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Relationship between age and autonomic neuropathy in diabetes mellitus
Diabetes Research and Clinical Practice, 9 (1990) 49-53
Elsevier
49
DIABET 00373
Relationship between age and autonomic neuropathy diabetes mellitus Nobutoshi
Kuroda,
Hiroshi Taniguchi,
Second Department of Internal Medicine and
in
Shigeaki Baba and ’ Misao Yamamoto
’ Department of Ophthalmology, Kobe University School of Medicine, Kobe, Japan (Received 3 August 1989) (Revision received 23 October 1989) (Accepted 24 October 1989)
Summary The influence of age on diabetic autonomic neuropathy was studied. In the present study autonomic neuropathy was assessed by cardiac beat-to-beat variation during deep breathing (BBV) and pupil area prior to photic stimulus (Al). In the studies on BBV a total of 440 subjects (11-82 years in age) were divided into three groups: those with a duration of diabetes of less than 5 years and without obvious diabetic complications; those with a duration of diabetes of longer than 5 years and with diabetic complications; and non-diabetic, healthy subjects. The relationship between BBV and age was examined in each group. In the studies on Al a total of 101 subjects (22-75 years in age) were investigated in the same way. The results were as follows: (1) The autonomic nerve function of young diabetics corresponds to that of old non-diabetics in terms of cardiac beat-to-beat variation and pupil area prior to photic stimulus; (2) in young diabetics duration of diabetes and the complications influence the autonomic nerve function; (3) autonomic nerve function is related to age. Age is more influential than duration of diabetes and diabetic complications, especially in the older subjects. Key words: Aging; Autonomic
neuropathy ; Cardiac beat-to-beat
Introduction Recently some quantitative methods for the measurement of autonomic nerve function have been developed. Especially, cardiac beat-to-beat variation and the pupillary light reflex are widely Address for correspondence: N. Kuroda, M.D., Second Department of Internal Medicine, Kobe University School of Medicine, 5-1, Kusunoki-cho 7 chome, Chuo-ku, Kobe 650, Japan. 0168-8227/90/$03.50
0 1990 Elsevier Science Publishers
variation;
Pupil
used in clinical practice, since they are simple and non-invasive [ l-41. Autonomic neuropathy is frequently observed in diabetes mellitus and is sometimes life-threatening [ 51. Therefore, its early detection is attempted using these methods. Autonomic neuropathy has been reported often to be present simultaneously with the development of impairment of carbohydrate metabolism [ 6-91. Hyperglycemia in diabetes mellitus is one of the most important causes of autonomic neuropathy. Moreover, it is well known that autonomic nerve
B.V. (Biomedical
Division)
50
dysfunction progresses with aging [ 10,111. In the present study we investigated whether age is influential on autonomic nerve function with regard to cardiac beat-to-beat variation and pupil area prior to photic stimulus in diabetic subjects as well as non-diabetic controls.
Subjects and methods Two hundred and forty people with diabetes mellitus (DM) and 204 non-diabetic healthy subjects (control) (128 men and 76 women, 1 l-80 years in age) took part in the study on cardiac beat-to-beat variation during deep breathing (BBV). Diabetic patients were divided into two groups : those with a duration of diabetes of less than 5 years and without obvious diabetic complications (DM-I); and those with a duration of diabetes of longer than 5 years and with diabetic complications (DM-II). DM-I and DM-II comprised 101 (57 men and 44 women, 11-77 years in age) and 135 (69 men and 66 women, 24-82 years in age) subjects, respectively, and the durations of DM were 1.6 k 0.1 (mean k SEM) and 13.5 + 0.6 years, respectively. Diabetic complication was defined as obvious retinopathy, nephropathy and neuropathy. Diabetic retinopathy was considered to be present by an ophthalmologist, one of the authors of this paper. Nephropathy was defined as consistent proteinuria, while neuropathy was defined as the existence of neural symptoms such as spontaneous pain and feeling of numbness in the extremities, orthostatic hypotension, abnormal bowel movement, dysuria and sexual dysfunction. The BBV, after a 20-min rest in supine position, was recorded during 5 successive maximal respiratory cycles with inspiration and expiration each lasting 5 s, using a computerized device developed in our laboratory (Autonomic R-105@‘, M. E. Commercial, Osaka, Japan), and expressed as the mean of differences between the maximal and the minimal heart rate which were obtained in five respiratory cycles. On the other hand, the pupil area prior to photic
stimulus (Al) was examined in 37 control subjects (14 men and 23 women, 24-64 years in age), 34 patients of DM-I (17 men and 17 women, 22-73 years in age) and 30 patients of DM-II (12 men and 18 women, 25-75 years in age), and the duration of DM in DM-I and DM-II was 1.6 k 0.2 (mean + SEM) and 12.8 k 1.2 years, respectively. The Al in bilateral eyes was measured after a 15-min adaptation to darkness using a computerized infrared video pupillography apparatus (HTV-C301, Hamamatsu TV Co., Ltd., Hamamatsu, Japan). The relationship between the data and the age in each group was examined and the analysis for comparison between the two regression lines was done using Student’s t-test.
Results In every group, the BBV values were negatively correlated with the age (Figs. l-3). The BBV values were maximal for the young control subjects, while minimal for DM-II. The slope of the regression line of BBV against age was the steepest in the control, while it was the most gentle in DM-II and there were significant differences among the three regression lines. With
y=-0.353x+30.135 n=204 r=-0.741 p
Fig. 1. Relationship between cardiac beat-to-beat variation and age in healthy subjects (control). The solid line indicates the regression line.
51 ‘lo
1 Y=-0.227x+22.363 .
rl=,Ol r=-0.553 P' 0.01
* . ..I
.
. .
.
. -
.
* : . ._
*
, *
-t._. -._. .,
*.
---.._..__
*
4..
.
* “__.,
.:
‘;-._.. . . q.. . 2. ‘._.. .- :
.
.
. .
.
.
.
l
--
-.. . .
. .
b.l.
. . .
*.
: :
.
.
a
10
20
30
.- . . . .I
.
.
o!
*
*
*-
I
40
50
60
70
90
90
Age (years)
Fig. 2. Relationship and age in subjects 5 years and without The dotted
between cardiac beat-to-beat variation with a duration of diabetes of less than obvious diabetic complications (DM-I). line indicates the regression line.
Fig. 4. Regression lines of cardiac beat-to-beat variation against age in control, DM-I and DM-II. The solid, dotted and broken lines indicate the regression line in control, DM-I and DM-II, respectively. *P < 0.005.
Y--0.114x+12.7U "=I35 r=-0.320 p
1
20
0
20
30
40 50 Age (years)
60
70
1
80
Fig. 5. Relationship between pupil area prior to photic stimulus and age in healthy subjects (control). The solid line indicates the regression line. Fig. 3. Relationship between cardiac beat-to-beat variation and age in subjects with a duration of diabetes of longer than 5 years and with diabetic complications (DM-II). The broken line indicates the regression line.
aging the lines came close and finally crossed each other after the age of 60 years (Fig. 4). The A 1 values showed a similar tendency to the above-mentioned results of BBV (Figs. 5-S). There was a significant difference between the two regression lines of the control and DM-II groups. The regression lines of Al against age crossed after the age of 70 years instead of 60 years for the BBV (Fig. 8).
; 80 k 3 ; 60 3v)
\ GOi+ io
io
40
!io
60
70
,
80
Age (years)
Fig. 6. Relationship between pupil stimulus and age in subjects with a less than 5 years and without obvious (DM-I). The dotted line indicates
area prior to photic duration of diabetes of diabetic complications the regression line.
52 i:
y=-o.2oox+27.563
807
d
n=f30
Y
; 60-
r=-0.345
(0
P
0 d
40s :, L t 20 m c a
. --'-----__&_ t
lf olf-1I
20
30
* f A : '::.a,, u,-I--&=:*a-___ ,r t+r:
40 50 Age (years)
60
70
80
Fig. 7. Relationship between pupil area prior to photic stimulus and age in subjects with a duration of diabetes of longer than 5 years and with diabetic complications (DM-II). The broken line indicates the regression line.
1
1 2 i 60 3Y)80 ;:
=
B 0
0
20
30
40
50
60
70
neuropathy was investigated in two groups of diabetics, i.e., relatively mild cases with short duration of diabetes and without obvious diabetic complications, and severe cases with longer duration of diabetes and with diabetic complications. Non-diabetic healthy subjects were included as controls. Consequently, in the older diabetics the age seemed to be more influential on diabetic autonomic neuropathy than duration of diabetes and the complications. Besides, in the diabetics with a longer duration of diabetes or other diabetic complications, autonomic neuropathy gets worse. Interestingly, similar suggestions were obtained from the studies on cardiovascular reflex and on pupillary changes both of which reflect autonomic nerve function but differ in the relevant anatomical site. Thus, the influence of aging should be considered for the assessment of diabetic autonomic neuropathy, and especially in older diabetics it is important to assess autonomic neuropathy carefully.
1
80
Age (years)
Fig. 8. Regression lines of pupil area prior to photic stimulus against age in control, DM-I and DM-II. The solid, dotted and broken lines indicate the regression line in control, DM-I and DM-II, respectively. *P < 0.005; ‘P < 0.5; “P < 0.1.
Discussion BBV has been established as a method for assessing parasympathetic nerve function and used commonly as a basic test for autonomic neuropathy [ 1,121. Pupillary change also reflects autonomic nerve function. The recent development of infrared videopupillography has enabled us to study pupillary light reflex quantitatively [ 131. Among various components of pupillary light reflex, Al is considered to chiefly reflect sympathetic function [ 14,151. Many studies regarding the influence of aging on BBV and Al have been reported in healthy subjects [ 16,171. In the present study, the influence of aging on diabetic autonomic
References Wheeler, T. and Watkins, P. J. (1973) Cardiac denervation in diabetes. Br. Med. J. 4, 584-586. Ishikawa, S., Naito, M. and Inaba, K. (1968) A new videopupillography. Ophthalmologica 160, 248-259. Utsumi, T. (1978) Open-loop infrared videopupillography - a preliminary report. Acta Sot. Ophthalmol. Jpn. 82, 315-321. Smith, S. A. and Dewhirst, R. R. (1986) A simple diagnostic test for pupillary abnormality in diabetic autonomic neuropathy. Diabet. Med. 3, 38-41. Ewing, D. J., Campbell, I. W. and Clarke, B. F. (1976) Mortality in diabetic autonomic neuropathy. Lancet i, 601-603. Himei, H., Aoyama, K. and Uehara, H. (1980) Autonomic nerve dysfunction in borderline diabetes mellitus. In: W. Waldhausl and K. G. M. M. Alberti (Eds.), Proceedings of the 10th Congress of the International Diabetes Federation (abstract), Excerpta Medica, Amsterdam, p. 92. Cederholm, J., Fagius, J. and Wibell, L. (1985) Peripheral and autonomic nerve function in glucose intolerance. Diabet. Metabol. 11, 87-91. Pfeifer, M. A., Weinberg, C. R., Cook, D. L. et al. (1984) Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care 7, 447-453.
53 9 Kuroda, N., Hiroshi, T., Shigeaki, B. et al. (1989) The pupillary light reflex in borderline diabetics. J. Intern. Med. Res. 17, 205-211. 10 Taniguchi, H., inui, M., Fujii, M. et al. (1983) Cardiac beat-to-beat variation as an indicator of neuropathy and the frequency of its abnormality in diabetes mellitus. Tohoku J. Exp. Med. 141,471-478. 11 Kuroda, N., Hiroshi, T., Shigeaki, B. et al. (1989) Pupillary light reflex in healthy subjects: influence of the aging. J. Auton. Nerv. Syst. 26, 78-81. 12 Kuroda, N., Hiroshi, T. and Shigeaki, B. (1989) Pharmacological assessment of cardiac beat-to-beat variation as an indicator of parasympathetic nerve function. J. Auton. Nerv. Syst. 26, 129-133. 13 Kuroda, N., Hiroshi, T., Shigeaki, B. et al. (1989) Pupillary light reflex in borderline diabetes mellitus. Diab. Res. Clin. Pratt. 6. 89-94.
14 Hashimoto, T., Utsumi, T. and Onishi, Y. (1978) Effect of topically administrated adrenergics and choline&s on pupillary dynamics under open-loop condition. Folia Ophthalmol. Jpn. 29, 1138-l 147. 15 Hashimoto, T., Utsumi, T. and Namba, K. (1979) Effects of topically administrated cholinolytic and adrenolytic agents on pupillary dynamics under open-loop photic stimulus. Folia Ophthalmol. Jpn. 30, 1008-1015. 16 Oikawa, N. (1983) Quantitative evaluation of diabetic autonomic neuropathy by measuring heart rate variations - establishment of the normal range for the diagnosis of autonomic neuropathy. J. Jpn. Diab. Sot. 26, 1123-I 13 1. 17 Onishi, Y., Utsumi, T., Hashimoto, T. et al. (1979) Pupillary dynamics under openloop photic stimulus - variations in age and sex. Folia Ophthalmol. Jpn. 30, 921-926.
Elsevier
49
DIABET 00373
Relationship between age and autonomic neuropathy diabetes mellitus Nobutoshi
Kuroda,
Hiroshi Taniguchi,
Second Department of Internal Medicine and
in
Shigeaki Baba and ’ Misao Yamamoto
’ Department of Ophthalmology, Kobe University School of Medicine, Kobe, Japan (Received 3 August 1989) (Revision received 23 October 1989) (Accepted 24 October 1989)
Summary The influence of age on diabetic autonomic neuropathy was studied. In the present study autonomic neuropathy was assessed by cardiac beat-to-beat variation during deep breathing (BBV) and pupil area prior to photic stimulus (Al). In the studies on BBV a total of 440 subjects (11-82 years in age) were divided into three groups: those with a duration of diabetes of less than 5 years and without obvious diabetic complications; those with a duration of diabetes of longer than 5 years and with diabetic complications; and non-diabetic, healthy subjects. The relationship between BBV and age was examined in each group. In the studies on Al a total of 101 subjects (22-75 years in age) were investigated in the same way. The results were as follows: (1) The autonomic nerve function of young diabetics corresponds to that of old non-diabetics in terms of cardiac beat-to-beat variation and pupil area prior to photic stimulus; (2) in young diabetics duration of diabetes and the complications influence the autonomic nerve function; (3) autonomic nerve function is related to age. Age is more influential than duration of diabetes and diabetic complications, especially in the older subjects. Key words: Aging; Autonomic
neuropathy ; Cardiac beat-to-beat
Introduction Recently some quantitative methods for the measurement of autonomic nerve function have been developed. Especially, cardiac beat-to-beat variation and the pupillary light reflex are widely Address for correspondence: N. Kuroda, M.D., Second Department of Internal Medicine, Kobe University School of Medicine, 5-1, Kusunoki-cho 7 chome, Chuo-ku, Kobe 650, Japan. 0168-8227/90/$03.50
0 1990 Elsevier Science Publishers
variation;
Pupil
used in clinical practice, since they are simple and non-invasive [ l-41. Autonomic neuropathy is frequently observed in diabetes mellitus and is sometimes life-threatening [ 51. Therefore, its early detection is attempted using these methods. Autonomic neuropathy has been reported often to be present simultaneously with the development of impairment of carbohydrate metabolism [ 6-91. Hyperglycemia in diabetes mellitus is one of the most important causes of autonomic neuropathy. Moreover, it is well known that autonomic nerve
B.V. (Biomedical
Division)
50
dysfunction progresses with aging [ 10,111. In the present study we investigated whether age is influential on autonomic nerve function with regard to cardiac beat-to-beat variation and pupil area prior to photic stimulus in diabetic subjects as well as non-diabetic controls.
Subjects and methods Two hundred and forty people with diabetes mellitus (DM) and 204 non-diabetic healthy subjects (control) (128 men and 76 women, 1 l-80 years in age) took part in the study on cardiac beat-to-beat variation during deep breathing (BBV). Diabetic patients were divided into two groups : those with a duration of diabetes of less than 5 years and without obvious diabetic complications (DM-I); and those with a duration of diabetes of longer than 5 years and with diabetic complications (DM-II). DM-I and DM-II comprised 101 (57 men and 44 women, 11-77 years in age) and 135 (69 men and 66 women, 24-82 years in age) subjects, respectively, and the durations of DM were 1.6 k 0.1 (mean k SEM) and 13.5 + 0.6 years, respectively. Diabetic complication was defined as obvious retinopathy, nephropathy and neuropathy. Diabetic retinopathy was considered to be present by an ophthalmologist, one of the authors of this paper. Nephropathy was defined as consistent proteinuria, while neuropathy was defined as the existence of neural symptoms such as spontaneous pain and feeling of numbness in the extremities, orthostatic hypotension, abnormal bowel movement, dysuria and sexual dysfunction. The BBV, after a 20-min rest in supine position, was recorded during 5 successive maximal respiratory cycles with inspiration and expiration each lasting 5 s, using a computerized device developed in our laboratory (Autonomic R-105@‘, M. E. Commercial, Osaka, Japan), and expressed as the mean of differences between the maximal and the minimal heart rate which were obtained in five respiratory cycles. On the other hand, the pupil area prior to photic
stimulus (Al) was examined in 37 control subjects (14 men and 23 women, 24-64 years in age), 34 patients of DM-I (17 men and 17 women, 22-73 years in age) and 30 patients of DM-II (12 men and 18 women, 25-75 years in age), and the duration of DM in DM-I and DM-II was 1.6 k 0.2 (mean + SEM) and 12.8 k 1.2 years, respectively. The Al in bilateral eyes was measured after a 15-min adaptation to darkness using a computerized infrared video pupillography apparatus (HTV-C301, Hamamatsu TV Co., Ltd., Hamamatsu, Japan). The relationship between the data and the age in each group was examined and the analysis for comparison between the two regression lines was done using Student’s t-test.
Results In every group, the BBV values were negatively correlated with the age (Figs. l-3). The BBV values were maximal for the young control subjects, while minimal for DM-II. The slope of the regression line of BBV against age was the steepest in the control, while it was the most gentle in DM-II and there were significant differences among the three regression lines. With
y=-0.353x+30.135 n=204 r=-0.741 p
Fig. 1. Relationship between cardiac beat-to-beat variation and age in healthy subjects (control). The solid line indicates the regression line.
51 ‘lo
1 Y=-0.227x+22.363 .
rl=,Ol r=-0.553 P' 0.01
* . ..I
.
. .
.
. -
.
* : . ._
*
, *
-t._. -._. .,
*.
---.._..__
*
4..
.
* “__.,
.:
‘;-._.. . . q.. . 2. ‘._.. .- :
.
.
. .
.
.
.
l
--
-.. . .
. .
b.l.
. . .
*.
: :
.
.
a
10
20
30
.- . . . .I
.
.
o!
*
*
*-
I
40
50
60
70
90
90
Age (years)
Fig. 2. Relationship and age in subjects 5 years and without The dotted
between cardiac beat-to-beat variation with a duration of diabetes of less than obvious diabetic complications (DM-I). line indicates the regression line.
Fig. 4. Regression lines of cardiac beat-to-beat variation against age in control, DM-I and DM-II. The solid, dotted and broken lines indicate the regression line in control, DM-I and DM-II, respectively. *P < 0.005.
Y--0.114x+12.7U "=I35 r=-0.320 p
1
20
0
20
30
40 50 Age (years)
60
70
1
80
Fig. 5. Relationship between pupil area prior to photic stimulus and age in healthy subjects (control). The solid line indicates the regression line. Fig. 3. Relationship between cardiac beat-to-beat variation and age in subjects with a duration of diabetes of longer than 5 years and with diabetic complications (DM-II). The broken line indicates the regression line.
aging the lines came close and finally crossed each other after the age of 60 years (Fig. 4). The A 1 values showed a similar tendency to the above-mentioned results of BBV (Figs. 5-S). There was a significant difference between the two regression lines of the control and DM-II groups. The regression lines of Al against age crossed after the age of 70 years instead of 60 years for the BBV (Fig. 8).
; 80 k 3 ; 60 3v)
\ GOi+ io
io
40
!io
60
70
,
80
Age (years)
Fig. 6. Relationship between pupil stimulus and age in subjects with a less than 5 years and without obvious (DM-I). The dotted line indicates
area prior to photic duration of diabetes of diabetic complications the regression line.
52 i:
y=-o.2oox+27.563
807
d
n=f30
Y
; 60-
r=-0.345
(0
P
0 d
40s :, L t 20 m c a
. --'-----__&_ t
lf olf-1I
20
30
* f A : '::.a,, u,-I--&=:*a-___ ,r t+r:
40 50 Age (years)
60
70
80
Fig. 7. Relationship between pupil area prior to photic stimulus and age in subjects with a duration of diabetes of longer than 5 years and with diabetic complications (DM-II). The broken line indicates the regression line.
1
1 2 i 60 3Y)80 ;:
=
B 0
0
20
30
40
50
60
70
neuropathy was investigated in two groups of diabetics, i.e., relatively mild cases with short duration of diabetes and without obvious diabetic complications, and severe cases with longer duration of diabetes and with diabetic complications. Non-diabetic healthy subjects were included as controls. Consequently, in the older diabetics the age seemed to be more influential on diabetic autonomic neuropathy than duration of diabetes and the complications. Besides, in the diabetics with a longer duration of diabetes or other diabetic complications, autonomic neuropathy gets worse. Interestingly, similar suggestions were obtained from the studies on cardiovascular reflex and on pupillary changes both of which reflect autonomic nerve function but differ in the relevant anatomical site. Thus, the influence of aging should be considered for the assessment of diabetic autonomic neuropathy, and especially in older diabetics it is important to assess autonomic neuropathy carefully.
1
80
Age (years)
Fig. 8. Regression lines of pupil area prior to photic stimulus against age in control, DM-I and DM-II. The solid, dotted and broken lines indicate the regression line in control, DM-I and DM-II, respectively. *P < 0.005; ‘P < 0.5; “P < 0.1.
Discussion BBV has been established as a method for assessing parasympathetic nerve function and used commonly as a basic test for autonomic neuropathy [ 1,121. Pupillary change also reflects autonomic nerve function. The recent development of infrared videopupillography has enabled us to study pupillary light reflex quantitatively [ 131. Among various components of pupillary light reflex, Al is considered to chiefly reflect sympathetic function [ 14,151. Many studies regarding the influence of aging on BBV and Al have been reported in healthy subjects [ 16,171. In the present study, the influence of aging on diabetic autonomic
References Wheeler, T. and Watkins, P. J. (1973) Cardiac denervation in diabetes. Br. Med. J. 4, 584-586. Ishikawa, S., Naito, M. and Inaba, K. (1968) A new videopupillography. Ophthalmologica 160, 248-259. Utsumi, T. (1978) Open-loop infrared videopupillography - a preliminary report. Acta Sot. Ophthalmol. Jpn. 82, 315-321. Smith, S. A. and Dewhirst, R. R. (1986) A simple diagnostic test for pupillary abnormality in diabetic autonomic neuropathy. Diabet. Med. 3, 38-41. Ewing, D. J., Campbell, I. W. and Clarke, B. F. (1976) Mortality in diabetic autonomic neuropathy. Lancet i, 601-603. Himei, H., Aoyama, K. and Uehara, H. (1980) Autonomic nerve dysfunction in borderline diabetes mellitus. In: W. Waldhausl and K. G. M. M. Alberti (Eds.), Proceedings of the 10th Congress of the International Diabetes Federation (abstract), Excerpta Medica, Amsterdam, p. 92. Cederholm, J., Fagius, J. and Wibell, L. (1985) Peripheral and autonomic nerve function in glucose intolerance. Diabet. Metabol. 11, 87-91. Pfeifer, M. A., Weinberg, C. R., Cook, D. L. et al. (1984) Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care 7, 447-453.
53 9 Kuroda, N., Hiroshi, T., Shigeaki, B. et al. (1989) The pupillary light reflex in borderline diabetics. J. Intern. Med. Res. 17, 205-211. 10 Taniguchi, H., inui, M., Fujii, M. et al. (1983) Cardiac beat-to-beat variation as an indicator of neuropathy and the frequency of its abnormality in diabetes mellitus. Tohoku J. Exp. Med. 141,471-478. 11 Kuroda, N., Hiroshi, T., Shigeaki, B. et al. (1989) Pupillary light reflex in healthy subjects: influence of the aging. J. Auton. Nerv. Syst. 26, 78-81. 12 Kuroda, N., Hiroshi, T. and Shigeaki, B. (1989) Pharmacological assessment of cardiac beat-to-beat variation as an indicator of parasympathetic nerve function. J. Auton. Nerv. Syst. 26, 129-133. 13 Kuroda, N., Hiroshi, T., Shigeaki, B. et al. (1989) Pupillary light reflex in borderline diabetes mellitus. Diab. Res. Clin. Pratt. 6. 89-94.
14 Hashimoto, T., Utsumi, T. and Onishi, Y. (1978) Effect of topically administrated adrenergics and choline&s on pupillary dynamics under open-loop condition. Folia Ophthalmol. Jpn. 29, 1138-l 147. 15 Hashimoto, T., Utsumi, T. and Namba, K. (1979) Effects of topically administrated cholinolytic and adrenolytic agents on pupillary dynamics under open-loop photic stimulus. Folia Ophthalmol. Jpn. 30, 1008-1015. 16 Oikawa, N. (1983) Quantitative evaluation of diabetic autonomic neuropathy by measuring heart rate variations - establishment of the normal range for the diagnosis of autonomic neuropathy. J. Jpn. Diab. Sot. 26, 1123-I 13 1. 17 Onishi, Y., Utsumi, T., Hashimoto, T. et al. (1979) Pupillary dynamics under openloop photic stimulus - variations in age and sex. Folia Ophthalmol. Jpn. 30, 921-926.