Monogr. neural Sci., vol. 3, pp. 60-66 (Karger, Basel 1976)
Changes in Serotonin Metabolism during Migraine Attacks 1 P.l. Kangasniemi Department of Neurology, University of Turku, Turku
Introduction Serotonin has many important roles in normal human physiologic functions. The symptoms of migraine patients resemble various effects of serotonin. Since the original finding of increased urinary 5-hydroxyindoleacetic acid (5-HIAA) during migraine headache (16), the central role of serotonin in migraine pathophysiology has been established. Although other interesting findings have followed this primary fact (4) there are still controversies and questions mainly because of nonhomogenous material and differing experimental methods (6). The purpose of the present study was to quantify the concentration of 5-HIAA in the cerebrospinal fluid (CSF) as well as homovanillic acid (HVA), kallikreinlike enzymes and (j-glucuronidase during spontaneous migraine attacks. 5-HIAA was also estimated as free acid and glucuronide conjugate in the urine of the same patients. These biochemical findings were correlated to each other and to various clinical variables which were registered from the same patients, although not all such variables were registered at the same time.
Material and Methods
I Supported by grants from the Finnish Medical Foundation, the Orion Medical Foundation and the Eemil Aaltonen Foundation.
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The material consisted of 61 migraine patients, 45 with common and 16 with classical migraine. The age of the migraine patients varied from 22 to 48 years, the average being 32 ± 1 years. There were l3 men and 48 women. 13 volunteers, neurologic patients without migraine, served as controls. All the control patients were subjected to the same studies
Kangasniemi
61
which were made on the migraine patients during headache-free intervals. The age of the control patients varied from 23 to 49 years, the average being 32 ± 2 years. The schedule of sampling the CSF and urine and the biochemical analyses of acid monoamines and kallikrein-like enzymes and iJ-glucuronidase activities were reported earlier (8, 9). For the purpose of the correlation studies between biochemical findings and clinical symptoms the patients were asked about the intensity of their headache during the attack, when the biochemical samples were taken. A generally approved scale was used: 1 = headache did not disturb daily activities; 2 = headache caused difficulties in carrying out everyday activities, and 3 = the patients had to lie down because of the headache. For further correlations, the patients were asked about the factors known to trigger their headaches. The following triggering factors were included in the correlation studies: menstrual cycle and oral contraceptives, stress, high temperature (sauna bath), food and early morning. EEG studies were performed routinely using a 16-channel Elema (mingograf 16) apparatus. To correlate the results of the EEG studies with the biochemical findings the EEGs of migraine patients were divided into six groups according to the results: (1) normal EEG; (2) focal abnormality; (3) generalized disturbances; (4) paroxysmal activity; (5) EEG reacting to hyperventilation (HV+), and (6) EEGs which reacted to flicker stimulation (FS+). In order to check the interval treatment every patient received a list to record the frequency and intensity of his headache. The effect of a known drug was calculated by multiplying the intensity of the headache (see above) with the frequency on a monthly basis. An open trial was considered adequate for pizotifen and methysergide. A double-blind crossover trial was used to evalutate the effect of clonidine.
Results
Correlation of Biochemical Changes When 5-HIAA in the CSF was correlated to the other biochemical findings a Significant positive correlation with HVA (p < 0.01) and a significant negative correlation with esterase activity in both early and late headache stages (p < 0.05) were found. 5-HIAA did not correlate either with the enzyme activities in the plasma or with the corresponding concentrations of 5-HIAA in the urine.
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Biochemical Studies 5-Hydroxyindoleacetic acid in the urine. Migraine patients showed the same concentration of 5-HIAA during the migraine-free interval as the control patients (table I). The results of the headache samples showed that rapid changes of 5-HT metabolism are best reflected by the conjugated form, whereas slow changes are best seen from free 5-HIAA. 5-Hydroxyindoleacetic acid in the cerebrospinal fluid. When the means of 5-HIAA in the CSF in different stages of headache and in the classical and common migraine groups were compared to one another and to the means of the control patients, there were no statistically Significant differences between the groups (table II).
total
conjugated
free
(11)
470 ± 50 (11) 140 ± 20 (11) 660 ± 70
510 ± 30 (54) 130±8 (54) 640 ± 40 (54)
550 ± 60 (15) 140 ± 20 (15) 700 ± 70 (15)
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* P < 0.05; ** p < 0.01; *** P < 0.001.
total
conjugated
Control patients free
All
total
conjugated
Classical free
total
conjugated
500 ± 40 (39)1 130 ± 9 (39) 620 ± 40 (39)
Subfraction Pre-geadache of 13-16 h 5-HIAA
Migraine patients Common free
Group
490 ± 50 (56) 470 ± 160* (56) 790 ± 90 (56)
580 ± 160 (15) 410 ± 140 (15) 990 ± 300 (15)
460 ± 30 (41) 490 ± 220 (41) 720 ± 50 (41)
560 ± 40 (58) 410 ± 70*** (58) 950 ± 80*** (58)
520 ± 70 (15) 340 ± 40*** (15) 850 ± 100 (15)
570 ± 40 (43) 440 ± 90** (43) 1,000 ± 100** (43)
750 ± 130 (53) 310 ± 60** (52) 1,030 ± 150* (52)
610 ± 60 (15) 260 ± 30** (14) 900 ± 90 (14)
810 ± 170 (38) 320 ± 10* (38) 1,080 ± 200* (38)
1 Number of patients.
610 ± 40* (56) 410 ± 90** (56) 1,070 ± 140** (56)
600 ± 80 (14) 340 ± 40*** (14) 950 ± 120 (14)
610 ± 40 (42) 430 ± 110* (42) 1,110 ± 180* (42)
first 4 h 20-24 h
third 4 h 8-12 h
rlIst 4 h 0-4h
second 4 h 4-8 h
Later headache
Early headache
720 ± 80* (55) 190 ± 10*** (55) 830 ± 30*** (55)
600 ± 50 (14) 150 ± 20 (14) 740 ± 70 (14)
760 ± 110* (41) 200 ± 20*** (41) 860 ± 40*** (41)
second 4 h 24-28 h
690 ± 30*** (53) 190 ± 8*** (53) 880 ± 40*** (53)
660 ± 70 (14) 190 ± 20 (14) 850 ± 90 (14)
700 ± 30*** (39) 190 ± 10*** (39) 890 ± 40*** (39)
third 4 h 28-32 h
Table I. Free, total and conjugated 5-HIAA (pg/4 h) in urine during different stages of headache attacks and during headache-free intervals in 61 migraine and 13 control patients (mean ± SEM)
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Changes in Serotonin Metabolism during Migraine Attacks
63
Table II. Concentration of 5-HIAA (ng/ml) in the CSF during the different stages of headache attacks and headache-free intervals (mean ± SEM)
Group
Interval stage
Headache stage 4h
24 h
20.9 ± 1.5 (41)1
24.2 ± 1.6 (45)
25.0 ± 1.9 (41)
Classical
23.2 ± 3.0 (15)
24.8±2.7 (16)
24.7 ± 2.9 (14)
All
21.5 ± 1.4 (56)
24.4 ± 1.4 (61)
24.9 ± 1.6 (55)
Migraine patients Common
Control patients
26.5 ± 3.1 (12)
1 Number of patients.
Clinical Correlations 5-HIAA in the CSF did not correlate with the headache intensity. The conjugated 5-HIAA in the urine during the second 4 h after the beginning of the headache showed a nonSignificant positive correlation with the headache. In the group of patients who showed a positive flicker response, 5-HIAA in the CSF was significantly increased in both headache stages compared to the pre-headache level (p < 0.05). In common migraine patients whose headache was triggered by different foods, 5-HIAA in the CSF increased Significantly fro~ the pre-headache to the early and from the early to the late headache stages (p < 0.05). In the migraine patients whose headache was relieved by methysergide treatment, 5-HIAA in the CSF showed an increase in amount from the pre-headache to the later headache stage (p < 0.05). 5-HIAA in the CSF also showed a significant increase from pre-headache to early and late headache stages in classical migraine patients who responded successfully to clonidine or pizotifen treatment (p
Changes in Serotonin Metabolism during Migraine Attacks 1 P.l. Kangasniemi Department of Neurology, University of Turku, Turku
Introduction Serotonin has many important roles in normal human physiologic functions. The symptoms of migraine patients resemble various effects of serotonin. Since the original finding of increased urinary 5-hydroxyindoleacetic acid (5-HIAA) during migraine headache (16), the central role of serotonin in migraine pathophysiology has been established. Although other interesting findings have followed this primary fact (4) there are still controversies and questions mainly because of nonhomogenous material and differing experimental methods (6). The purpose of the present study was to quantify the concentration of 5-HIAA in the cerebrospinal fluid (CSF) as well as homovanillic acid (HVA), kallikreinlike enzymes and (j-glucuronidase during spontaneous migraine attacks. 5-HIAA was also estimated as free acid and glucuronide conjugate in the urine of the same patients. These biochemical findings were correlated to each other and to various clinical variables which were registered from the same patients, although not all such variables were registered at the same time.
Material and Methods
I Supported by grants from the Finnish Medical Foundation, the Orion Medical Foundation and the Eemil Aaltonen Foundation.
Downloaded by: Université de Paris 193.51.85.197 - 1/19/2020 1:14:31 PM
The material consisted of 61 migraine patients, 45 with common and 16 with classical migraine. The age of the migraine patients varied from 22 to 48 years, the average being 32 ± 1 years. There were l3 men and 48 women. 13 volunteers, neurologic patients without migraine, served as controls. All the control patients were subjected to the same studies
Kangasniemi
61
which were made on the migraine patients during headache-free intervals. The age of the control patients varied from 23 to 49 years, the average being 32 ± 2 years. The schedule of sampling the CSF and urine and the biochemical analyses of acid monoamines and kallikrein-like enzymes and iJ-glucuronidase activities were reported earlier (8, 9). For the purpose of the correlation studies between biochemical findings and clinical symptoms the patients were asked about the intensity of their headache during the attack, when the biochemical samples were taken. A generally approved scale was used: 1 = headache did not disturb daily activities; 2 = headache caused difficulties in carrying out everyday activities, and 3 = the patients had to lie down because of the headache. For further correlations, the patients were asked about the factors known to trigger their headaches. The following triggering factors were included in the correlation studies: menstrual cycle and oral contraceptives, stress, high temperature (sauna bath), food and early morning. EEG studies were performed routinely using a 16-channel Elema (mingograf 16) apparatus. To correlate the results of the EEG studies with the biochemical findings the EEGs of migraine patients were divided into six groups according to the results: (1) normal EEG; (2) focal abnormality; (3) generalized disturbances; (4) paroxysmal activity; (5) EEG reacting to hyperventilation (HV+), and (6) EEGs which reacted to flicker stimulation (FS+). In order to check the interval treatment every patient received a list to record the frequency and intensity of his headache. The effect of a known drug was calculated by multiplying the intensity of the headache (see above) with the frequency on a monthly basis. An open trial was considered adequate for pizotifen and methysergide. A double-blind crossover trial was used to evalutate the effect of clonidine.
Results
Correlation of Biochemical Changes When 5-HIAA in the CSF was correlated to the other biochemical findings a Significant positive correlation with HVA (p < 0.01) and a significant negative correlation with esterase activity in both early and late headache stages (p < 0.05) were found. 5-HIAA did not correlate either with the enzyme activities in the plasma or with the corresponding concentrations of 5-HIAA in the urine.
Downloaded by: Université de Paris 193.51.85.197 - 1/19/2020 1:14:31 PM
Biochemical Studies 5-Hydroxyindoleacetic acid in the urine. Migraine patients showed the same concentration of 5-HIAA during the migraine-free interval as the control patients (table I). The results of the headache samples showed that rapid changes of 5-HT metabolism are best reflected by the conjugated form, whereas slow changes are best seen from free 5-HIAA. 5-Hydroxyindoleacetic acid in the cerebrospinal fluid. When the means of 5-HIAA in the CSF in different stages of headache and in the classical and common migraine groups were compared to one another and to the means of the control patients, there were no statistically Significant differences between the groups (table II).
total
conjugated
free
(11)
470 ± 50 (11) 140 ± 20 (11) 660 ± 70
510 ± 30 (54) 130±8 (54) 640 ± 40 (54)
550 ± 60 (15) 140 ± 20 (15) 700 ± 70 (15)
Downloaded by: Université de Paris 193.51.85.197 - 1/19/2020 1:14:31 PM
* P < 0.05; ** p < 0.01; *** P < 0.001.
total
conjugated
Control patients free
All
total
conjugated
Classical free
total
conjugated
500 ± 40 (39)1 130 ± 9 (39) 620 ± 40 (39)
Subfraction Pre-geadache of 13-16 h 5-HIAA
Migraine patients Common free
Group
490 ± 50 (56) 470 ± 160* (56) 790 ± 90 (56)
580 ± 160 (15) 410 ± 140 (15) 990 ± 300 (15)
460 ± 30 (41) 490 ± 220 (41) 720 ± 50 (41)
560 ± 40 (58) 410 ± 70*** (58) 950 ± 80*** (58)
520 ± 70 (15) 340 ± 40*** (15) 850 ± 100 (15)
570 ± 40 (43) 440 ± 90** (43) 1,000 ± 100** (43)
750 ± 130 (53) 310 ± 60** (52) 1,030 ± 150* (52)
610 ± 60 (15) 260 ± 30** (14) 900 ± 90 (14)
810 ± 170 (38) 320 ± 10* (38) 1,080 ± 200* (38)
1 Number of patients.
610 ± 40* (56) 410 ± 90** (56) 1,070 ± 140** (56)
600 ± 80 (14) 340 ± 40*** (14) 950 ± 120 (14)
610 ± 40 (42) 430 ± 110* (42) 1,110 ± 180* (42)
first 4 h 20-24 h
third 4 h 8-12 h
rlIst 4 h 0-4h
second 4 h 4-8 h
Later headache
Early headache
720 ± 80* (55) 190 ± 10*** (55) 830 ± 30*** (55)
600 ± 50 (14) 150 ± 20 (14) 740 ± 70 (14)
760 ± 110* (41) 200 ± 20*** (41) 860 ± 40*** (41)
second 4 h 24-28 h
690 ± 30*** (53) 190 ± 8*** (53) 880 ± 40*** (53)
660 ± 70 (14) 190 ± 20 (14) 850 ± 90 (14)
700 ± 30*** (39) 190 ± 10*** (39) 890 ± 40*** (39)
third 4 h 28-32 h
Table I. Free, total and conjugated 5-HIAA (pg/4 h) in urine during different stages of headache attacks and during headache-free intervals in 61 migraine and 13 control patients (mean ± SEM)
to.>
0'1
~:
!;
~
~
Changes in Serotonin Metabolism during Migraine Attacks
63
Table II. Concentration of 5-HIAA (ng/ml) in the CSF during the different stages of headache attacks and headache-free intervals (mean ± SEM)
Group
Interval stage
Headache stage 4h
24 h
20.9 ± 1.5 (41)1
24.2 ± 1.6 (45)
25.0 ± 1.9 (41)
Classical
23.2 ± 3.0 (15)
24.8±2.7 (16)
24.7 ± 2.9 (14)
All
21.5 ± 1.4 (56)
24.4 ± 1.4 (61)
24.9 ± 1.6 (55)
Migraine patients Common
Control patients
26.5 ± 3.1 (12)
1 Number of patients.
Clinical Correlations 5-HIAA in the CSF did not correlate with the headache intensity. The conjugated 5-HIAA in the urine during the second 4 h after the beginning of the headache showed a nonSignificant positive correlation with the headache. In the group of patients who showed a positive flicker response, 5-HIAA in the CSF was significantly increased in both headache stages compared to the pre-headache level (p < 0.05). In common migraine patients whose headache was triggered by different foods, 5-HIAA in the CSF increased Significantly fro~ the pre-headache to the early and from the early to the late headache stages (p < 0.05). In the migraine patients whose headache was relieved by methysergide treatment, 5-HIAA in the CSF showed an increase in amount from the pre-headache to the later headache stage (p < 0.05). 5-HIAA in the CSF also showed a significant increase from pre-headache to early and late headache stages in classical migraine patients who responded successfully to clonidine or pizotifen treatment (p
