191
Clinical Neurology and Neurosurgery, 94 ( 1992) 19 1-l 95 0
1992 Elsevier Science Publishers B.V. All rights reserved 0303~8467/92/$05.00
CLINEU 00193
Evaluation of the visual system in multiple sclerosis: a comparative study of diagnostic tests H.A.M. van Diemena, P. Lanting”, J.C. Koetsier”, R.L.M. Strijersb, H.K. van Walbeek” and C.H. Polmana Departments
of “Neurology and
bClinical Neurophysiology, Free University Hospital, and “Department of Neurology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands (Received 21 August, 1991) (Revised, received 10 February, 1992) (Accepted 12 February, 1992)
Key words:
Multiple sclerosis; Visual system; Visual evoked potential; Contrast sensitivity; Flight of colours test; Colour vision test; Pupillary light reflex
Summary In 22 patients with clinically definite multiple sclerosis (MS) who were without visual symptoms and had a visual
acuity of at least 1.0 in both eyes at the time of measurement, the following tests were performed to detect subclinical lesions in the visual system: visual evoked potential (VEP), contrast sensitivity test (CS), flight of colours test (FOC), colour vision test (Ishihara plates) (CV) and the pupillary light reflex (PLR). VEP was abnormal in 8 1.8%, CS in 72.7%, FOC in 36.4%, CV in 31.8%, and PLR in 52.3% of the patients. VEP and CS together were most sensitive: combining these techniques subclinical lesions of the visual system were detected in 90.9% (20/22) of these asymptomatic patients.
Introduction
Neuro-ophthalmological signs and symptoms play an important role in patients with multiple sclerosis (MS). From neuropathological studies it can be learned that the prevalence of optic nerve lesions in MS is approximately 100% in patients with and without optic neuritis [1,2]. The demonstration of these lesions is important, both in making a diagnosis and in the follow-up of the visual function. For this reason in the last decade a num-
Correspondence to; H.A.M. van Diemen, MD, Department of Neurology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Phone: 31(20)5482)X23;Fax: 31(20)5484898.
ber of tests have been employed in the investigation of optic nerve function in patients with MS. Besides the routinely used visual acuity these methods include visual evoked potentials, contrast sensitivity tests, the flight of colours test, colour vision tests and the measurement of the pupillary light reflex. Especially VEPs are nowadays routinely used as a sensitive method for the detection of lesions in the visual system, as reviewed by Chiappa [3]. A number of studies have been published in which some of these tests were compared [4-151. However, to our knowledge in none of these studies all the mentioned tests were performed in the same MS patient group. It was our aim to compare the diagnostic value of all these examinations in order to investigate their usefulness in the detection of subclinical lesions in the visual pathway in MS. Therefore these tests were performed in patients with clinically definite MS who were without visual symptoms and had a visual acuity of at least 1.O in both eyes at the time of measurement.
192 Materials and methods CS was measured using the contrast sensitivity test chart (VCTS 6500). as described in detail elsewhere From a patient
group of 70 patients
inite MS according
to the Poser criteria.
with clinically 22 patients
selected for this study on the basis of the absence ual complaints
and the presence
least 1.O in both eyes as measured (with refractive
errors corrected)
defwere
of vis-
of a visual acuity
of at
with the Snellen chart at the time of mensure-
ment [ 161.
[ 19,201. An advantage is that
comparable displays
without
and 8 with a history of
optic neuritis
(6 unilateral
optic neuritis
(ON) was defined as acute or subacute
of vision associated
and 2 bilateral).
with pain on movement
A history
of loss
of the globe,
lasting more than 24 h 1171. They were 14 female and 8 male patients, their mean age being 42.4 years (range: 28860 years). To quantitate the clinical neuroiogical status of the patient the Kurtzke Expanded Disability Status Scale (KEDSS) was used [ 181. The KEDSS ranged from 2.0 to 7.5. the mean KEDSS being 4.5. The examinations mentioned below took place in one session. during the morning hours and in the same sequence. In ail patients the tests were performed in each eye separately. None of the selected patients had other abnormalities or diseases that could influence the visual system. For the contrast sensitivity test and the flight of colours test a group of 30 healthy volunteers served as a control group. They were 18 women and 12 men, their age ranging 24 to 67 years (mean 38.6 years).
from
out, rapid,
to those obtained
stable
light source
test system
and gives results
using computer-generated
[20]. Both the patients
teers viewed the test chart quencies
There were 14 patients
of this Vistech contrast
it is easy to carry
and the healthy
volun-
which was illuminated
from a distance
by a
of 3 m. Spatial
fre-
of I .5. 3.6, I?, I8 cycles per degree were tested.
The contrast
ranged
from
contrast
above
to contrast
below visual levels in about 0.1 log unit steps with a maximum
of 9 steps for each spatial
score ranged
from 0 to 45. Normal
from the control
group
of healthy
frequency.
The total
values were obtained volunteers.
A total
score of less than 25 was considered abnormal (mean - 2 SD: 30-5.2). The contrast thresholds were converted to contrast sensitivity. the reciprocal of threshold.
When perforlnii~g the Flight of Colours Test, we used the method described by Feldman [21]. Dark adaptation was achieved by placing the patient in a dark room for 5 min. Then with one eye closed and one eye open, a bright pocket torch. transformator guided to obtain a stable source of light, was directed at the open eye for 10 set at a distance of 2 cm. Afterwards the patient closed both eyes and described all after-images. Each eye was tested twice with an interval of 5 min between the tests (left, right. left. right). The test was ended 40 set after the last
VEPs were recorded with a Nihon Kohden System, using a full field pattern reversal of a black and white
after-image was seen. The best result of each session for each eye was used for further calculation. Colours that were taken into account were white, yellow, green, blue,
checkerboard (contrast level = 92%) using a mirror galvanometer, The checkerboard pattern reversed at ran-
orange, red or purple. Black, grey or colourless light spots were excluded [9]. The normal values (lower limits)
dom with a frequency of I Hz. The patient was seated in a chair in front of the screen, which measured 23 x 23 centimeter. at a distance of 43 centimeter. The check size was I centimeter, so the subtending angle was l”20’. The patient was required to concentrate at a central fixation square in the middle of the screen. Two series of 64 responses were averaged (bandwidth -3 dB, 0.5 70 Hz). The latency of the first major positive peak (PlOO) was measured after stimulation of each eye. The VEPs were recorded by surface electrodes, the reference electrode placed at Fz, the active ones at 01 and 02. The average of 01 and 02 was used for further analysis. Our own laboratory reference values of PI00 latency were used. A PI00 of more than 103 set was considered abnormal (mean + 2 SD: 93.6 + 9.4).
were obtained from the healthy control group. The FOC was considered abnormal if at least two of the following three values were below their lower limits: (1) a duration of the after-images of 145 set (mean duration - 2SD: 203 -5X). (2) a total of 3 different colours (mean number of colors -- 2SD: 5.2-l .8). and (3) a total of 10 colour changes (mean number of color changes -2SD: 16.7- 7.2).
To evaluate the CV the first 25 Ishihara plates were used [22]. Testing was done against a neutral table cover at a distance of one meter, at day-light light intensity. CV was regarded abnormal if 2 or more plates were read wrong [X,23].
193 Pupillary light reflex (PLR)
The PLR was measured using an infra-red light registration technique, called IRIS [24,25]. To registrate the variation in pupil size, infra-red light emitting diodes and sensors mounted on a spectacle frame in front of each eye were used. Measurements were performed in a dark room, in which the patient had adapted for 5 min. The retina was stimulated with a block-shaped stimulus, under maxwellian view conditions with a fixed background and light step intensity, corresponding to a retinal illuminance of 1000-6000 Troland, respectively. The duration of the stimulus was 1.2 set, the time interval between two consecutive stimuli was 5 sec. The pupillary light reflex latency was defined as the time interval between the onset of the stimulus and the start of the constriction and it was determined using the velocity signal (dOS/dt and dODldt), because the starting point of the PLRL in the velocity signal is more pronounced [24,25]. An example is shown in Fig. 1. The latency of the PLRL was measured from at least 4 artefact free responses. In accordance to our laboratory standards a latency difference of more than 15 msec between intra-individual eyes was considered indicative of a relative pupillary defect [15]. Data analysis
Since in MS the detection of an abnormal test in one eye is sufficient in clinical practice to be helpful in making a diagnosis, and because the average of both eyes
does not give the same information (due to possible asymmetric occurrence of plaques in MS), tests were regarded to be abnormal if abnormal values were measured in one or both eyes. The much used approach to use the measurements of both eyes and thus “double” the sample size is, in our view, incorrect. Such measurements are pairwise correlated and hence cannot be treated as independent. For statistical comparison the Student ttest for paired samples was used.
Results
The results are summarized in Table 1. The VEP latency was abnormal in 8 1.8% (18/22) of the patients. CS was abnormal in 72.7% (16/22) of the patients. At all spatial frequencies there were statistically significant differences (P
Clinical Neurology and Neurosurgery, 94 ( 1992) 19 1-l 95 0
1992 Elsevier Science Publishers B.V. All rights reserved 0303~8467/92/$05.00
CLINEU 00193
Evaluation of the visual system in multiple sclerosis: a comparative study of diagnostic tests H.A.M. van Diemena, P. Lanting”, J.C. Koetsier”, R.L.M. Strijersb, H.K. van Walbeek” and C.H. Polmana Departments
of “Neurology and
bClinical Neurophysiology, Free University Hospital, and “Department of Neurology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands (Received 21 August, 1991) (Revised, received 10 February, 1992) (Accepted 12 February, 1992)
Key words:
Multiple sclerosis; Visual system; Visual evoked potential; Contrast sensitivity; Flight of colours test; Colour vision test; Pupillary light reflex
Summary In 22 patients with clinically definite multiple sclerosis (MS) who were without visual symptoms and had a visual
acuity of at least 1.0 in both eyes at the time of measurement, the following tests were performed to detect subclinical lesions in the visual system: visual evoked potential (VEP), contrast sensitivity test (CS), flight of colours test (FOC), colour vision test (Ishihara plates) (CV) and the pupillary light reflex (PLR). VEP was abnormal in 8 1.8%, CS in 72.7%, FOC in 36.4%, CV in 31.8%, and PLR in 52.3% of the patients. VEP and CS together were most sensitive: combining these techniques subclinical lesions of the visual system were detected in 90.9% (20/22) of these asymptomatic patients.
Introduction
Neuro-ophthalmological signs and symptoms play an important role in patients with multiple sclerosis (MS). From neuropathological studies it can be learned that the prevalence of optic nerve lesions in MS is approximately 100% in patients with and without optic neuritis [1,2]. The demonstration of these lesions is important, both in making a diagnosis and in the follow-up of the visual function. For this reason in the last decade a num-
Correspondence to; H.A.M. van Diemen, MD, Department of Neurology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Phone: 31(20)5482)X23;Fax: 31(20)5484898.
ber of tests have been employed in the investigation of optic nerve function in patients with MS. Besides the routinely used visual acuity these methods include visual evoked potentials, contrast sensitivity tests, the flight of colours test, colour vision tests and the measurement of the pupillary light reflex. Especially VEPs are nowadays routinely used as a sensitive method for the detection of lesions in the visual system, as reviewed by Chiappa [3]. A number of studies have been published in which some of these tests were compared [4-151. However, to our knowledge in none of these studies all the mentioned tests were performed in the same MS patient group. It was our aim to compare the diagnostic value of all these examinations in order to investigate their usefulness in the detection of subclinical lesions in the visual pathway in MS. Therefore these tests were performed in patients with clinically definite MS who were without visual symptoms and had a visual acuity of at least 1.O in both eyes at the time of measurement.
192 Materials and methods CS was measured using the contrast sensitivity test chart (VCTS 6500). as described in detail elsewhere From a patient
group of 70 patients
inite MS according
to the Poser criteria.
with clinically 22 patients
selected for this study on the basis of the absence ual complaints
and the presence
least 1.O in both eyes as measured (with refractive
errors corrected)
defwere
of vis-
of a visual acuity
of at
with the Snellen chart at the time of mensure-
ment [ 161.
[ 19,201. An advantage is that
comparable displays
without
and 8 with a history of
optic neuritis
(6 unilateral
optic neuritis
(ON) was defined as acute or subacute
of vision associated
and 2 bilateral).
with pain on movement
A history
of loss
of the globe,
lasting more than 24 h 1171. They were 14 female and 8 male patients, their mean age being 42.4 years (range: 28860 years). To quantitate the clinical neuroiogical status of the patient the Kurtzke Expanded Disability Status Scale (KEDSS) was used [ 181. The KEDSS ranged from 2.0 to 7.5. the mean KEDSS being 4.5. The examinations mentioned below took place in one session. during the morning hours and in the same sequence. In ail patients the tests were performed in each eye separately. None of the selected patients had other abnormalities or diseases that could influence the visual system. For the contrast sensitivity test and the flight of colours test a group of 30 healthy volunteers served as a control group. They were 18 women and 12 men, their age ranging 24 to 67 years (mean 38.6 years).
from
out, rapid,
to those obtained
stable
light source
test system
and gives results
using computer-generated
[20]. Both the patients
teers viewed the test chart quencies
There were 14 patients
of this Vistech contrast
it is easy to carry
and the healthy
volun-
which was illuminated
from a distance
by a
of 3 m. Spatial
fre-
of I .5. 3.6, I?, I8 cycles per degree were tested.
The contrast
ranged
from
contrast
above
to contrast
below visual levels in about 0.1 log unit steps with a maximum
of 9 steps for each spatial
score ranged
from 0 to 45. Normal
from the control
group
of healthy
frequency.
The total
values were obtained volunteers.
A total
score of less than 25 was considered abnormal (mean - 2 SD: 30-5.2). The contrast thresholds were converted to contrast sensitivity. the reciprocal of threshold.
When perforlnii~g the Flight of Colours Test, we used the method described by Feldman [21]. Dark adaptation was achieved by placing the patient in a dark room for 5 min. Then with one eye closed and one eye open, a bright pocket torch. transformator guided to obtain a stable source of light, was directed at the open eye for 10 set at a distance of 2 cm. Afterwards the patient closed both eyes and described all after-images. Each eye was tested twice with an interval of 5 min between the tests (left, right. left. right). The test was ended 40 set after the last
VEPs were recorded with a Nihon Kohden System, using a full field pattern reversal of a black and white
after-image was seen. The best result of each session for each eye was used for further calculation. Colours that were taken into account were white, yellow, green, blue,
checkerboard (contrast level = 92%) using a mirror galvanometer, The checkerboard pattern reversed at ran-
orange, red or purple. Black, grey or colourless light spots were excluded [9]. The normal values (lower limits)
dom with a frequency of I Hz. The patient was seated in a chair in front of the screen, which measured 23 x 23 centimeter. at a distance of 43 centimeter. The check size was I centimeter, so the subtending angle was l”20’. The patient was required to concentrate at a central fixation square in the middle of the screen. Two series of 64 responses were averaged (bandwidth -3 dB, 0.5 70 Hz). The latency of the first major positive peak (PlOO) was measured after stimulation of each eye. The VEPs were recorded by surface electrodes, the reference electrode placed at Fz, the active ones at 01 and 02. The average of 01 and 02 was used for further analysis. Our own laboratory reference values of PI00 latency were used. A PI00 of more than 103 set was considered abnormal (mean + 2 SD: 93.6 + 9.4).
were obtained from the healthy control group. The FOC was considered abnormal if at least two of the following three values were below their lower limits: (1) a duration of the after-images of 145 set (mean duration - 2SD: 203 -5X). (2) a total of 3 different colours (mean number of colors -- 2SD: 5.2-l .8). and (3) a total of 10 colour changes (mean number of color changes -2SD: 16.7- 7.2).
To evaluate the CV the first 25 Ishihara plates were used [22]. Testing was done against a neutral table cover at a distance of one meter, at day-light light intensity. CV was regarded abnormal if 2 or more plates were read wrong [X,23].
193 Pupillary light reflex (PLR)
The PLR was measured using an infra-red light registration technique, called IRIS [24,25]. To registrate the variation in pupil size, infra-red light emitting diodes and sensors mounted on a spectacle frame in front of each eye were used. Measurements were performed in a dark room, in which the patient had adapted for 5 min. The retina was stimulated with a block-shaped stimulus, under maxwellian view conditions with a fixed background and light step intensity, corresponding to a retinal illuminance of 1000-6000 Troland, respectively. The duration of the stimulus was 1.2 set, the time interval between two consecutive stimuli was 5 sec. The pupillary light reflex latency was defined as the time interval between the onset of the stimulus and the start of the constriction and it was determined using the velocity signal (dOS/dt and dODldt), because the starting point of the PLRL in the velocity signal is more pronounced [24,25]. An example is shown in Fig. 1. The latency of the PLRL was measured from at least 4 artefact free responses. In accordance to our laboratory standards a latency difference of more than 15 msec between intra-individual eyes was considered indicative of a relative pupillary defect [15]. Data analysis
Since in MS the detection of an abnormal test in one eye is sufficient in clinical practice to be helpful in making a diagnosis, and because the average of both eyes
does not give the same information (due to possible asymmetric occurrence of plaques in MS), tests were regarded to be abnormal if abnormal values were measured in one or both eyes. The much used approach to use the measurements of both eyes and thus “double” the sample size is, in our view, incorrect. Such measurements are pairwise correlated and hence cannot be treated as independent. For statistical comparison the Student ttest for paired samples was used.
Results
The results are summarized in Table 1. The VEP latency was abnormal in 8 1.8% (18/22) of the patients. CS was abnormal in 72.7% (16/22) of the patients. At all spatial frequencies there were statistically significant differences (P
