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Differences in the pattern visual evoked potential between pregnant and non-pregnant women
Electroencephalography and clinical Neurophysiology, 92 (1994) 102-106
102
© 1994 Elsevier Science Ireland Ltd. 0168-5597/94/$07.00
EEP 93501
Differences in the pattern visual evoked potential between pregnant and non-pregnant women M.S. M a r s h a and S. Smith b a Department of Obstetrics and Gynae¢ology, and b Department of Clinical Neurophysiology, St. Mary's Hospital, Praed Street, Kennington, London (UK) (Accepted for publication: 26 October 1993)
Summary It has been proposed that latencies of some components of the pattern-reversal visual evoked potential (PRVEP) are shorter in women than in m e n because of differences in levels of circulating sex steroids. Pregnancy is a time when serum levels of oestrogen and progestogen are considerably greater than in the non-pregnant state. Whole and half field P R V E P latencies and amplitudes have been compared in 16 pregnant and 38 healthy non-pregnant women. The m e a n P100 latencies for all responses were shorter in the pregnant women, with statistically significant differences for the left eye whole field latency ( P < 0.05) and the left eye right and left half field latencies ( P < 0.005 and P < 0.05, respectively) and the right eye right half field latency ( P < 0.05). The latencies in women in the pregnant group showed a negative correlation with gestation, which reached statistical significance for the R E W F (r = - 0 . 5 5 , P < 0.05). These observed differences in P R V E P latencies in pregnant and non-pregnant women and the association between latency and gestation are likely to be due to differences in circulating sex steroids, and this effect may be the principal reason for latency differences between the sexes. Key words: Evoked potential; Pattern; Pregnancy; Visual
The latencies of certain components of the patternreversal visual evoked potential (PRVEP) are shorter in women than in men (Halliday 1982; Allison et al. 1983; Celesia et al. 1987; Guthkelch et al. 1987). It has been postulated that these differences are due to the smaller head size of women (Guthkelch et al. 1987), the higher core temperature (Christie and McCrearty 1977; Stockard et al. 1979), absence of the Y chromosome (Buchsbaum et al. 1974) or endocrine factors (Celesia et al. 1987). If the latter, it might be expected that further differences would be seen during pregnancy, when levels of sex steroids both in serum and the cerebrospinal fluid may be 8 or more times those in the non-pregnant state (Backstrom et al. 1976; Datta et al. 1986; Shearman 1986).
Methods Subjects
Sixteen pregnant and 38 non-pregnant women volunteers ranging in age from 17 to 40 years were studied. The pregnant subjects were recruited from inpa-
Correspondence to: M.S. Marsh, 26 1 / 2 Methley Street, London S E l l 4AJ (UK). Tel.: 07l 582 0458.
SSDI 0 1 6 8 - 5 5 9 7 ( 9 3 ) E 0 2 7 9 - F
tient ante-natal wards following admission for observation of obstetric non-medical complications of pregnancy. The non-pregnant subjects were nursing, midwifery and medical staff. All volunteers were medically healthy with no past history of serious or relevant illness and had 2 0 / 2 0 vision with or without correction. Informed consent was obtained from all women. Testing of pregnant volunteers was approved by the District Ethics Committee. Procedures Evoked potentials were recorded using standard techniques (Halliday 1982). Silver/silver-chloride electrodes were applied to the scalp with a mid-occipital electrode sited 5 cm above the inion. Lateral occipital electrodes were placed at sites 5 and 10 cm to the right and left of this point. All recording electrodes were referred to a common mid-frontal reference electrode at Fz. The ground electrode was at the vertex. All electrode impedances were less than 5000 ~2. The subject was seated in a comfortable chair positioned such that the distance from the stimulating screen to the cornea was 130 cm. The pattern reversal stimulus was produced by displacement of a checkerboard screen of 16 × 16 squares through 1 square. The square diameter was 2.0 cm. The stimulus was backprojected onto the viewing screen via a galvanometer
P R V E P IN P R E G N A N T WOIVlEN
103
and mirror apparatus. Each check subtended 53' of visual field. The subject was instructed to fixate on one of 3 red dots on the screen. Responses from 128 reversals at 2 Hz were recorded using a bandwidth of 0.5-300 Hz (sampling rate 1 kHz.) Whole field (right eye whole field: REWF, and left eye whole field: LEWF) and half field (right and left half fields: R H F and LHF) responses were recorded from each eye with the non-stimulated eye occluded. Each run was performed at least twice to ensure reproducibility (two wave forms with P100 latencies within 3 msec). The patient was closely observed at all times for signs of inattention and, where appropriate, was alerted using an auditory stimulus. The P100 latency was defined as the time from the sweep onset to the peak of the major positive deflection and the P100 amplitude measured from the peak of the major negative deflection preceding P100 (N70) to the peak of P100. Whole responses were measured from the central occipital electrode and half field responses from the electrodes 5 cm lateral to this point.
Statistical analysis" The VEP amplitude and latency assumed a normal distribution with log transformation. Log transformed VEP results between groups were compared using Student's t test assuming different variances for pregnant and non-pregnant women. Demographic characteristics were compared using Kruskal-Wallis one-way ANOVA. Correlations between VEP results and subject characteristics were tested using Spearman's method.
Results The mean age of the pregnant women was 27 years (range 19-34) and that of the non-pregnant women 24 years (range 17-40). The difference was significant ( P < 0.05, Kruskal-Wallis ANOVA). The mean gestation at testing within the pregnant volunteers was 33 completed weeks of pregnancy (range 22-41).
102
-
1 O0 -
•
•
"
•
r = - 0.55
[
p < 0.05
I
98
Latency (msec) 96 949290-
88
•
~o
3;
~;
Gestation (completed weeks) Fig. 1. Right eye whole field P100 latency vs. gestation.
The whole and half field VEP P100 latencies and amplitudes for the pregnant and non-pregnant women are shown in Table I. The mean latencies for all responses were shorter in the pregnant women, with a statistically significant difference for the LEWF, R E R H F , L E L H F ( P < 0.05 for all) and L E R H F ( P < 0.005). The mean amplitude for the pregnant women was significantly greater for the R E R H F and R E L H F ( P < 0.05 for both). The P100 latencies of women in the pregnant group showed a negative correlation with gestation, which reached statistical significance for the R E W F ( r = -0.55, P < 0 . 0 5 ) (Fig. 1). There was no correlation between P100 amplitude and gestation. Comparison of P100 amplitudes and latencies between the non-pregnant group and those women with gestations longer than the median gestation (34.5 weeks, n = 8) revealed shorter P100 latencies for the women of advanced gestation for all field tests except the R E L H F field recording ( R E W F L antilog mean = 93 msec, mean _+ S.D. = 90-95, P < 0.05, compared with pregnant women.) There were no differences in amplitude for any field test between these groups (data not shown). Discussion Both P100 amplitude and latency measurements may be altered by visual inattention leading to defocussing,
TABLE I Whole and half field VEP latencies and amplitudes in pregnant and non-pregnant women (mean, m e a n - S . D . - m e a n + S.D.: log transformed data). PRVEP
Pregnant (n = 16) Latency (msec)
Amplitude (pN)
Latency (msec)
Amplitude (pN)
REWF LEWF RERHF RELHF LERHF LELHF
94 95 96 96 95 96
10.9 (7.7-15.4) 10.3 (6.1-17.3) 7.6 (5.7- 7.2) * 7.1 (5.2- 9.7) * 8.2 (5.9-11.4) 6.4 (4.7- 8.8)
96 (89-102) 98 (93-103) 98 (92-104) 98 (91-105) 100 (96-1041 100 (95-105)
9.1 8.7 6.0 5.8 6.7 5.3
(91- 98) (91- 99) (92- 99) (91-100) (91- 98) (91-100)
* * ** *
Non-pregnant (n = 38)
** P < 0.005, * P < 0.05 (Student's t test), compared with non-pregnant. RE = right eye, LE = left eye, W F = whole field, H F = half field.
(5.3-15.9) (5.2-14.61 (3.8- 9.4) (4.0- 8.4) (4.4-11/.2) (3.6- 7.7)
104 with a greater effect on amplitude (Halliday 1982). In this study particular care was taken to ensure that the subject was alert and concentrating on the stimulus, and recordings from each whole or half field were repeated until two results of comparable latency were obtained. Therefore, it is unlikely that the observed differences in the P R V E P latency were due to any difference in attention between pregnant and nonpregnant women. Although the mean ages of the pregnant and nonpregnant groups differed, this is unlikely to account for the observed latency differences. No significant correlations were observed between age and whole field latency in either the pregnant or non-pregnant women. Increasing age has been shown to cause the P100 latency to rise slightly or remain unchanged in women in the reproductive years (Allison et al. 1983; Celesia et al. 1987). It has been suggested that the shorter P100 latency in women compared with men is due to the smaller brain volume (Allison et al. 1983) or head size (Guthkelch et al. 1987) of women. It is improbable that in the present study either of these factors differed between the pregnant and non-pregnant groups, although no measurements of the head size of the subjects were made to confirm this assumption. Core temperature is greater in women than in men (Christie and McCrearty 1977) but we are not aware of any published evidence showing differences between core temperature in pregnant and non-pregnant women. The body temperature of normal subjects has been shown to have no effect on the latency of the P100 component of the P R V E P (Matthews et al. 1979). Therefore, the findings in our subjects are unlikely to be due to differences in core temperatures between the groups. We propose that the observed differences in the PRVEP between pregnant and non-pregnant women are due to the differences in the oestrogenic and progestogenic sex hormone ratio. Total unconjugated 17/3-oestradiol may peak to 300 p g / m l at ovulation in the non-pregnant women; in pregnancy levels 4 times this are reached in the first trimester, rising to 40 times this value by term (13.321.5 n g / m l ) (Pasqualini and Kincl 1985). Similar changes occur in the plasma concentrations of oestrone. Oestrogens have been shown to have excitatory effects on the CNS at the cellular level, including potentiation of the effects of glutamate (Smith et al. 1988) and alteration of the frequency of opening of L-type voltage-dependent calcium channels, thereby amplifying the response to neurotransmitters (Drouva et al. 1988). Oestrogens also cause inhibition of the 7-aminobutyric acid (GABA) synthesizing enzyme glutamate decarboxylase (Nicoletti et al. 1982). This effect on G A B A is particularly relevant as GABA is known
M.S. MARSH, S. SMITH to be an important inhibitory neurotransmitter in the cerebral cortex, and the visual cortex in particular (Iversen et al. 1971). GABA mediated intracortical inhibition appears to play an important role in generation of the VEP. In cats, blocking GABA inhibition with bicuculline has a marked effect on the morphology and latency of VEP components, causing the predominant positive wave form to be replaced by a negative wave form of longer latency (Zemon et al. 1986). Some of the diverse effects of oestrogen on the CNS may be mediated by oestrogen receptors, which are known to be widely distributed in the brain of several species (Gerlach et al. 1976; Pfaff 1976; MacLusky 1990). It is likely that the effects of oestrogens on the CNS are antagonised by progestogens and their metabolites, which enhance cellular responses to GABA, reduce responses to glutamate (Smith et al. 1987a,b, 1988) and suppress foci of seizure discharges both by direct application (Landgren et al. 1978) and systemic administration (Zimmerman et al. 1973). Serum progesterone, 17-hydroxyprogesterone and pregnenolone concentrations rise during pregnancy and in pregnant women at term are approximately 5-12, 8 and 6 times non-pregnant values respectively (Strott and Lipsett 1968; Pasqualini and Kincl 1985; Grainger et al. 1990). In the present study the R E W F latency was significantly negatively correlated with gestation. It appears that as gestation advances stimulatory effects of sex steroids on the CNS predominate over inhibitory effects, perhaps because of an increased ratio of o e s t r o g e n / progestogen activity within the CNS. Other studies of visual function in non-pregnant women are in accord with this interpretation of our data. In a longitudinal study of 10 women, the P180 latency of the flash VEP was found to be significantly shorter in the follicular phase (when oestrogens alone are raised) than in the luteal phase (when oestrogens and progestogens are elevated) for recordings made over the left occipital hemisphere; no such changes were found over the right hemisphere (Simpson et al. 1981). The ability of spontaneously menstruating women to detect a test light in a darkened environment has been shown to increase in midcycle, when oestrogen levels are rising (Diamond et al. 1972). However, findings in other studies are at variance with our results. No significant differences in simultaneous bilateral whole field flash evoked visual potentials were found between 87 normal females and 10 patients with gonadal dysgenesis (45 XO) who bad not received oestrogen replacement therapy for 30 days prior to testing (Buchsbaum et al. 1974). However, the flash evoked potential is a more variable response than the pattern evoked response (Halliday 1982) and the number of subjects was small. Pattern VEP recordings in pre- and postmenopausal women have not shown
PRVEP IN PREGNANT WOMEN
changes at the time of menopause that are independent of the increase with age (Allison et al. 1983; Celesia et al. 1987) although these studies did not specifically address the role of the menopause, a time of considerable hormonal change. In a further study comparing pre- and postmenopausal women and two groups of men of similar ages, La Marche and coworkers found that sex per se did not appear to affect VEP latency at any age (La Marche et al. 1986) but 25% of the postmenopausal women were receiving oestrogen hormone replacement. We believe that differences in the VEP latency in pregnant and non-pregnant women, and men and women in general, may be explained by differences in concentrations of sex steroids acting on the CNS and that evoked potential analysis may prove to be a useful tool for study of the actions of sex hormones on the central nervous system.
We would like to thank the midwifery, nursing and secretarial staff in the Departments of Obstetrics and Neurology at St Mary's Hospital for their help in recruiting subjects. MSM would like to thank Mrs Zosia Cockbain for technical advice concerning VEP recording.
References Allison, T., Wood, C.C. and Goff, W.R. Brain stem auditory, pattern-reversal visual, and short-latency somatosensory evoked potentials: latencies in relation to age, sex, and brain and body size. Electroenceph. clin. Neurophysiol., 1983, 55: 619-636. Backstrom, T., Carstensen, H. and Sodergord, R. Concentration of estradiol, testosterone and progesterone in cerebrospinal fluid, compared to plasma unbound and total concentrations. J. Steroid Biochem., 1976, 7: 469-472. Buchsbaum, M.S., Henkin, R.I. and Christiansen, R.L. Age and sex differences in averaged evoked responses in a normal population, with observations on patients with gonadal dysgenesis. Electroenceph. clin. Neurophysiol., 1974, 37: 137-144. Celesia, G.G., Kaufman, D. and Cone, S. Effect of age and sex on pattern electroretinograms and visual evoked potentials. Electroenceph, clin. Neurophysiol., 1987, 68: 161-171. Christie, M. and McCreary, E. Deep body temperature diurnal variation, sex and personality. J. Psychosom. Res., 1977, 21: 21)7-211. Datta, D., Hurley, R.J., Naulty, J.S., Stern, P., Lambert, D.H., Concepcion, M., Tulchinsky, D., Weiss, J.B. and Ostheimer, G.W. Plasma and cerebrospinal fluid progesterone concentrations in pregnant and nonpregnant women. Anesth. Analg., 1986, 65: 950-954. Diamond, M., Diamond, L. and Mast, M. Visual sensitivity and sexual arousal levels during the menstrual cycle. J. Nerv. Merit. Dis., 1972, 155: 170-176. Drouva~ S.V., Rerat, E., Bihoreau C., Laplante, E., Rasolonjanakary, R., Clauser, H. and Kordon, C. Dyhydropyridine sensitive calcium channel activity related to prolactin, growth hormone and luteinizing hormone release from anterior pituitary cells in culture: interactions with somatostatin, dopamine and estrogens. Endocrinology, 1988, 123: 2762-2773.
105 Gerlach, J., McEwen, B., Pfaff, D., Moskovitz, S., Ferin, M., Carmel, P. and Zimmerman, E. Cells in regions of rhesus monkey brain and pituitary retain radioactive estradiol, corticosterone and cortisol differently. Brain Res., 1976, 103: 603-612. Grainger, D.A., DeCherney, A.H. and Naftolin, F. Ovarian secretions in cycling women. In: F. Naftolin, J. Gutmann, A. DeCherney and P. Sarrel (Eds.), Ovarian Secretions and Cardiovascular and Neurological Function. Raven Press, New York, 1990: 21-33. Guthkelch, A.N., Bursick, D. and Sclabassi, R.J. The relationship of the latency of the visual P100 wave to gender and head size. Electroenceph. clin. Neurophysiol., 1987, 68: 219-222. Halliday, A.M. The visual evoked potential in healthy subjects. In: A. Halliday (Ed.), Evoked Potentials in Clinical Testing. Churchill Livingstone, Edinburgh, 1982: 71-120. Iversen, L.L., Mitchell, J.F. and Srinivasan, V. The release of GABA during inhibition in the cat visual cortex. J. Physiol. (Lond.), 1971, 212:519-534 La Marche, J.A., Dobson, W.R., Cohn, N.B. and Dustman, R.E. Amplitudes of visual evoked potentials to patterned stimuli: age and sex comparisons. Electroenceph. clin. Neurophysiol., 1986, 65: 81-85. Landgren, S., Backstrom, T. and Kalistratov, G. The effect of progesterone on the spontaneous interictal spike evoked by application of penicillin to the cat's cerebral cortex. J. Neurol. Sci., 1978, 36: 119-133. MacLusky, N.J. Gonadal steroids and cognitive function, In: F. Natoflin, A. DeCherney, J. Gutmann and P. Sarrel (Eds.), Ovarian Secretions and Cardiovascular and Neurological Function. Raven Press, New York, 1990: 166-178. Manhews, W.B., Read, D.J. and Poutney, E. Effect of raising body temperature on visual and somatosensory evoked potentials in patients with multiple sclerosis. J. Neurol. Neurosurg. Psychiat., 1979, 42: 250-255. Nicoletti, F., Patti, F., Ferrara, N, Canonico, P.L., Giamonna, G., Condorelli, D.F. and Scapagnini, U. Comparative effects of estrogens and prolactin on nigral and striatal GAD activity. Brain Res., 1982, 232: 238-241. Oken, B.S., Chiappa, K.H. and Gill, E. Normal temporal variability of the P100. Electroenceph. clin. Neurophysiol., 1987, 68: 153165. Pasqualini, J.R. and Kincl, F.A. Hormones and the Fetus, 1st ed. Pergamon Press, Oxford, 1985. Pfaff, D.W. The neuroanatomy of sex hormone receptors in the vertebrate brain. In: T. Kumar (Ed.), Neuroendocrine Regulation of Fertility. Karger, Basel, 1976: 30-45. Shearman, R.P. Endocrine changes during pregnancy. In: C. Whirfield (Ed.), Dewhurst's Textbook of Obstetrics and Gynaecology for Postgraduates. Blackwell Scientific Publications, Oxford, 1986: 115-125. Simpson, D., Erwin, C.W. and Linnoila, M. Ethanol and menstrual cycle interactions in the visual evoked response. Electroenceph. clin. Neurophysiol., 1981, 52: 28-35. Smith, S.S., Waterhouse, B.D. and Woodward, D.J. Sex steroid effects on extrahypothalamic CNS.I. Estrogen augments neuronal responsiveness to ionophoretically applied glutamate in the cerebellum. Brain Res., 1987a, 422: 40-51. Smith, S.S., Waterhouse, B.D. and Woodward, D.J. Sex steroid effects on extrahypothalanfic CNS. If. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransminers. Brain Res., 1987b, 422: 52-62. Smith, S.S.. Waterhouse, B.D. and Woodward, D.J. Locally applied estrogens potentiate glutamate-evoked excitation of cerebellar Purkinje cells. Brain Res., 1988, 475: 272-282. Stockard, J.J., Hughes, J.F. and Sharbrough, F.W. Visually evoked potentials to electronic pattern reversal: latency variables with gender, age and technical factors. Am. J. EEG Technol., 1979, 19: 171-204.
106 Strott, C.A. and Lipsett, M.B. Measurement of 17-hydroxyprogesterone in human plasma. J. Clin. Endocr, Metab., 1968, 28: 1426-1430. Zemon, V., Kaplan, E. and Ratcliff, F. The role of GABA-mediated intracortical inhibition in the generation of visual evoked poten-
M.S. MARSH, S. SMITH tials. In: R. Cracco and J. Bodis-Wollner (Eds.), Evoked Potentials. Alan R. Liss Inc., New York, 1986: 287-295. Zimmerman, E.W., Holden, K.R., Reiter, E.O. and Dekaban, E.S. Medroxyprogesterone acetate in the treatment of seizures associated with menstruation. J. Pediat.. 1973, 83: 959-101)3.
102
© 1994 Elsevier Science Ireland Ltd. 0168-5597/94/$07.00
EEP 93501
Differences in the pattern visual evoked potential between pregnant and non-pregnant women M.S. M a r s h a and S. Smith b a Department of Obstetrics and Gynae¢ology, and b Department of Clinical Neurophysiology, St. Mary's Hospital, Praed Street, Kennington, London (UK) (Accepted for publication: 26 October 1993)
Summary It has been proposed that latencies of some components of the pattern-reversal visual evoked potential (PRVEP) are shorter in women than in m e n because of differences in levels of circulating sex steroids. Pregnancy is a time when serum levels of oestrogen and progestogen are considerably greater than in the non-pregnant state. Whole and half field P R V E P latencies and amplitudes have been compared in 16 pregnant and 38 healthy non-pregnant women. The m e a n P100 latencies for all responses were shorter in the pregnant women, with statistically significant differences for the left eye whole field latency ( P < 0.05) and the left eye right and left half field latencies ( P < 0.005 and P < 0.05, respectively) and the right eye right half field latency ( P < 0.05). The latencies in women in the pregnant group showed a negative correlation with gestation, which reached statistical significance for the R E W F (r = - 0 . 5 5 , P < 0.05). These observed differences in P R V E P latencies in pregnant and non-pregnant women and the association between latency and gestation are likely to be due to differences in circulating sex steroids, and this effect may be the principal reason for latency differences between the sexes. Key words: Evoked potential; Pattern; Pregnancy; Visual
The latencies of certain components of the patternreversal visual evoked potential (PRVEP) are shorter in women than in men (Halliday 1982; Allison et al. 1983; Celesia et al. 1987; Guthkelch et al. 1987). It has been postulated that these differences are due to the smaller head size of women (Guthkelch et al. 1987), the higher core temperature (Christie and McCrearty 1977; Stockard et al. 1979), absence of the Y chromosome (Buchsbaum et al. 1974) or endocrine factors (Celesia et al. 1987). If the latter, it might be expected that further differences would be seen during pregnancy, when levels of sex steroids both in serum and the cerebrospinal fluid may be 8 or more times those in the non-pregnant state (Backstrom et al. 1976; Datta et al. 1986; Shearman 1986).
Methods Subjects
Sixteen pregnant and 38 non-pregnant women volunteers ranging in age from 17 to 40 years were studied. The pregnant subjects were recruited from inpa-
Correspondence to: M.S. Marsh, 26 1 / 2 Methley Street, London S E l l 4AJ (UK). Tel.: 07l 582 0458.
SSDI 0 1 6 8 - 5 5 9 7 ( 9 3 ) E 0 2 7 9 - F
tient ante-natal wards following admission for observation of obstetric non-medical complications of pregnancy. The non-pregnant subjects were nursing, midwifery and medical staff. All volunteers were medically healthy with no past history of serious or relevant illness and had 2 0 / 2 0 vision with or without correction. Informed consent was obtained from all women. Testing of pregnant volunteers was approved by the District Ethics Committee. Procedures Evoked potentials were recorded using standard techniques (Halliday 1982). Silver/silver-chloride electrodes were applied to the scalp with a mid-occipital electrode sited 5 cm above the inion. Lateral occipital electrodes were placed at sites 5 and 10 cm to the right and left of this point. All recording electrodes were referred to a common mid-frontal reference electrode at Fz. The ground electrode was at the vertex. All electrode impedances were less than 5000 ~2. The subject was seated in a comfortable chair positioned such that the distance from the stimulating screen to the cornea was 130 cm. The pattern reversal stimulus was produced by displacement of a checkerboard screen of 16 × 16 squares through 1 square. The square diameter was 2.0 cm. The stimulus was backprojected onto the viewing screen via a galvanometer
P R V E P IN P R E G N A N T WOIVlEN
103
and mirror apparatus. Each check subtended 53' of visual field. The subject was instructed to fixate on one of 3 red dots on the screen. Responses from 128 reversals at 2 Hz were recorded using a bandwidth of 0.5-300 Hz (sampling rate 1 kHz.) Whole field (right eye whole field: REWF, and left eye whole field: LEWF) and half field (right and left half fields: R H F and LHF) responses were recorded from each eye with the non-stimulated eye occluded. Each run was performed at least twice to ensure reproducibility (two wave forms with P100 latencies within 3 msec). The patient was closely observed at all times for signs of inattention and, where appropriate, was alerted using an auditory stimulus. The P100 latency was defined as the time from the sweep onset to the peak of the major positive deflection and the P100 amplitude measured from the peak of the major negative deflection preceding P100 (N70) to the peak of P100. Whole responses were measured from the central occipital electrode and half field responses from the electrodes 5 cm lateral to this point.
Statistical analysis" The VEP amplitude and latency assumed a normal distribution with log transformation. Log transformed VEP results between groups were compared using Student's t test assuming different variances for pregnant and non-pregnant women. Demographic characteristics were compared using Kruskal-Wallis one-way ANOVA. Correlations between VEP results and subject characteristics were tested using Spearman's method.
Results The mean age of the pregnant women was 27 years (range 19-34) and that of the non-pregnant women 24 years (range 17-40). The difference was significant ( P < 0.05, Kruskal-Wallis ANOVA). The mean gestation at testing within the pregnant volunteers was 33 completed weeks of pregnancy (range 22-41).
102
-
1 O0 -
•
•
"
•
r = - 0.55
[
p < 0.05
I
98
Latency (msec) 96 949290-
88
•
~o
3;
~;
Gestation (completed weeks) Fig. 1. Right eye whole field P100 latency vs. gestation.
The whole and half field VEP P100 latencies and amplitudes for the pregnant and non-pregnant women are shown in Table I. The mean latencies for all responses were shorter in the pregnant women, with a statistically significant difference for the LEWF, R E R H F , L E L H F ( P < 0.05 for all) and L E R H F ( P < 0.005). The mean amplitude for the pregnant women was significantly greater for the R E R H F and R E L H F ( P < 0.05 for both). The P100 latencies of women in the pregnant group showed a negative correlation with gestation, which reached statistical significance for the R E W F ( r = -0.55, P < 0 . 0 5 ) (Fig. 1). There was no correlation between P100 amplitude and gestation. Comparison of P100 amplitudes and latencies between the non-pregnant group and those women with gestations longer than the median gestation (34.5 weeks, n = 8) revealed shorter P100 latencies for the women of advanced gestation for all field tests except the R E L H F field recording ( R E W F L antilog mean = 93 msec, mean _+ S.D. = 90-95, P < 0.05, compared with pregnant women.) There were no differences in amplitude for any field test between these groups (data not shown). Discussion Both P100 amplitude and latency measurements may be altered by visual inattention leading to defocussing,
TABLE I Whole and half field VEP latencies and amplitudes in pregnant and non-pregnant women (mean, m e a n - S . D . - m e a n + S.D.: log transformed data). PRVEP
Pregnant (n = 16) Latency (msec)
Amplitude (pN)
Latency (msec)
Amplitude (pN)
REWF LEWF RERHF RELHF LERHF LELHF
94 95 96 96 95 96
10.9 (7.7-15.4) 10.3 (6.1-17.3) 7.6 (5.7- 7.2) * 7.1 (5.2- 9.7) * 8.2 (5.9-11.4) 6.4 (4.7- 8.8)
96 (89-102) 98 (93-103) 98 (92-104) 98 (91-105) 100 (96-1041 100 (95-105)
9.1 8.7 6.0 5.8 6.7 5.3
(91- 98) (91- 99) (92- 99) (91-100) (91- 98) (91-100)
* * ** *
Non-pregnant (n = 38)
** P < 0.005, * P < 0.05 (Student's t test), compared with non-pregnant. RE = right eye, LE = left eye, W F = whole field, H F = half field.
(5.3-15.9) (5.2-14.61 (3.8- 9.4) (4.0- 8.4) (4.4-11/.2) (3.6- 7.7)
104 with a greater effect on amplitude (Halliday 1982). In this study particular care was taken to ensure that the subject was alert and concentrating on the stimulus, and recordings from each whole or half field were repeated until two results of comparable latency were obtained. Therefore, it is unlikely that the observed differences in the P R V E P latency were due to any difference in attention between pregnant and nonpregnant women. Although the mean ages of the pregnant and nonpregnant groups differed, this is unlikely to account for the observed latency differences. No significant correlations were observed between age and whole field latency in either the pregnant or non-pregnant women. Increasing age has been shown to cause the P100 latency to rise slightly or remain unchanged in women in the reproductive years (Allison et al. 1983; Celesia et al. 1987). It has been suggested that the shorter P100 latency in women compared with men is due to the smaller brain volume (Allison et al. 1983) or head size (Guthkelch et al. 1987) of women. It is improbable that in the present study either of these factors differed between the pregnant and non-pregnant groups, although no measurements of the head size of the subjects were made to confirm this assumption. Core temperature is greater in women than in men (Christie and McCrearty 1977) but we are not aware of any published evidence showing differences between core temperature in pregnant and non-pregnant women. The body temperature of normal subjects has been shown to have no effect on the latency of the P100 component of the P R V E P (Matthews et al. 1979). Therefore, the findings in our subjects are unlikely to be due to differences in core temperatures between the groups. We propose that the observed differences in the PRVEP between pregnant and non-pregnant women are due to the differences in the oestrogenic and progestogenic sex hormone ratio. Total unconjugated 17/3-oestradiol may peak to 300 p g / m l at ovulation in the non-pregnant women; in pregnancy levels 4 times this are reached in the first trimester, rising to 40 times this value by term (13.321.5 n g / m l ) (Pasqualini and Kincl 1985). Similar changes occur in the plasma concentrations of oestrone. Oestrogens have been shown to have excitatory effects on the CNS at the cellular level, including potentiation of the effects of glutamate (Smith et al. 1988) and alteration of the frequency of opening of L-type voltage-dependent calcium channels, thereby amplifying the response to neurotransmitters (Drouva et al. 1988). Oestrogens also cause inhibition of the 7-aminobutyric acid (GABA) synthesizing enzyme glutamate decarboxylase (Nicoletti et al. 1982). This effect on G A B A is particularly relevant as GABA is known
M.S. MARSH, S. SMITH to be an important inhibitory neurotransmitter in the cerebral cortex, and the visual cortex in particular (Iversen et al. 1971). GABA mediated intracortical inhibition appears to play an important role in generation of the VEP. In cats, blocking GABA inhibition with bicuculline has a marked effect on the morphology and latency of VEP components, causing the predominant positive wave form to be replaced by a negative wave form of longer latency (Zemon et al. 1986). Some of the diverse effects of oestrogen on the CNS may be mediated by oestrogen receptors, which are known to be widely distributed in the brain of several species (Gerlach et al. 1976; Pfaff 1976; MacLusky 1990). It is likely that the effects of oestrogens on the CNS are antagonised by progestogens and their metabolites, which enhance cellular responses to GABA, reduce responses to glutamate (Smith et al. 1987a,b, 1988) and suppress foci of seizure discharges both by direct application (Landgren et al. 1978) and systemic administration (Zimmerman et al. 1973). Serum progesterone, 17-hydroxyprogesterone and pregnenolone concentrations rise during pregnancy and in pregnant women at term are approximately 5-12, 8 and 6 times non-pregnant values respectively (Strott and Lipsett 1968; Pasqualini and Kincl 1985; Grainger et al. 1990). In the present study the R E W F latency was significantly negatively correlated with gestation. It appears that as gestation advances stimulatory effects of sex steroids on the CNS predominate over inhibitory effects, perhaps because of an increased ratio of o e s t r o g e n / progestogen activity within the CNS. Other studies of visual function in non-pregnant women are in accord with this interpretation of our data. In a longitudinal study of 10 women, the P180 latency of the flash VEP was found to be significantly shorter in the follicular phase (when oestrogens alone are raised) than in the luteal phase (when oestrogens and progestogens are elevated) for recordings made over the left occipital hemisphere; no such changes were found over the right hemisphere (Simpson et al. 1981). The ability of spontaneously menstruating women to detect a test light in a darkened environment has been shown to increase in midcycle, when oestrogen levels are rising (Diamond et al. 1972). However, findings in other studies are at variance with our results. No significant differences in simultaneous bilateral whole field flash evoked visual potentials were found between 87 normal females and 10 patients with gonadal dysgenesis (45 XO) who bad not received oestrogen replacement therapy for 30 days prior to testing (Buchsbaum et al. 1974). However, the flash evoked potential is a more variable response than the pattern evoked response (Halliday 1982) and the number of subjects was small. Pattern VEP recordings in pre- and postmenopausal women have not shown
PRVEP IN PREGNANT WOMEN
changes at the time of menopause that are independent of the increase with age (Allison et al. 1983; Celesia et al. 1987) although these studies did not specifically address the role of the menopause, a time of considerable hormonal change. In a further study comparing pre- and postmenopausal women and two groups of men of similar ages, La Marche and coworkers found that sex per se did not appear to affect VEP latency at any age (La Marche et al. 1986) but 25% of the postmenopausal women were receiving oestrogen hormone replacement. We believe that differences in the VEP latency in pregnant and non-pregnant women, and men and women in general, may be explained by differences in concentrations of sex steroids acting on the CNS and that evoked potential analysis may prove to be a useful tool for study of the actions of sex hormones on the central nervous system.
We would like to thank the midwifery, nursing and secretarial staff in the Departments of Obstetrics and Neurology at St Mary's Hospital for their help in recruiting subjects. MSM would like to thank Mrs Zosia Cockbain for technical advice concerning VEP recording.
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