The subtraction method we described may be
a valuable adjunct to comprehensive physical examination for early diagnosis of small
choroidal melanoma in cases which are situated in the area of fundus which can be seen
in digital images.
6.2.3 Epidemiological aspects of choroidal melanoma
We found a mean annual incidence of choroidal melanoma of 0.80 per 100,000
population in the Hospital District of Southwest Finland during 1987-2003. This is in
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good agreement with the incidence of uveal melanoma varying from 0.6 to 1.2 per
100,000 population during 1960-1998 in Sweden.19 The annual number of new cases of
uveal melanoma has showed a slight increase with time, which may be accounted for by
the increase in the old age groups of the population.175 Because the incidence of uveal
melanoma is low, it is not feasible to mass screen even the age group which would be at
highest risk of developing it.64 As a rare disease, a small choroidal melanoma may
remain unnoticed, and in the office of a general ophthalmologist the misdiagnosis rate
of ocular melanoma was 29% in Finland and 37% in San Francisco, California.23,68 On
the other hand, in our study 75% of the patients referred to a tertiary center with the
diagnosis of choroidal melanoma proved to have a pseudomelanoma. The results
suggest that in the remitting eye centers combined use of digital colour, red-free, and
red light imaging of the ocular fundus may help in the diagnosis and differential
diagnosis of small choroidal melanoma. It is an easy, rapid and useful method for the
diagnosis, differential diagnosis, and follow-up of choroidal melanocytic tumors in
every eye center with a digital imaging system.
6.3 Digital infrared transillumination imaging of the iris (III, IV, V)
Progress from the analog stereophotography of the anterior eye to digital imaging
suggested the development of a new method for digital IRT imaging of the iris. In our
study the illumination taken from the Zeiss slitlamp 6V 30W incandescent lamp was
guided through a Kodak Wratten filter 87 transmitting only IR light (Table 1, Fig. 2). In
the 1.9 m long light fiber optic cable the attenuation was only about 0.008-0.04 dB,
because in modern optic fibers the attenuations is 4-20dB/km.98
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A major part of the optical radiation is backscattered by the sclera which accounts for
the white colour of the sclera.73 The strong light scattering within the sclera is mainly
caused by the heterogenous distribution and the variable diameter of the collagen
fibrils.73,106 Another reason is the difference of the refractive indices between the
collagen fibrils (n=1.47) and the ground substance surrounding the fibrils (n=1.36).73
Fine at al. observed that 0.07 – 0.09 of the 632 nm light was transmitted by the sclera.73
With increasing wavelength the scattering in scleral tissue and its optical density
became weaker (Fig. 5).73 Vogel et al. observed that the scleral transmission was only
6% at 442 nm but increased to 35% at 804 nm and to 53% at 1064 nm. 236 Thus, in OCT
anterior segment imaging the IR light of 830 nm showed limited penetration depth
through the highly backscattering sclera, but the 1310 nm IR light was useful in
reducing backscattering of the sclera and in improving imaging of the iris and ciliary
body.106
Fig. 5. Dependence of relative optical density of sclera on the wavelength of the incident radiation.
Experimental results of three different sclera (A, B, C).73
Discussion
- 85 -
Fig. 6. Measured refractive index vs. wavelength and dispersion curves for human aqueous and vitreous
humor.205
Vogel et al. observed that the scleral absorption was 40% at 442 nm but only 6% at 804
nm and 1064 nm. 236 Fiber contact increases transmission, with a factor of 3.5 at 442
nm, of 2.0 at 804 nm, and 1.5 at 1064 nm.236 The biological tissue effect of the laser
light depends not only on the total transmission of the sclera, but also on the directional
distribution of the transmitted light. 236 The pigment epithelium of the ciliary body and
choroid drastically reduces the red light transmitted by the sclera.73 The penetration of
the sclera by red light and IR rays has been used in the transcleral
cyclophotocoagulation treatment of uncontrolled glaucoma.127,176 The IR Nd:YAG laser
is most widely used for this purpose. Transcleral red-laser cyclophotocoagulation
Discussion
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combined with either 647 nm krypton or a 670 nm diode laser may also be used
although they penetrate the sclera less well than the IR Nd:YAG laser but are better
absorbed by the pigment epithelium in the ciliary body.127,176
Sardar et al. studied the optical properties of human aqueous humor and vitreous.205 The
measured refractive indices at different wavelengths and dispersion curves are shown in
Fig. 6. Table 8 shows their results on measured diffuse reflectance, total transmittance
and index of refraction values for human aqueous humor and vitreous at 980 nm and
1310 nm.
Table 8. Measured diffuse reflectance (DR), total transmittance (TT) and index of
refraction (n) of human aqueous humor and and vitreous at 980 nm and 1310 nm.18
Wavelength (nm) Sample DR TT n
980 Aqueous 0.0041 0.8416 1.33 humor
980 Vitreous 0.0030 0.8266 1.34
1310 Aqueous 0.0038 0.7671 1.34 humor
1310 Vitreous 0.0018 0.668 1.34
Berg and Spekreijse studied the near IR light absorption in the human eye media and
represented for cornea, aqueous, lens and vitreous the transmittance spectra replotted
here from literature (Fig 7).18 They concluded that in the near IR region the light losses
in the eye media are best estimated with the absorption coefficient for pure water.18
Discussion
- 87 -
Fig. 7. Transmittance spectra for the eye media replotted from literature.18
Our digital IRT findings are in good agreement with the above transmittance and
absorption calculations. In the clinical digital IRT images of the iris the IR light coming
through the pupil appeared somewhat weaker than that going through the sclera (Fig. 3
and 4 pg 56).
The digital IRT imaging of the iris showed the stroma and posterior surface of the iris
including the sphincter muscle and the radial contraction folds of Schwalbe in the
pupillary zone, and the radial structural folds of Schwalbe in the ciliary zone in the same
way as with the IRT stereophotography of the iris.195,198 The in vivo findings of the
structural pattern of the posterior iris surface we observed are in good agreement with
those observed with light and scanning electron microscopical examinations.52,58
Discussion
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Circular contraction furrows were somewhat better seen in IRT stereophotographs than
in the digital IRT images of the iris.199 On the other hand, digital IRT images showed
the reflex of the temporal equatorial border of the lens in 93% of the eyes, whereas this
finding was not reported in IRT stereophotographs.199 These differences may be
explained on the basis that infrared transillumination stereophotographs were taken with
a standard Zeiss stereo slit-lamp, camera whereas digital IRT images were taken with a
digital Topcon retinal camera.
Digital colour imaging showed the anterior surface of the iris and the IRT imaging the
structural pattern of the stroma and posterior surface of the iris. The iris nevi seen in
colour photographs were not clearly discernible in IRT stereophotographs but a thick,
elevated pigmented patch did not transmit infrared light.199 Similarly, we saw more
dense or thicker nevi as dark areas in digital IRT images of the iris.
The Finns are one of the fairest populations in the world. In our study, 73.3% of the
eyes were classified to grade 1 and 16 eyes were classified to grades 2-5 of Seddon et
al.209 The results of this study showed that neither the colour of the iris nor gender had
any significant effect on the visualization of the structures of the stroma and posterior
surface of the iris or the temporal equatorial border of the lens in digital IRT images of
the iris.
Digital IRT imaging is convenient for the patient, easy to repeat, and it does not require
any stain injection or darkening of the examination room. Digital imaging systems
provide immediate, magnified images that can easily be analysed, enhanced, archived,
printed or transferred electronically to remote computers. Adaptation of the light and
Discussion
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contrast of the digital images of the iris helped to visualise different changes of the iris
structure and pigmentation. Because no film was used, small foreign bodies and other
artefacts of the film development stage were avoided.
By using the transcleral transillumination with bright light the photographs of the iris
showed widespread pseudoluminance of the exceptionally fair normal iris and
generalised the peripheral iris transluminance in 45% of eyes with pseudoexfoliation
syndrome and in 18% of the eyes in the control group (p < 0.01). All the eyes in that
study were blue to bluish-gray in colour.183 In transcleral transillumination photography
the very bright white light directed through the temporal sclera as posteriorly as possible
may cause greater translucency of the iris than the reflection of the light beam of the
slit-lamp in the transpupillary transillumination of the iris. We found that (III-V) digital
IRT imaging of the iris showed the structural changes of the posterior surface and
stroma of the iris more evenly and clearly and the iris colour did not have any
significant effect on the visualization of the iris structures with IRT images. Different
findings in the transcleral transillumination photography of the iris and digital IRT
imaging of the iris depend on the different wavelengths used. Transcleral
transillumination photography registered the atrophic areas of the iris seen by using
visible light and ASA 400 film, where the panchromatic emulsion was not sensitive to
radiation beyond the visible red, or about 700 nm.62 In the digital IRT imaging we used
the Kodak Wratten filter 87 cutting away all radiation below 740 nm (Fig. 2 pg 55).
Anterior segment OCT may be used to study cross-sections of the iris. It is comfortable
for the patient due to its noncontact nature. The IRT imaging of the iris shows changes
Discussion
- 90 -
of the posterior surface and stroma of the whole iris. Thus, digital IRT imaging of the
iris and anterior segment OCT may be used to supplement each other.
6.4 Infrared transillumination findings of the iris and ciliary body in chronic
phase of Vogt-Koyanagi Harada disease (IV)
We showed the usefulness of digital IRT imaging for examination of the iris and ciliary
body in VKH disease. In the chronic phase of VKH disease both biomicroscopy and
conventional digital colour imaging showed the iris rather normal and the conventional
transpupillary transillumination technique by using the white light only showed minute
patches of atrophy of the pigment epithelium in the pupillary zone of the iris even four
years after beginning of the uveitic phase. Using IRT imaging two years after the
beginning of the uveitic phase of VKH disease we showed small and large patches of
iris atrophy in the pupillary and ciliary zones in both eyes, and a large gathering of
pigment to the inner half of the ciliary zone. A further two years later in the chronic
phase of VKH disease an extensive atrophy of the iris stroma existed, but most of the
pigment gathering had disappeared, and only small pigment clumps were seen in the
pupillary and ciliary zones of the iris in both eyes. In addition, IRT images showed
detachment of the ciliary body in both eyes. In the iris stroma IRT imaging reveals the
nodules and atrophic patches more clearly than other clinical methods. Thus, it can be
used in the diagnosis and follow-up not only in VKH disease, but also e.g. in sarcoid
uveitis and in Fuchs’ heterochromic cyclitis.121,200
The present case helps us to understand the morphological changes of the iris stroma in
VKH disease. In the uveitic phase the iris is thickened by diffuse infiltration of
lymphocytes, macrophages, and epitheloid cells.115,168 Iris nodules may be noted on the
Discussion
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pupillary margin, as well as in the iris stroma in 5 % of the cases in the uveitic phase
and in 29 % of the cases in the chronic phase of VKH disease.168,189 These nodules
transmit IR light and may be seen in the uveitic phase as round light patches in IRT
images of the iris in the same manner as reported in sarcoid uveitis.121 In our study, two
years after the beginning of the uveitic phase of VKH disease, the nodules had become
atrophic and appeared as small and large patches of atrophy in IRT images. Melanocyte
destruction was seen as a large gathering of pigment in the inner half of the ciliary zone.
Two years later in the chronic phase of VKH disease, the iris showed extensive atrophy
and only occasional small pigment clumps. The chronic phase of VKH disease has been
characterised by the depigmentation of the fundus (sunset glow fundus) and limbus
(Sugiura sign).116,178 The Sugiura sign does not occur in caucasian patients with VKH
disease.168,189 We suggest that characteristic findings of the chronic phase of VKH
disease may together with the sunset glow fundus also include the depigmentation and
atrophy of the iris stroma.
Cataracts may develop in 10.5-40 % of patients with VKH disease.158,159,178,189 In VKH
disease a cataract operation can be recommended only in eyes where the inflammation
has been controlled for at least two to three months with high dose systemic
corticosteroids.159 The present case had already developed cataract two years prior, and
was operated on in a private eye center during the active uveitic phase without any
preoperative control of inflammation one year before admittance to the Turku
University Central Hospital. In Finland VKH disease is very rare and only one case has
previously been reported.171,195
Discussion
- 92 -
Glaucoma may occur in VKH disease in 6-45 % of the cases.81,159,178,189 Of these 56 %
had open angle glaucoma and 44 % angle closure glaucoma.81 On the other hand, severe
inflammation of the anterior uvea may cause oedema of the ciliary body and swelling of
the ciliary processes early in VKH disease, and may occasionally lead to transient
hypotony in the uveitic phase of the disease.126,168 We are not, however, aware of any
reported cases of chronic hypotony in VKH disease. Our patient already had bilateral
hypotony before the cataract surgery and over one year before the peroral corticosteroid
and cyclosporine treatment was started. Ultrasound biomicroscopy showed in the
uveitic phase of VKH disease, the transient accumulation of exudation between the
ciliary body and sclera.123 After treatment with systemic corticosteroids, the supraciliary
exudation disappears. If steroid therapy is stopped too soon, recurrence or progression
of disease may ensue and ciliochoroidal detachments may persist.162 The present patient
remained without any systemic corticosteroid treatment for two years after the
beginning of the uveitic phase of the disease. In addition, during this time she
underwent cataract extraction and intraocular lens implantation in both eyes which may
have further deteriorated the situation. The IRT images showed a persistent detachment
of the ciliary body in both eyes two and four years after the beginning of the uveitic
phase. Atrophy of the ciliary processes and cyclitis as part of the severe chronic anterior
uveitis,115 and detachment of the ciliary body may explain the ocular hypotony in this
case. Future studies with larger material may confirm the findings seen in our case.
Evaluation of the ocular fundus of our patient with chronic VKH disease showed
macular oedema and subtle chorioretinal folds in the posterior pole, and patches of
depigmentation and mottled hyperpigmentation causing a “blond” sunset glow
fundus.168 Macular oedema has been reported in eyes with a more protracted chronic
Discussion
- 93 -
VKH disease.190 In our case with aggressive therapy for two years the shallow
detachment of the macular area did not reattach. Obviously poor function of the pigment
epithelium, chorioretinal folds, and ocular hypotony precluded normal reattachment of
the sensory retina in the posterior pole.
In VKH disease it is important to suppress the initial intraocular inflammation with
early and aggressive use of systemic corticosteroids, followed by their slow tapering
over three to six months.159,168 This treatment may shorten the duration of the disease
and prevent progression into the chronic stage. Steroidresistant recurrences may only
respond to cytotoxic/immunosuppressive agents.159,168 In the present case the patient
was admitted to the University Hospital in the chronic phase. The patient was treated for
two years with peroral and topical prednisolone and with oral cyclosporine. During the
treatment the aqueous cells disappeared but the treatment did not have any improving
effect on the hypotony or iris atrophy, and the ocular fundus still showed oedema of the
optic disc and macular area in both eyes.
6.5 Infrared transillumination imaging and fluorescein angiography in differential
diagnosis of iris nevus and melanoma (V)
This is the first study to statistically evaluate the differentiation of iris nevus and
melanoma by using both IRT imaging and FAG of the iris. IRT imaging showed that
the lesion was translucent in 40 % of iris melanomas and in 8 % of iris nevi, partly
translucent in 29 % of iris nevi, and opaque to IR light in 60 % of iris melanomas and in
63 % of iris nevi. Thus IRT imaging cannot be used to differentiate iris nevus and
melanoma (p = 0.53). IRT images are useful in defining the area of tumour
Discussion
- 94 -
involvement. It can identify iris atrophy, cysts, foreign bodies, and granulomas,196 and
in this way it also contributes to the differential diagnosis of iris melanoma.
In an earlier study complete masking in iris angiograms at the site of the lesion
occurred in none of the four iris melanomas but in 4/9 iris nevi,41 a difference which
can be calculated to be not statistically significant (p = 0.10). In our study, complete
masking occurred in 62 % of iris nevi and in 3/5 iris melanomas, indicating that
complete masking in iris angiograms cannot be used to differentiate between iris nevus
and melanoma (p = 0.69).
Observed growth of a melanocytic iris lesion is a predicting factor of malignancy.97,229
A clinical follow-up study showed that vascularity of the lesion was unassociated with
the growth of the melanocytic iris tumour (p = 0.42).229 Fluorescein angiograms of the
iris showed irregularly arranged vessels both in five histologically confirmed nevi and
in four melanomas.48 Histological studies showed prominent superficial vasculature
only in 10 - 20 % of iris melanomas.124 Our results are in good agreement with these
earlier studies. In our study, disorganised vessels were seen in 21% of 53 iris nevi and
in two of five iris melanomas, suggesting that disorganised vessels were not diagnostic
for malignancy (p = 0.32). In an earlier study, fluorescein leakage occurred in all four
iris melanomas and in 5/9 iris nevi,41 a difference which can be calculated to be
statistically nearly significant (p = 0.07). In our larger study, however, fluorescein
leakage was not a significant predicting factor for iris melanoma (p = 1.0). Our results
confirm the view that fluorescein angiograms provide little useful diagnostic aid to
distinguish between benign iris nevi and melanomas.6,7,124
Discussion
- 95 -
Our results (V) suggest, that suspicious iris nevi should be observed carefully over time
by using slit-lamp photography or digital colour imaging to evaluate growth regardless
of their IRT imaging and fluorescein angiographic characteristics. When growth occurs,
local excision of the tumour is usually indicated. Four of the eight melanocytic iris
tumours, however, which were excised due to growth were histologically proved nevi.
This is in good agreement with earlier findings showing that growth does not always
confirm malignancy as both benign and malignant tumours including iris nevi and
spindle A melanomas can grow and invade the trabecular meshwork.59,215 Nevertheless
growth is still the single most consistent indicator of malignancy and the periodic
measurement of tumour size is a standard procedure. IRT images and fluorescein
angiograms cannot be used to determine if the melanocytic iris tumour is benign or
malignant.
6.6 Teleophthalmology and future directions
The invention of colour CCD cameras has enabled tertiary referral centres, university
eye clinics and other facilities to capture and store digital pictures on a computer.211 The
price of the technology remains prohibitive to smaller facilities. The high equipment
costs of the camera and image acquisition system are compensated by the minimal cost
of additional images, possibility for telecommunication, and no need for films and their
development to paper prints, archiving of photographs, and time consuming manual
image evaluation. Telemedical projects encourage central planning and the collecting of
patient records from primary care units so that they are readily available for use by
specialists in the referral centre.169 Technical failures happen less often when using
digital imaging instead of film.210
Discussion
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Converting an analog signal to digital form causes a loss of information. Therefore the
theoretical maximum resolution of digital imaging is always worse than that of film.
Today in experimental studies the images of the future digital fundus cameras have a
spatial resolution of 9μm/pixel for a 30 degree field, about twice the SLO resolution. 251
In clinical work, the digital image is displayed on a large computer screen allowing full
resolution whereas film edges reduce the effective resolution of film-based photographs.
Duplicates of digital images can be produced with no loss of resolution. Magnifying an
image e.g. for laser guidance is enhanced with digital images.
The capacity of computer technology to calculate has gone up exponentially and the
basic technological know-how exists to create many tools that have not yet found wide-
spread use in ophthalmology. Pioneering work in testing and developing new equipment
and software applications is required. The price of complicated medical equipment
gives importance to comparative testing between equipment of different companies.
The advances of digital imaging systems and telecommunication technology have made
digital imaging the new standard in the ophthalmic community.251 The ICG angiography
and OCT can only be obtained using digital imaging. It is likely that film-based imaging
will vanish from the profession within the next decade.251
Summary and Conclusions
- 97 -
7. SUMMARY AND CONCLUSIONS
This study was initiated to develop and assess new digital photographic methods for the
diagnosis and follow-up of ocular diseases.
1. A randomised and masked multicentre study to assess digital fundus cameras for DR
screening showed that digital 50° red-free imaging (Topcon TRC 50 IA) had 97.7%
(95%CI 95.8 – 99.7) sensitivity, 98.9% (95%CI 96.9 – 100) specificity, and 98.1%
exact agreement with the reference standard for detecting at least mild NPDR. Digital
two-field 50° colour imaging (Topcon TRC 50 IA) showed 94% (95%CI 90.8 – 97.2)
sensitivity, 99.0% (95%CI 96.9 – 100) specificity, and 95.5% exact agreement for
detection of at least mild NPDR when compared with the reference standard. Digital
two-field 45° colour imaging (Canon CR6-45NM) showed 88.9% (95%CI 82.0 – 95.8)
sensitivity, 100% specificity, and 89.3% exact agreement for detection of at least mild
NPDR when compared with the reference standard. Only 1.3% of digital red-free and
1.2 – 1.6% of digital colour images were ungradeable. These digital imaging modalities
surpass the 80% sensitivity, 95% specificity, and 5% failure rate considered acceptable
for any photographic method for screening of DR.24,226 When using the handheld digital
colour video camera (MediTell) the still images taken of the ocular fundus showed only
6.9%; 95%CI 2.3 – 11.5 sensitivity for detection of at least mild NPDR when compared
with the reference standard and ungradeable images represented 92.3%. These figures
did not reach the criteria for DR screening
2. Digital colour, red-free and red light images were evaluated in a randomised and
masked manner and by a new subtraction method for differential diagnosis of small
Summary and Conclusions
- 98 -
choroidal melanoma. Comparative use of digital colour, red-free, and red light imaging
had 85.7% (95%CI 42.1 – 99.6) sensitivity, 99% (95%CI 94.7 – 99.9) specificity, and
98.2% (95%CI 93.6 – 99.8) exact agreement versus reference standard in differentiation
of small choroidal melanoma from pseudomelanoma. Excellent agreement occurred
between the comparative use of digital images and the reference standard in detecting
small choroidal melanoma from suspect choroidal lesions (κ 0.847; 95%CI 0.639 – 1.0).
The subtraction method was useful in showing growth in four of 94 melanocytic
tumours (4.3%) during a minimum follow-up of 9-36 (mean ± SD of 23 ± 11) months.
These figures show that comparative use of digital colour, red-free and red light
imaging is a suitable method in differentiation of small choroidal melanoma from
pseudomelanomas. The new subtraction method may reveal early growth of
melanocytic choroidal tumours in cases which occur in the area of the fundus that can
be seen in digital images.
3. In the development of a new digital IRT imaging of the iris and ciliary body the
examination light from a Zeiss photo slit-lamp was passed through a Kodak Wratten
gelatine filter No. 87 transmitting only IR light. A fiber optic cable was used to transmit
the IR light through the lateral wall of the eye. The IR images were captured using a
Topcon TRC 50 IA retinal camera focused on the iris. Digital IRT imaging of a normal
eye showed the sphincter muscle and delicate radial contraction folds of Schwalbe in
the pupillary zone and radial structural folds of Schwalbe and circular contraction
furrows in the ciliary zone of the iris. Digital IRT images also showed the reflex of the
temporal equatorial border of the lens as a dark circular band. Neither the iris colour nor
gender had any significant effect on the visualization of the iris structures with digital
Summary and Conclusions
- 99 -
IRT images. Digital IRT images may be used to study changes of the stroma and
posterior surface of the iris in various diseases of the uvea.
4. Ocular examination and follow-up, including digital IRT imaging of the iris and
ciliary body, was done in a 52-year old woman with chronic phase of VKH disease. IRT
imaging showed extensive atrophy of the iris stroma and occasional pigment clumps
both in the pupillary and the ciliary zones of the iris, and detachment of the ciliary body
in both eyes. Treatment did not normalise bilateral shallow retinal detachment of the
posterior pole, serous detachment of the ciliary body, or severe ocular hypotony. We
showed that severe atrophy of the iris stroma, retinal detachment of the posterior pole,
serous detachment of the ciliary body, and ocular hypotony are new findings of chronic
phase of VKH disease.
5. IRT imaging and FAG findings of the iris in 53 eyes with an iris nevus and five eyes
with an iris melanoma showed that IR translucence (37% in iris nevi and 40% in iris
melanomas) was not a differentiating factor between an iris nevus and melanoma
(p = 0.53). Complete masking of fluorescence (62% in iris nevi and 60% in iris
melanomas, p = 0.69), presence of disorganised vessels (21% in iris nevi and 40% in
iris melanomas, p = 0.32), and fluorescein leakage (34% in iris nevi and 40% in iris
melanomas, p = 1.0) at the site of the lesion did not differentiate an iris nevus from a
melanoma. IRT imaging and FAG of the iris are useful in the differential diagnosis of
melanocytic iris tumours but they cannot be used to determine if the lesion is benign or
malignant.
Summary and Conclusions
- 100 -
Acknowledgements
- 101 -
8. ACKNOWLEDGEMENTS
I express my deepest gratitude to my supervisors, Professor Tero Kivelä MD, FEBO,
Department of Ophthalmology, University of Helsinki and Professor Matti Saari, MD,
FEBO, Department of Ophthalmology, University of Turku for their guidance in
planning and executing this research project. Their encouraging attitudes and scientific
support have been a persistent force motivating me during each step of this work.
I am grateful to Docent Paula Summanen, MD, FEBO, for kindly consenting to oversee
my research project of screening diabetic retinopathy and for her positive and bright
words and encouragement during this study.
I wish to express my sincere thanks and gratitude to the official reviewers of my thesis,
Docent Eero Aarnisalo, M.D. Department of Ophthalmology, Satakunta Central
Hospital, Pori and Docent Markku Teräsvirta, M.D. FEBO, Department of
Ophthalmology, Kuopio University Central Hospital, Kuopio, for their valuable
criticism and constructive comments, which I highly appreciate.
I wish to thank Professor Juhani Tuominen, Lic in Soc Science, Department of
Biostatistics, University of Turku for statistical advice.
I would like to give thanks to Ophthalmic Photographer Kari Nummelin, BSc,
Department of Ophthalmology, Turku University Central Hospital, without whose
work, assistance and skillful technical expertise it would have been impossible to
conduct research on ophthalmic photography with quality.
Acknowledgements
- 102 -
Finally, I want to thank Erika for always being there.
This study was financially supported by grants from the Finnish Medical Foundation,
Helsinki, Finland and the Instrumentarium Science Foundation, Helsinki, Finland.
References
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