Pupillary function in multiple sclerosis Jacobsen J. Pupillary function in multiple sclerosis. Acta Neurol Scand 1990: 82: 392-395.
J. Jakobsen
Eighteen MS patients with visual acuity of 20/30 or better and without recent visual complaints, and 14 age- and sex-matched controls were studied by TV pupillography. The response amplitude and the maximum rate of pupillary constriction or dilation of the light, dark, accommodation and ciliospinal reflexes were unchanged. The latency of the pupillary light response (PLR), however, was prolonged and closely related to walking performance (R = 0.76; p < 0.001). No relationship was established between PLR latency and previous history of optic neuritis or latency of the VEP. It is concluded that MS patients with preserved visual acuity haye only discrete autonomic pupillary disturbances and that the PLR delay is related to disease progression.
Slmptoms of dysfunction of the autonomic nervous s>stem are common in multiple sclerosis (MS). Ssx-ere disturbances of sexual functions and of the urinw bladder and the bowel develop in many paricnts. In addition, simple bedside tests have demonstrated abnormalities of sweating and of cardiox-ascular tone (1-4). It is generally assumed that autonomic dysfunction in MS is due to multiple discrete lesions of various central pathways rather than to a generalized dysautonomic state. Pupillary functions have attracted only little attention in studies of autonomic function in MS. However, a simple measure of duration of light-provoked pupillary oscillations, the pupil cycle time, is considerably prolonged in optic neuritis (5-7). Pupillographic studies of optic neuritis patients have demonstrated decreased amplitude and increased latency of the response of the pupillary light reflex (PLR) as well as irregular pupillary cycling (8, 9). Whether similar pupillary abnormalities occur in MS patients without signs of active optic neuritis and with preserved visual acuity is unknown. To examine the extent of autonomic dysfunction of the pupil in MS the light, dark, accommodation and ciliospinal reflexes, as well as pupillary unrest, were studied by continuous registration of pupil area as a function of time in MS patients with visual acuity of 20/30 or better and without recent symptoms of eye disease. Subjects and methods
Eighteen patients with definite multiple sclerosis (10) and 14 controls were accepted for study and gave informed consent to the protocol. Inclusion criteria were no visual complaints within the last year, no clinical detectable visual field defects, visual acuity of 20/30 or better, no history other than MS of diseases
392
Department of Neurology, Aarhus University Hospital, Denmark
Key words: multiple sclerosis; pupillary function; autonomic function Department of Neurology (208 11, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen 0, Denmark Accepted for publication August 15, 1990
known to influence autonomic functions and no constant medication. No analgesics or sedatives were allowed for the last 72 h before pupillography and on the day of study subjects were fasting and not allowed to drink tea, coffee or alcohol, or to smoke. To preserve statistical power severity of MS was classified apriori into three stages only: Stage 1 patients could walk 1OOOm without any support; Stage 2 patients needed a cane for walking; and Stage 3 patients either were wheelchair-bound or needed personal support to move more than 50 m. Controls were age and sex matched with no history of ophthalmologc disease. For comparison with the pupillographic data, pattern-shift evoked potentials (VEP) were recorded bilaterally in both groups of subject. Pupillography
Continuous registration of pupil area of the left eye was performed with an infrared sensitive TV camera (Iriscorder, Hamamatsu, Japan) (1 1). Analogue output was delivered to an electrocardiograph (Elena Schbnander, Sweden) which also recorded time and the intensity of the light stimulus. Examination took place in darkness to which the subject had adapted for 15 min. A red fixation point at an individually adjusted optically infinite distance was used to prevent accommodation. In darkness pupil area was registered for 2 min. Then the accommodation response was provoked by asking the subject to focus a red fixation cross in the near point of the right eye. For study of the PLR a stimulus of yellow-green light was presented to the right eye by a photostimulator (Hamamatsu, Japan) (1 1). In the plane of the pupil the converging light beam had a diameter of 1 mm thereby eliminating variation in light input
Pupillary function in MS
due to changes of pupil size. At the retinal level the light beam covered an area of approximately the size of the optic disc and was located one papillary diameter above the disc. The threshold and the stimulus needed for the maximum pupillary response was registered following gradual increase of the square waves‘ light intensity from 0.1 to 52 microLumen, while the stimulus duration was kept constant at 256 ms. The PLR response was elicited by a 2 to 4 times supramaximal light stimulus with a 60 s interval between recordings. Autonomic nervous system homeostasis of pupil area is maintained by a state of fluctuation, so called pupillary unrest. The mean amplitude of pupillary fluctuations and its variance during two 10-s intervals in darkness and during constant increase of the light stimulus by 0.8 microLumen/s was studied also. Subsequently, the pupillary dark reflex was recorded after 30 s of constant illumination at 52 microLumen followed by abrupt photostimulator switch off. Eventually, the ciliospinal reflex was regntered during room illumination and pinching of the skin in the left supraclavicular fossa. A minimum of 3 responses of each reflex was recorded for each subject. The speed of the paper was 50 mm/s during reflex registration and 10 mm/s during area registration in darkness and during determination of threshold and maximum intensity of the light stimulus. Areas and latencies were measured with a ruler from coded curves. The following parameters were obtained: the dark area was the mean area during the 2-min recording interval, the latency of the PLR was the period from start of stimulus until pupil area had decreased by 3 % of the amplitude response, start areas for the various reflexes were the mean areas during the last second before stimulus application, the amplitude the difference between start area and maximum response area, the maximum response rate was the maximum declination or inclination of the reflex response and the 50 % redilatation time of the PLR the period from maximum pupillary constriction until half of the amplitude response was regained.
Statistics
The following 13 pupillographic measures were defined apriori as statistical study parameters : pupil area in darkness, the threshold, the latency and the 50 % redilatation time of PLR, the relative amplitude and the maximum response rate of the light, dark, accommodation and ciliospinal reflexes, as well as the amplitude of pupillary unrest in darkness. According to Bonferroni a 0.0038 level of significance was applied for the t-test. For further aposteriori analysis of the results McPerson’s correlation moment, an analysis of variance and the Mann Whitney test were applied using a 5 % limit of significance. Latencies of visual evoked potentials were considered abnormal if values exceeded the normal mean k 3SD’s. Values are means k SD’s or means and ranges. Results
Clinical data are shown in Table 1. Three subjects in both groups had a visual acuity of 20/30, 7 MS patients and 6 controls had an acuity of 20/20 and 8 MS patients and 5 controls 20/10. The latency of VEP (P100) was abnormal bilaterally in 13 patients and unilaterally in 5. No VEP abnormalities were detected in any of the control subjects. Rest pupil area in darkness was unchanged (38.9 t 1.8 mm2 in MS vs 35.7 2 1.5 mm2 in controls). The amplitude of spontaneous pupillary oscillations was similar in patients and controls during darkness (2.35 0.41% vs 2.45 0.33%, respectively) and increasing light intensity (8.09 & 1.45% vs 8.52 2.10%, respectively). Also the individual variances of the mean amplitude of pupillary unrest were unchanged in MS. Neither were any irregularities of pupillary cycling observed during constant increase of light intensity. Table 2 shows that pupil start area, response amplitude and maximum response rate of the light, dark, accommodation and ciliospinal reflexes all were unchanged. The stimulus
Table 1. Clinical data from 18 MS patients divided into three groups by walking performance (1: without support; 2: with cane; 3: personal support only) Values are means and ranges.
(n = 18)
Group 1 (n = 5)
Group 2 (n = 8)
Group 3 (n = 5)
32 (20-45) 919 11 (2-19) 132 (90-172)
27 (20-32) 312 8 (2-1 1) 117 (90-150)
34 (24-45) 414 11 (5-19) 134 (110-172)
33 (26-41) 213 14 (8-17) 144 (128-170)
All
Age (yr) Sex (rim) MS duration (yr) VEP (ms) (left-side stimulation)
Fourteen controls (6 women) were aged 31 (23-44) yr and had VEP latency values of 100 (94-1 10) ms.
393
Jakobsen Table 2. Pupillary start area, amplitude and maximum response velocity of the evoked light, dark, accommodation and ciliospinal reflexes in 14 controls and in 18 MS patients. Values are group means and their SD's.
Start area
Response amplitude
Response amplitude
lmm2)
hm'1
1%)
Maximum response velocity Imm'lsec) ~~~
tight reflex
C MS
33.1 k 5.0 34.9 k 7.0
- 13.952.6 - 15.5 f3.8
-42.15 5.5 -45.1 k 8.0
-53.2f 1.2 -57.2+ 13.5
Accommodation reflex
C MS
35.5k6.7 37.05 6.9
- 12.3f5.4
-13.4k7.7
- 36.9 k 19.3 - 35.7 f 19.2
- 19.0+ 12.1 - 19.6+ 9.2
Dark reflex
C MS
23.7 5.6 26.1 k 7.5
6.6 3.0 5.3 2.4
31.0k 19.3 22.2k 15.7
5.1+ 2.1 5.0+ 1.9
Ciliospinal reflex
C MS
25.0k6.2 28.1 k 6 . 6
5.5 f2.6 4.4 k 2.4
22.4k 10.1 17.1 k 10.7
5.0+ 1.1 4.ak 1.7
threshold (0.27 0.13 microLumen in MS vs 0.25 2 0.12 microLumen in controls) and the 50% redilatation time of the PLR (803 305 ms in MS vs 724 f. 152 ms in controls) remained intact also. However, the latency of the PLR was significantly prolonged from 240 & 10 ms in controls to 263 k 23 ms in MS, the p-value being
J. Jakobsen
Eighteen MS patients with visual acuity of 20/30 or better and without recent visual complaints, and 14 age- and sex-matched controls were studied by TV pupillography. The response amplitude and the maximum rate of pupillary constriction or dilation of the light, dark, accommodation and ciliospinal reflexes were unchanged. The latency of the pupillary light response (PLR), however, was prolonged and closely related to walking performance (R = 0.76; p < 0.001). No relationship was established between PLR latency and previous history of optic neuritis or latency of the VEP. It is concluded that MS patients with preserved visual acuity haye only discrete autonomic pupillary disturbances and that the PLR delay is related to disease progression.
Slmptoms of dysfunction of the autonomic nervous s>stem are common in multiple sclerosis (MS). Ssx-ere disturbances of sexual functions and of the urinw bladder and the bowel develop in many paricnts. In addition, simple bedside tests have demonstrated abnormalities of sweating and of cardiox-ascular tone (1-4). It is generally assumed that autonomic dysfunction in MS is due to multiple discrete lesions of various central pathways rather than to a generalized dysautonomic state. Pupillary functions have attracted only little attention in studies of autonomic function in MS. However, a simple measure of duration of light-provoked pupillary oscillations, the pupil cycle time, is considerably prolonged in optic neuritis (5-7). Pupillographic studies of optic neuritis patients have demonstrated decreased amplitude and increased latency of the response of the pupillary light reflex (PLR) as well as irregular pupillary cycling (8, 9). Whether similar pupillary abnormalities occur in MS patients without signs of active optic neuritis and with preserved visual acuity is unknown. To examine the extent of autonomic dysfunction of the pupil in MS the light, dark, accommodation and ciliospinal reflexes, as well as pupillary unrest, were studied by continuous registration of pupil area as a function of time in MS patients with visual acuity of 20/30 or better and without recent symptoms of eye disease. Subjects and methods
Eighteen patients with definite multiple sclerosis (10) and 14 controls were accepted for study and gave informed consent to the protocol. Inclusion criteria were no visual complaints within the last year, no clinical detectable visual field defects, visual acuity of 20/30 or better, no history other than MS of diseases
392
Department of Neurology, Aarhus University Hospital, Denmark
Key words: multiple sclerosis; pupillary function; autonomic function Department of Neurology (208 11, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen 0, Denmark Accepted for publication August 15, 1990
known to influence autonomic functions and no constant medication. No analgesics or sedatives were allowed for the last 72 h before pupillography and on the day of study subjects were fasting and not allowed to drink tea, coffee or alcohol, or to smoke. To preserve statistical power severity of MS was classified apriori into three stages only: Stage 1 patients could walk 1OOOm without any support; Stage 2 patients needed a cane for walking; and Stage 3 patients either were wheelchair-bound or needed personal support to move more than 50 m. Controls were age and sex matched with no history of ophthalmologc disease. For comparison with the pupillographic data, pattern-shift evoked potentials (VEP) were recorded bilaterally in both groups of subject. Pupillography
Continuous registration of pupil area of the left eye was performed with an infrared sensitive TV camera (Iriscorder, Hamamatsu, Japan) (1 1). Analogue output was delivered to an electrocardiograph (Elena Schbnander, Sweden) which also recorded time and the intensity of the light stimulus. Examination took place in darkness to which the subject had adapted for 15 min. A red fixation point at an individually adjusted optically infinite distance was used to prevent accommodation. In darkness pupil area was registered for 2 min. Then the accommodation response was provoked by asking the subject to focus a red fixation cross in the near point of the right eye. For study of the PLR a stimulus of yellow-green light was presented to the right eye by a photostimulator (Hamamatsu, Japan) (1 1). In the plane of the pupil the converging light beam had a diameter of 1 mm thereby eliminating variation in light input
Pupillary function in MS
due to changes of pupil size. At the retinal level the light beam covered an area of approximately the size of the optic disc and was located one papillary diameter above the disc. The threshold and the stimulus needed for the maximum pupillary response was registered following gradual increase of the square waves‘ light intensity from 0.1 to 52 microLumen, while the stimulus duration was kept constant at 256 ms. The PLR response was elicited by a 2 to 4 times supramaximal light stimulus with a 60 s interval between recordings. Autonomic nervous system homeostasis of pupil area is maintained by a state of fluctuation, so called pupillary unrest. The mean amplitude of pupillary fluctuations and its variance during two 10-s intervals in darkness and during constant increase of the light stimulus by 0.8 microLumen/s was studied also. Subsequently, the pupillary dark reflex was recorded after 30 s of constant illumination at 52 microLumen followed by abrupt photostimulator switch off. Eventually, the ciliospinal reflex was regntered during room illumination and pinching of the skin in the left supraclavicular fossa. A minimum of 3 responses of each reflex was recorded for each subject. The speed of the paper was 50 mm/s during reflex registration and 10 mm/s during area registration in darkness and during determination of threshold and maximum intensity of the light stimulus. Areas and latencies were measured with a ruler from coded curves. The following parameters were obtained: the dark area was the mean area during the 2-min recording interval, the latency of the PLR was the period from start of stimulus until pupil area had decreased by 3 % of the amplitude response, start areas for the various reflexes were the mean areas during the last second before stimulus application, the amplitude the difference between start area and maximum response area, the maximum response rate was the maximum declination or inclination of the reflex response and the 50 % redilatation time of the PLR the period from maximum pupillary constriction until half of the amplitude response was regained.
Statistics
The following 13 pupillographic measures were defined apriori as statistical study parameters : pupil area in darkness, the threshold, the latency and the 50 % redilatation time of PLR, the relative amplitude and the maximum response rate of the light, dark, accommodation and ciliospinal reflexes, as well as the amplitude of pupillary unrest in darkness. According to Bonferroni a 0.0038 level of significance was applied for the t-test. For further aposteriori analysis of the results McPerson’s correlation moment, an analysis of variance and the Mann Whitney test were applied using a 5 % limit of significance. Latencies of visual evoked potentials were considered abnormal if values exceeded the normal mean k 3SD’s. Values are means k SD’s or means and ranges. Results
Clinical data are shown in Table 1. Three subjects in both groups had a visual acuity of 20/30, 7 MS patients and 6 controls had an acuity of 20/20 and 8 MS patients and 5 controls 20/10. The latency of VEP (P100) was abnormal bilaterally in 13 patients and unilaterally in 5. No VEP abnormalities were detected in any of the control subjects. Rest pupil area in darkness was unchanged (38.9 t 1.8 mm2 in MS vs 35.7 2 1.5 mm2 in controls). The amplitude of spontaneous pupillary oscillations was similar in patients and controls during darkness (2.35 0.41% vs 2.45 0.33%, respectively) and increasing light intensity (8.09 & 1.45% vs 8.52 2.10%, respectively). Also the individual variances of the mean amplitude of pupillary unrest were unchanged in MS. Neither were any irregularities of pupillary cycling observed during constant increase of light intensity. Table 2 shows that pupil start area, response amplitude and maximum response rate of the light, dark, accommodation and ciliospinal reflexes all were unchanged. The stimulus
Table 1. Clinical data from 18 MS patients divided into three groups by walking performance (1: without support; 2: with cane; 3: personal support only) Values are means and ranges.
(n = 18)
Group 1 (n = 5)
Group 2 (n = 8)
Group 3 (n = 5)
32 (20-45) 919 11 (2-19) 132 (90-172)
27 (20-32) 312 8 (2-1 1) 117 (90-150)
34 (24-45) 414 11 (5-19) 134 (110-172)
33 (26-41) 213 14 (8-17) 144 (128-170)
All
Age (yr) Sex (rim) MS duration (yr) VEP (ms) (left-side stimulation)
Fourteen controls (6 women) were aged 31 (23-44) yr and had VEP latency values of 100 (94-1 10) ms.
393
Jakobsen Table 2. Pupillary start area, amplitude and maximum response velocity of the evoked light, dark, accommodation and ciliospinal reflexes in 14 controls and in 18 MS patients. Values are group means and their SD's.
Start area
Response amplitude
Response amplitude
lmm2)
hm'1
1%)
Maximum response velocity Imm'lsec) ~~~
tight reflex
C MS
33.1 k 5.0 34.9 k 7.0
- 13.952.6 - 15.5 f3.8
-42.15 5.5 -45.1 k 8.0
-53.2f 1.2 -57.2+ 13.5
Accommodation reflex
C MS
35.5k6.7 37.05 6.9
- 12.3f5.4
-13.4k7.7
- 36.9 k 19.3 - 35.7 f 19.2
- 19.0+ 12.1 - 19.6+ 9.2
Dark reflex
C MS
23.7 5.6 26.1 k 7.5
6.6 3.0 5.3 2.4
31.0k 19.3 22.2k 15.7
5.1+ 2.1 5.0+ 1.9
Ciliospinal reflex
C MS
25.0k6.2 28.1 k 6 . 6
5.5 f2.6 4.4 k 2.4
22.4k 10.1 17.1 k 10.7
5.0+ 1.1 4.ak 1.7
threshold (0.27 0.13 microLumen in MS vs 0.25 2 0.12 microLumen in controls) and the 50% redilatation time of the PLR (803 305 ms in MS vs 724 f. 152 ms in controls) remained intact also. However, the latency of the PLR was significantly prolonged from 240 & 10 ms in controls to 263 k 23 ms in MS, the p-value being
