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Description  |
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FIELD OF THE INVENTION
This invention relates to medical diagnostic and monitoring methods and, in
particular, to a method for detecting, diagnosing and monitoring diabetes
mellitus.
BACKGROUND OF THE INVENTION
Diabetes mellitus is one of the leading causes of morbidity and mortality
in the United States. Although the disease, once diagnosed, can be
controlled, the diabetic patient faces many complications, some of them
life-threatening. For example, the average life expectancy of the diabetic
patient is one third less than that of the general population; blindness
is twenty five times as common, renal disease is seventeen times more
common, gangrene is five times as common and heart disease is twice as
common in diabetics as compared to the non diabetic.
In addition, the incidence of this disease appears to be
increasing--between 1936 and 1978 there was a six fold increase in the
prevalence of the disease.
It is believed by many researchers in the field that many complications
suffered by diabetic patients can be minimized or avoided by early
detection of the onset of the disease and proper long-term control of the
patient's blood glucose.
Unfortunately, prior art detection and monitoring methods have been unable
to either accurately detect the onset of the disease at an early stage or
assess the degree of control on a long-term basis. Such prior art
detection methods, other than interpretation of clinical symptoms, rely on
blood sugar measurements which reflect the presence of the disease. Prior
art monitoring methods involve either spot blood sugar measurements or
more complicated blood tests which reflect blood glucose levels that
existed in the patient's body at a time three to five weeks prior to the
time of measurement. Both prior art measurement methods require bodily
invasion and the results are difficult to interpret.
Accordingly, it is an object of this invention to detect the onset of
diabetes mellitus prior to the appearance of clinical symptoms.
It is another object of this invention to detect the development of
diabetic eye disease.
It is still another object of this invention to assess the effectiveness of
various methods of diabetic treatment.
It is yet another object of this invention to determine the relationship
and degree of control required to prevent the occurrence of diabetic
complications.
It is a further object of this invention to provide a method for
objectively quantifying the effects of systemic disease, trauma, drugs,
local inflammatory conditions of the eye, and aging.
SUMMARY OF THE INVENTION
The foregoing objects are achieved from the ascertainment of the diffusion
coefficient of the lens of a patient's in vivo eye by directing a beam of
light from a low-power laser at a clear site in the lens of the patient's
eye and measuring the intensity of the back-scattered light. A number of
measurements are taken of the diffusion coefficient for patients known to
be normal to establish a diffusion coefficient-age relationship. The
ascertained lens diffusion coefficient of the patient is compared to the
established relationship. Where a significant decrease of lens diffusion
coefficient over the normal diffusion coefficient-age relationship is
obtained, there is a likelihood that the patient is diabetic. The amount
of decrease of lens diffusion coefficient over the normal established
diffusion coefficient can be used as a measure of the severity of the
disease or to monitor the progress and treatment of the disease.
The optical apparatus used in the performance of the method preferably
consists of a low-power laser and associated optics attached to a
slit-lamp biomicroscope equipped with precision mechanical adjustments to
focus the light beam on the patient's lens. A photomultiplier is used to
detect the intensity of the back-scattered light and a correlator is used
to process the output of the photomultiplier to provide a set of numbers
that can be used to calculate the diffusion coefficient.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a slit-lamp biomicroscope and added
equipment used to focus the light beam on the patient's lens.
FIG. 2 shows an overall schematic view of the optical arrangement to
irradiate the patient's lens and the apparatus used to process the
resulting signal.
FIG. 3 is a graph of lens diffusion coefficient versus patient age. The
graph was developed from information obtained by using the apparatus
described herein.
DETAILED DESCRIPTION OF THE METHOD
FIG. 1 shows an optical arrangement for making measurements required in the
performance of the method. That optical arrangement utilizes a
modification of a commercially-available instrument known as a slit-lamp
biomicroscope. This device is well-known and is typically used in
ophthalmological studies of the cornea, lens and retina of the human eye.
Slit-lamp biomicroscopes suitable for modification are manufactured by
several companies and the operation and use of those devices are well
known to ophthalmologists and others engaged in the examination of human
eyes.
Basically, a slit-lamp biomicroscope consists of a light source, a
microscope and a mechanical supporting arrangement that allows precise
positioning of the light source and microscope relative to the patient to
enable focusing of the light on selected portions of the patient's eye.
Specifically, light produced by source 100 is reflected from mirror 105
and directed as beam 110 to the patient's eye shown schematically as eye
120. The apparatus also includes frame 115 and support 125 which position
and hold the patient's head in a fixed position. Light which is reflected
or scattered by the patient's cornea, lens or retina, shown schematically
as beam 130, is received by a binocular microscope arrangement 150 which
has two eyepieces, 155 and 160. The lamp arrangement and microscope are
supported by arms 140 and 145 from a common post, all in a well-known
manner.
To facilitate making the requisite measurements, the standard slit-lamp
biomicroscope is modified by the addition of an XYZ positioning apparatus
to the microscope arrangement 150. In particular, the XYZ position
apparatus consists of commercial XYZ positioner 190 which can obtain
precise three-dimensional movement which is controlled by three orthogonal
micrometers, 191-193. Positioner 190 is mounted on plate 194 which is in
turn fastened to microscope arrangement 150 by means of a threaded hole
153 which is normally found on the arrangement and used for other
purposes.
Attached to the movable surface of XYZ positioner 190 are arms 180 and 186
which support a lens arrangement 165. As will be hereinafter further
explained, lens arrangement 165 is connected via fiber optic cable 170 to
a laser and used to illuminate the patient's lens via beam 135. The
back-scattered light shown schematically as beam 130 is detected by a
sensor located in the focal plane of eyepiece 155 and conveyed via cable
195 to a photomultipler (not shown).
FIG. 2 of the drawings shows a schematic diagram of the preferred optical
arrangement for making the measurements necessary to the performance of
the method. The apparatus consists of a light source for illuminating a
clear site in the lens of a patient's in vivo eye and a detecting or
receiving portion for receiving the back-scattered radiation.
The light source part of the apparatus consists of laser 200, two filters
mounted in housing 215, microscope objective lens 231, fiber optic
termination 235, fiber optic cable 240 and focusing lens arrangement 245.
Laser 200 is a 5 milliwatt helium-neon laser of conventional design which
is commercially available from several companies. A laser suitable for use
with the illustrative embodiment is a model U-1305P, available from the
Newport Corporation, 18235 Mount Baldy Circle, Fountain Valley, Calif. The
output of laser 200 passes through two neutral density filters, mounted in
housing 215. One filter is permanently mounted in the laser beam path and
reduced the power output of laser 200 to 1.5 milliwatts. The other filter
is solenoid-controlled so that it can automatically be moved out of the
laser beam path during the measurement operation. When both filters are in
place, they reduce the laser output power to 0.50 milliwatts. The movable
filter is used during premeasurement focusing, as will hereinafter be
described, in order to reduce the patient's exposure to unnecessary laser
irradiation. The movable filter is controlled by solenoid 203 which is
under control of a footswitch operated by the person making the
measurement. When solenoid 203 is operated, arm 220 retracts, in turn,
sliding the movable filter in housing 215 by means of bell-crank 225.
After passing through one or both filters the attenuated laser output light
enters lens 231. Lens 231 is a 40x microscope objective lens which is
mounted so that it focuses the laser light on the end of the optical fiber
which transmits the light to the irradiating apparatus. Light passing
through lens 231 falls onto an optical fiber 240 mounted in termination
235. The end of fiber 240 which enters termination 235 is attached to an
XYZ positioner. The positioner is used to align the end of the optical
fiber with the focusing lens to obtain maximum light transmission.
The other end of optical fiber 240 is attached to focusing lens arrangement
245. Lens arrangement 245 consists of a fiber optic holder which is
slidably mounted in a lens holder tube. Lens 248 is a 18 mm focal-length
converging lens which is mounted at the other end of the lens holder tube.
The moveable arrangement between the fiber optic holder and the lens
allows small adjustments to be made between the end of the optical fiber
and the lens to permit fine focusing of the laser output beam at a given
position within the patient's lens. Lens arrangement 245 is connected to
the XYZ positioner attached to the slit-lamp biomicroscope as previously
described and is used to focus the laser beam, 246, such that a sharp
focus is achieved at a clear site in the patient's lens 250. After passing
through the focal point in the lens the beam becomes sharply defocused in
order to maintain a low radiation level at the retina and prevent any
possibility of injury or damage.
The detection optical system uses portions of the optical system of the
slit-lamp biomicroscope. In particular, light back-scattered from the
clear site in the patient's lens (represented schematically as beam 247)
is focused by one objective of the binocular portion of microscope 255
onto a commercially-available optical fiber light guide, 260, located at
the center of the focal point of the eyepiece. In the illustrated
embodiment, the end termination of optical fiber light guide 260 replaces
the normal left ocular of slit-lamp biomicroscope 255. The arrangement is
such that the end of fiber cable 260 can be seen when looking through the
left ocular to allow focusing of the back-scattered radiation on the end
of the fiber cable.
Scattered light received at microscope 255 is fed by fiber optic guide 260
to photomultiplier 210 which is a well-known, commercially-available
device. A photomultiplier suitable for use with the illustrative
embodiment is a model number 9863B/350 manufactured by EMI Gencom, Inc.,
80 Express Street, Plainview N.Y. The output of photomultiplier 210 is
provided to amplifier-discriminator 265 which also is a well-known device
that amplifies the output pulse signals produced by the photomultiplier
and selectively sends to correlator 270 only those signals which have an
amplitude above a preset threshold. A suitable amplifier-discriminator for
use with the illustrated embodiment is a model number AD6 manufactured by
Pacific Photometric Instruments, Inc., 5675 Landregan Street, Emeryville,
Calif.
The output of amplifier-discriminator 265 is, in turn, provided to a
commercial photon correlation spectrometer 270 (a suitable spectrometer is
a model DC64 manufactured by Langley-Ford Instruments, 85 North Whitney
Street, Amherst, Mass.). Correlator 270 counts the number of pulses
received from amplifier-discriminator 265 for a predetermined time
interval and performs a well-known mathematical operation to obtain the
correlation function. A suitable time interval is ten microseconds. The
time interval, however, does not appear to be critical inasmuch as
satisfactory measurements have been made in a time interval as short as
1.5 microseconds. The sample time may be chosen to further characterize
the population of light scatterers. Measurements taken at shorter sample
times, i.e., at 1.5 microseconds, appear to be more characteristic of
smaller and/or faster scattering elements whereas measurements made at
longer sample times, i.e. 200 microseconds, appear more characteristic of
larger and/or slower scattering elements.
The correlator utilizes the received counts to solve the following equation
for the autocorrelation function C.sub.m (t):
##EQU1##
where t=the length of the predetermined time interval
i=an index number whose range is one to the total number of intervals.
p.sub.i =the number of pulses occurring during the ith time interval.
n=the total number of intervals.
m=an integer whose range is one to sixty-four.
In accordance with the above equation correlator 270 produces 64 solutions
or points (one for each value of m) in a time sequence, each measurement
separated by the value of t. These measurements may be plotted against
time to produce a curve which may then be displayed for examination on
oscilloscope 275. The values of the solutions may also be provided to
computer 280 for further processing to determine the diffusion
coefficient. A computer suitable for use with the illustrative embodiment
is a personal computer manufactured by the International Business Machines
Corporation, Armonk, N.Y.
In particular, the diffusion coefficient (D) is also related to the
correlation function C.sub.m (t) determined by the correlator by the
following equation:
C.sub.m (t)=A+Be.sup.-2DK.spsp.2.sup.m(t)
where
A, B=constants dependent on the physical details of the measurement
K=the scattering constant for the eye which is 4 .pi./.lambda. (sin
.theta./2) where .lambda. is the wavelength and .theta. is the scattering
angle
t=the length of the predetermined time interval
m=an integer whose range is one to sixty-four.
Therefore, the values of the diffusion coefficient D and the constants A
and B in the above equation can be determined, with the aid of computer
280, from the autocorrelation curve produced by the correlator 270 by
using standard curve fitting and analysis techniques. The calculated
diffusion coefficient can be stored in the computer along with other
patient data including, in accordance with the invention, the patient's
age.
The apparatus shown in FIGS. 1 and 2 is used to perform a measurement of
the lens diffusion coefficient as follows: with a patient sitting at the
slit-lamp biomicroscope, the operator sets up the device in the same way
that the device would be set up during a normal ophthalmic evaluation. In
order to measure various positions within the periphery of the patient's
lens it is necessary that the pupil be dilated using routinely-available
dilating drops as normally used during the course of complete ophthalmic
evaluation. Both the light produced by lamp 100 and the laser light with
both filters in place are used to align the laser output as seen through
the ocular 155 and 160 with the end of optical fiber light guide 195 in
left ocular 155. Due to the standard adjustments on the biomicroscope and
XYZ positioner 190, this alignment may be achieved at any selected site
within the patient's lens. The operator selects a site that is clear, i.e.
a site that is free of opacities.
Lamp 100 is then turned off and the operator depresses a foot switch which
operates solenoid 203 sliding the movable filter in housing 215 out of the
way to allow the actual measurement to be made using 1.5 milliwatts laser
light power. A second foot switch adjacent to the first can be used to
turn laser 200 off should any emergency arise.
The back-scattered light output is measured by the photomultiplier through
the optical system previously described and the photomultiplier output is
processed as previously described by the photon correlation spectrometer.
While measurements are in progress, the output of the spectrometer may be
monitored by the oscilloscope connected to it. A measurement is made, for
example, for 5 seconds at which point the first foot switch is released,
reinserting the movable filter into the optical path, and concluding the
measurement.
When performing the method to screen for diabetes mellitus, measurements
are taken only from "clear" sites in the lens of the eye. That is,
measurements are taken only from sites in the lens that are non-opaque.
The yellowing of the lens that is normal in the human aging process is
deemed not to be an opacity. In normal humans, discernable yellowing of
the lens first appears at about 30 years of age and thereafter that
yellowing tends to increase with age. Measurements taken from cataracts
(i.e. from opacities in the lens) are deemed, at this time, to be
unreliable because sufficient information has not yet been developed from
clinical studies to enable such measurements to be linked with any
certainty to diabetes mellitus.
In order to accurately compare measurements made from an individual with
measurements made from the same individual at a later time or with
measurements from a different individual, the compared measurements should
be made from approximately the same position in the lens. Measurements
obtained from other positions in the lens may give somewhat different
results which can provide additional information concerning the health of
the patient. For standardization purposes, it has been my practice to take
measurements from a non-opaque site in the central nucleus of the lens.
By using the apparatus described herein, no contact lens, nor anesthetic
drops are necessary to make a measurement. Although commonly used in eye
examinations, anesthetic drops have various deleterious side effects. Such
side effects include stinging, burning and conjunctival redness as well as
severe allergic reactions with resulting central nervous system
stimulation or corneal damage. In addition, application of a contact lens
following the use of a topical anesthetic requires much patient
cooperation as well as experience on the part of the examiner. Further
complications arising from the use of a contact lens include corneal
abrasions and infection as well as recurrent and chronic corneal erosions.
In contrast, by employing the described apparatus, the method can truly be
"non-invasive".
In using the method to detect and monitor diabetes, a calculation of the
diffusion coefficient is made on a series of patients whose health is
known and are believed to be nondiabetic. The resulting measurements are
compared to the patient's age resulting in a curve or graph similar to
that shown in FIG. 3 (hypothetical measurements are shown for illustrative
purposes). FIG. 3 shows the value of the diffusion coefficient increasing
in an upwards direction along the vertical axis and patient age increasing
rightward in the horizontal direction.
It has been discovered that the diffusion coefficient for patients who do
not have diabetes (represented for example by points 300-305) all lie
above a line (marked "normal" on the graph) while the diffusion
coefficient for patients having diabetes lie below the line (represented
by points 306-310). In addition, the severity of the disease is directly
related to the distance below the line at which the ascertained diffusion
coefficient lies, with increasing distance indicating greater severity.
For example, the patient represented by point 308 usually exhibits more
severe symptoms than the patient represented by point 310.
When a curve such as that shown in FIG. 3 has been established, patients
can be screened for diabetes by comparing their ascertained diffusion
coefficients with the "normal" line. If the measurement is significantly
below the "normal" line as shown in FIG. 3 the patient is likely to have
diabetes or a disease which affects the lens similarly. Known diabetic
patients can be monitored by making repeated measurements over a fixed
period of time. The series of measurements are compared to the graph. An
increasing distance from the "normal" line indicates an acceleration in
the disease. A fixed distance indicates the disease appears to be under
reasonable control.
Changes and modifications within the spirit and scope of the invention will
be apparent to those skilled in the art. I have, for example, found that
measurements of back-scattered light may also be taken from the cornea or
the retina of the eye. However, measurements taken from the lens have thus
far given the best results. As another example the diffusion coefficient
can be replaced by an equivalent measure such as the decay constant. The
essential point is that variations in the intensity of the back scattered
light is utilized to obtain a measurement. That measurement may then be
used to obtain derivatives. Such modifications and changes are intended to
be covered by the claims herein.
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