Download Hormonal Changes In Epileptic Children

Hormonal Changes In Epileptic Children with Primary Generalized
Tonic-Clonic Seizures
Mohammed Abdel-Fadeel Ragab and Ashraf Moustafa Abdou*
From the departments of Pediatrics and Neurology*, Faculty of Medicine, Alexandria
University, Egypt
Abstract
We studied the hormonal changes in 24 epileptic children with primary generalized tonic-clonic
seizures . Their ages ranged between 3 and 16 years with a mean of 9.08+/- 4.05 years , 13 were males
and 11 were females . Electroencephalographic studies showed high voltage slow waves pattern in 17
patients while computed tomography of brain was normal in all cases . As regards the acute changes
following an attack , we found significant elevation of both prolactin and ACTH levels after 20 minutes ,
1 , 2 , and 3 hours of seizure compared with baseline level ( after 24 hours ) . The increase in plasma
ACTH level was accompanied with significant elevation in plasma cortisol level after 1 , 2 and 3 hours of
the seizure onset . Plasma TSH level after 1 and 2 hours were significantly higher than the baseline
value . Early postictal significant elevation of growth hormone levels was observed after 20 minutes and
1 hour . Concerning chronic hormonal changes , we found that the baseline levels of prolactin , ACTH
and cortisol in epileptic children with generalized tonic-clonic seizures were significantly higher than the
levels recorded in healthy children while no significant differences could be detected as regards TSH and
growth hormone . We suggest conducting other studies in pediatric age to assess the role of
neurotransmitters in producing the variable hormonal changes following the onset of seizures .
Introduction
Epilepsy in children is not only a common
problem involving seizures , but is also a disorder
with many other complications . As seizure affects
many brain functions , there has been long-standing
interest in its relationship with endocrine system .
The extensive anatomical and physiological
connections between the limbic system and
hypothalamus provide the basis of the effects of
seizures on the neuroendocrine system (1,2) . Cells ,
fibers and terminals containing hypothalamic
peptides are found throughout the cerebral cortex
and limbic system (3) . Most informations
concerning endocrine changes following seizures
derive from studies of electrochemically induced
attacks in animals (4 - 8) and from electroconvulsive
therapy ( ECT ) in adult patients ( 9 - 12) . The most
unambiguous chronic endocrine changes with
epilepsy are related to the reproductive system and
prolactin (9 - 15) while other hormonal changes in
epileptic patients especially in children have not
been studied thoroughly and need to be evaluated .
This study was undertaken to estimate the hormonal
changes (acute and chronic ) that follow
generalized tonic - clonic seizures in epileptic
children
Subjects and Methods
This study included twenty four well
documented cases of generalized tonic-clonic
seizures who were followed up in Pediatric
Outpatient Clinic for Epilepsy , King Fahd Central
Hospital , K.S.A. and admitted for control of their
repeated convulsive attacks . The studied cases
ranged in age between 4 and 16 years and all were
receiving either monoor polytherapy with
combination of anticonvulsant drugs . None of the
patients were taking any other medications or under
treatment for any other organic disorders .
Selected cases were subjected to : (1) - Full medical
history including description , duration and
frequency of convulsive attacks . (2) - Thorough
clinical examination with exclusion of children with
any signs of neurological deficits . ( 3) - A
description of the seizure pattern was recorded at
the time of the attack by a member of the nursing
staff experienced at observing patients with epilepsy
and only cases with generalized tonic-clonic
seizures were included in the study . (4) Electroencephalogram during seizure - free period .
(5) . Computed tomography of the brain . We
tried to obtain blood samples at fixed intervals of
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Alex. J. Pediatr. 12 (1); Jan 1998
noassay . None of the assays for each of the
hormones showed significant cross-reaction with
any of the other tested hormones . Growth hormone , TSH , prolactin and ACTH were assayed
using a commercial kit provided by Diagnostic
Systems Laboratories ( DSL ) , Texas , USA while
cortisol was measured using kit produced by
Immunotech , France . Results were expressed as
mean/ standard deviation and analyzed by un paired
t- test to compare mean values at each time - point
with baseline mean values , which for the present
purpose were taken as levels measured after 24
hours of the last attack . Similarly mean baseline
values in epileptic children were compared with the
mean values of the hormones in the control group .
time after seizures . The samples were obtained
with the child recumbent and efforts were made to
obtain them within 20 minutes of the seizure and
then 1, 2 and 3 hours . For assessment of the
mean baseline hormonal levels , three blood
samples were obtained over a period of 12 hours
( 8pm - 8am ) for each patient at least 24 hours after
last seizure and from 10 healthy children , age and
sex matched who served as control .
HORMONAL ASSAY: Blood was collected into
EDTA- containing tubes for measurement of TSH ,
ACTH , cortisol , prolactin and growth hormone .
Plasma was promptly separated from blood cells ,
aliquoted for the various hormone assay , frozen
and stored at -20 oC until assayed . All hormone
determinations were performed by radioimmu-
Results
significantly from the baseline level . We found
significant elevations above baseline for plasma
ACTH at each time point . ACTH level increased
in 21 cases after 20 minutes and after 1 hour in the
remaining 3 cases . Following the elevations of
plasma ACTH , plasma cortisol levels after 1 , 2
and 3 hours were significantly higher than the
baseline . The plasma growth hormone data for the
epileptic children suggested an early postseizure (
after 20 min. and 1 hour ) elevations that reached
statistical significance . Review of the individual
data suggested that in 3 patients there was no
change over time whereas in 21 others the growth
hormone level did appear to be elevated after the
seizure , subsequently declining with time . Table
(II) shows comparison between the patients and
healthy children concerning the mean baseline
levels of the assayed hormones . Prolactin , ACTH
and cortisol were statistically significantly higher in
children with generalized tonic - clonic seizures
while no significant difference could be detected as
regards TSH or growth hormone.
This study included 24 epileptic children
presented with generalized tonic-clonic seizures and
10 healthy children , age and sex matched , who
served as control
. Electroencephalographic
studies were normal in 7 cases and showed high
voltage slow waves in 17 patients while all cases
had normal computed tomographic ( C T ) images of
the brain . Table (I) and figures 1,2 and 3 portray
the acute changes in the mean levels of the
hormones recorded in epileptic children after 20
min . , 1 ,2, and 3 hours of the seizure onset
compared with the mean baseline level recorded
after 24 hours of seizure-free period . The group
data indicated that the plasma prolactin level
showed a sharp rise in the first 20 minutes after the
seizure onset ( generally to between 300% and
400% of baseline values in > 90% of cases ) ,
remained elevated at 1 , 2 and 3 hours with
significant difference from the baseline levels . The
level of TSH after 20 minutes increased in 18
patients but the mean value was significantly higher
than the baseline only after 1 and 2 hours then
decreased and subsequently did not differ
Discussion
In this research we tried to study the acute
and chronic hormonal changes in epileptic children
with primary generalized tonic-clonic seizures .
There was an immediate and significant rise in
serum prolactin ( PRL) following generalized tonic clonic seizure in more than 90 % of our patients and
this elevation ranged between 3 and 4 times
Alex. J. Pediatr. 12 (1); Jan 1998
baseline value . This finding is in harmony with
those reported by other researchers(10,11,13, 16 - 20 )
that PRL rises rapidly following spontaneous and
induced generalized seizures in human beings
reaching a peak between 15 - 25 minutes after
the seizure and that these prolactin changes can
serve as a reliable confirmation of the
56
Table (I) : Mean and standard deviation of hormonal values in 24 epileptic children 20 min. ,
1 , 2 , 3 and 24 hours after generalized tonic - clonic seizure .
Prolactin
ng / ml
TSH
mU/L
ACTH
pg/ml
Cortisol
nmol/L
Growth H.
mU/L
20
minutes
65.9 **
(7.56)
1
hour
49 *
(6.48)
2
hours
35 *
(4.52)
4
hours
26 *
(6.0)
24
hours
19
(3.9)
3.72
(0.97)
4.87 *
(0.92)
5.22 *
(0.82)
4.00
(1.03)
3.7
(0.78)
85 *
(11.94)
73 *
(10.65)
67 *
(10.13)
52 *
(9.79)
43
(9.38)
317
(24.4)
365 *
(28.6)
405 *
(28.2)
345 *
(30.3)
310
(30.2)
7.76 *
(1.9)
6.82 *
(1.2)
6.5
(1.5)
6.36
(1.14)
6.0
(1.04)
* significant compared to baseline value ( 24 hours value ) P < 0.05
70
** significant P < 0.0001 .
*
*
60
50
*
40
*
Prolactin ng/ml
30
20
10
0
20 min
1 hour
2hours
3 hours
24 hours
Figure (1) : Plasma prolactin response to a single generalized tonic-clonic seizure. Arithmetic
mean for the group of patients studied is shown . Asterisks * indicate significant difference from
baseline values at 24 hours .
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Alex. J. Pediatr. 12 (1); Jan 1998
*
8
*
7
6
*
*
5
TSHmU/L
4
Growth H.mU/L
3
2
1
0
20 min
1 hour
2 hours
3 hours
24 hours
Figure (2) : Plasma TSH and growth hormone responses to a single generalized tonic-clonic
seizure . Arithmetic mean of studied patients is shown . Asterisks * indicate significant
difference from baseline values at 24 hours .
450
*
400
*
*
350
300
250
ACTH pg/ml
200
*
Cortisol nmol/L
150
100
*
*
*
*
50
0
20 min.
1 hour
2 hour
3 hour
24 hours
Figure (3) : Plasma ACTH and cortisol responses to a single generalized tonic-clonic seizure .
Arithmetic mean for the group of patients studied is shown . Asterisks * indicate significant
difference from baseline values at 24 hours .
Alex. J. Pediatr. 12 (1); Jan 1998
58
Table (II) : Mean and standard deviation of the baseline hormonal values in epileptic children and control .
Epiletic cases
(n = 24 )
Prolactin
ng/ml
TSH
mU/L
ACTH
(pg/ml)
Cortisol
nmol/L
Growth H.
mU/L
* Significant ( P < 0.05 ) .
Control
( n = 10 )
t Value
19(3.9)
12.6(3.27)
4.93*
3.7(0.78)
3.58(1.19)
0.29
43(9.38)
35(10.17)
2.13 *
310 (30.3)
243 (85.8)
2.40 *
6.0 (1.04)
5.72 (3.24 )
0.26
occurrence of a seizure but its absence does not
exclude completely the occurrence of a seizure as
PRL rises only with the limbic seizures and that
bilateral limbic seizure activity was usually required before PRL increases were seen ( 19 , 21 - 25 ) .
In our study PRL level after 3 hours was still
significantly higher than the baseline value which is
different from what reported by others( 13 , 16 ) in
epileptic adults that PRL level is reverting to normal
in about 2 hours after seizure . Furthermore, we
found that the mean baseline PRL level in epileptic
children is significantly higher than that in healthy
control which is the same result recorded by Molaie
M and his colleagues ( 26 ) . This finding supports the
notion that interictal discharges in epileptics with
primary generalized
tonic - clonic seizures
spread to suprahypothalamic structures , such as
the limbic system , thus a moderate increase in PRL
baseline level may be the result of interference by
these discharges with either PRL inhibitory
mechanisms mediated by dopaminergic pathway (27)
or PRL stimulating factors such as neuropeptides (28) . The level of TSH increased after 20
minutes of seizure in 18 cases but reached
significant difference only at 2 time-points ; after 1
and 2 hours while the difference between the
baseline values in both patients and control was not
statistically significant . The same finding was
reported by other investigator (29) who found a
significant increase in TSH only 30 minutes after
electroconvulsive therapy ( ECT ) and explained it
by the antidopaminergic effect of ECT at either the
pituitary or the hypothalamic level . We found
significant elevations above the baseline for plasma
ACTH at each time point followed by a significant
increase in plasma cortisol level after 1 hour of the
seizure onset and this difference was still significant
after 3 hours . These findings are
consistent
with the results
reported by
other
investigators ( 30 - 33 ) who found elevation of plasma
ACTH and cortisol levels following ECT and
generalized tonic-clonic seizures . Furthermore , like
our finding concerning prolactin , the mean baseline
plasma ACTH and cortisol levels in epileptic children
with primary generalized tonic-clonic seizure were
significantly higher than the baseline levels in
healthy children . This result is similar to that
described in one of the most interesting studies
concerning the chronic changes in endocrine
functions in adults with epilepsy which concluded
that patients with intractable epilepsy had higher
mean plasma ACTH and cortisol concentrations
than normal adults . This consistent chronic
elevation of PRL and ACTH can be explained by the
presence of common pathway or mechanism
involved in pituitary release of PRL and ACTH (34) .
Acute and chronic changes in growth hormone level
had a special interest in our study due to its direct
impact on growth and because the previously
mentioned data concerning changes in this hormone
following ECT are conflicting . Unlike others (13, 18, 35
- 37 ) who did not find elevation in growth hormone
level postictally in adults , our results showed
significant elevation in G.H after 20 minutes and 1
hour in 21 children with epilepsy . Our result is
supported by other researchers (25,38,39) who
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Alex. J. Pediatr. 12 (1); Jan 1998
described a significant increase in growth hormone
level within 30 minutes of ECT in adults . This
variability in hormonal changes makes it difficult to
be attributed completely to non - specific stress
reactions which can not be excluded at the same
time as different classes of stress may produce
different patterns of hormonal respon-ses (40) .
Hypothalamic peptides now are known to act in
other parts in the brain as neurotransmitters or
neuromodulators and their role in hormonal
responses to generalized seizures should be
considered . The results of this study clearly imply
that the neuroendocrine system is susceptible to
pathologic plasticity as a result of generalized tonicclonic seizures . This task is particularly important
for children where the consequences of seizure related neuroendocrine disruption have greater
significance for the developing nervous system . It
is suggested that attempts to alter hormonal release
following seizures using various drugs that block
neurotransmitters may lead to a further
understanding of the neurochemistry of epilepsy that
might minimize the impact of seizures on the quality
of life .
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ACKNOWLEDGEMENT
The authors would like to express their deep appreciation and thanks to their patients and
colleagues in K.F.C.H . Thanks to our nursing staff ; Mr Ashraf Taqie Al-Din , our computer
programmer and Mr FA . Lukanmbi ( M.Phil , FIMLS , London ) for his efforts in the hormonal assay
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Alex. J. Pediatr. 12 (1); Jan 1998