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Vasopressin in the cerebrospinal fluid of febrile children with or without seizures
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ELSEVIER
Brain & Development 1996; 18: 110-113
Original article
Vasopressin in the cerebrospinal fluid of febrile children with or without seizures Tuula Kiviranta
a,*,
Leena Tuomisto b, Jukka Jolkkonen c, Eila M. Airaksinen
a
a Department ofPaediatrics, Kuopio University tto,spital, P.O. Box 1777, FIN-7021/Kuopio. Finland b Department of Pharmacology and Toxwology. University of Kuopio, FIN-70211 Kuopio, Finland c Department of Neurology, University of Kuopio, FIN-70211 Kuopio, Finland Received 3 August 1995; accepted 12 November 1995
Immaturity in water and electrolyte balance in the brain has been considered to increase the susceptibility of young animals and children to febrile convulsions (FCs). Arginine-vasopressin (AVP) is involved in the regulation of several centrally mediated events such as modulation of fever and the ease with which water permeates into and out of the brain. To evaluate the possible role of AVP in the control of water balance and susceptibility to convulsions during fever we measured the AVP concentration in the cerebrospinal fluid (CSF) and plasma of febrile children with or without convulsions. The febrile population consisted of 47 children, of whom 29 experienced seizures during fever• Seven children with epileptic symptoms and 18 children without seizures were included as nonfebrile controls. The CSF AVP concentration in febrile children without seizures and in nonfebrile convulsive children was significantly lower (0.60 + 0.07 p m o l / l , mean + SEM, P < 0.01 and 0.65 + 0.19 p m o l / I , P < 0.05, respectively) than in nonfebrile children without convulsions (0.83 + 0 . 0 6 p m o l / I ) . However, the levels of CSF AVP were not significantly different in children with FCs (0.71 + 0.06 p m o l / I ) compared with other groups. CSF AVP correlated with the CSF osmolality (r= 0.33, P = 0.02). No statistical differences in plasma AVP levels between the groups could be found. The present data provide support for the hypothesis of synchronous regulation of osmolality and AVP concentration in CSF. During fever the concentration of CSF AVP was lower in nonconvulsive children compared with nonfebrile nonconvulsive children• CSF AVP levels were not affected in febrile children by convulsions. Keywords: Vasopressin; Febrile convulsion; Fever; Seizure; Cerebrospinal fluid
1. I N T R O D U C T I O N Arginine vasopressin (AVP) has generally been regarded as a peripheral regulator of water balance and vasoconstriction [I]. AVP is predominantly synthesized in two hypothalamic nuclei, the paraventricular (PVN) and supraoptic nuclei (SON), transported into the neural lobe of the pituitary and secreted from there into the circulation [2]. On the other hand, AVP released from the PVN or extrahypothalamic projections ('central pool') has been suggested to play an important role in the regulation of brain water permeability and intracranial pressure [2-8]. AVP has
• Corresponding author. Taivallahdentie 7, FIN-70620 Kuopio, Finland. Fax: (358) (71) 262 6696. 0387-7604/96/$15.00 © 1996 Elsevier Science B.V. All fights reserved SSDI 03 87-7604(95)001 46-8
also been demonstrated to have a physiological role as an endogenous antipyretic in the regulation of fever in several mammalian species [9]. Convulsions occur frequently in conjunction with febrile diseases during childhood: 2 - 5 % of all children will experience febrile convulsions (FCs) before the age of 5 years [10,11]. AVP has been proposed to be one of the agents responsible for inducing convulsions during fever in animals [12,13]. To our knowledge, there are no earlier studies published of cerebrospinal fluid (CSF) AVP measurements in children with febrile convulsions. To evaluate how fever and convulsions, alone or in combination, affect the vasopressinergic system, we measured the concentrations of AVP in CSF and plasma of febrile and nonfebrile children with or without convulsions.
I11
T. Kiviranta et al./Brain & Development 1996; 18:110-113
2. P A T I E N T S
Table 2 Concentrations of CSF and plasma vasopressin o? children in
AND METHODS
different groups
The study population consisted of 72 children admitted to the Department of Pediatrics at Kuopio University Hospital (Table 1). When clinical indications existed, CSF samples were taken after obtaining informed consent from the parents. The study protocol was accepted by the ethical committee of the Kuopio University Hospital. The body temperature was recorded immediately before lumbar puncture. Forty-two of the children had received antipyretic analgetics during the last 24 h (Table 1). Diazepam or other benzodiazepines were used as anticonvulsant or sedative drugs before the lumbar puncture, when needed. Clinical signs of dehydration were not found in any of the children. There was no significant difference in the mean temperature of febrile convulsive and nonconvulsive children (38.7°C and 38.8°C, respectively) before the lumbar puncture. The group of febrile children consisted of 47 children, 29 of whom had had febrile seizures before admission to the hospital. A single seizure lasting less than 15 min without focal features in children under 5 years was defined as a simple febrile convulsion. Febrile seizures were considered complicated if they did not fulfil the above criteria. Twenty-one of the children (72%) had simple seizures and eight children (28%) were classified as having complicated convulsions. The CSF samples were taken shortly after the patients' admission to the hospital, on average 4 h (range 1.5-20 h) after the convulsive attacks. The nonconvulsive febrile group consisted of 18 children with a variety of acute infectious illnesses, but not having seizures. Patients with meningitis or encephalitis were excluded. The nonfebrile group without seizures consisted of 18 children. Seven children with nonfebrile seizures formed the nonfebrile convulsive group. The duration of the convulsions varied from a few seconds (repeated in series such as in infantile spasms) to status epilepticus lasting for 30 min. Also in this group, the CSF samples were obtained on average 4 h after the last epileptic fit (range 2 - 8 h).
2.1. Sample collection and analysis CSF samples (3.5 ml) were taken by lumbar puncture. Plasma samples for AVP determination were taken within 2 h of the CSF samples ( n - 18), or during the next 10 h if the patient was admitted to the hospital during the night (n = 30). AVP was
Group Febrile convulsive nonconvulsive Non febrile convulsive nonconvulsive
Vasopressin (pmol/1) CSF
Plasma
0.71 _+0.06 (29) 0.60=0.07(18) " "
1.70 + 0.33 (24) 2.53_+0.93(10)
0.65 + 0.19 (7) " 0.83:t:0.06 (18)
0.75 _+0. I I (5) 3.41 _+ 1.16(9)
Statistical significance compared with nonfebrile, nonconvulsive children, • " P < 0.01, " P < 0.05 (KruskaI-Wallis test). Values are expressed as mean + SEM with the number of patients in parentheses.
measured by a specific radioimmunoassay as described previously for CSF [14] and for plasma [15]. The detection limit of the assay was 0.35 p m o l / l , which was used in the data analysis as the lowest value for those measurements below that level. Osmolality was analyzed by the freezing point depression method (Advanced Instruments Model 3).
2.2. Statistical methods Kruskal-Wallis analysis was used to test the differences of CSF and plasma AVP concentrations in the various diagnosis groups. Student's t-test was used to study the effects of sex and the use of benzodiazepines or antipyretic analgetics on CSF and plasma AVP levels. Correlations between variables were determined by Pearson's correlation analysis. All results are presented as the mean + SEM.
3. R E S U L T S CSF and plasma AVP concentrations are presented in Table 2. The concentration of AVP in CSF of febrile children without seizures and in nonfebrile children with convulsions was significantly lower than that of nonfebrile children without convulsions ( P < 0.01 and P < 0.05, respectively). In children with febrile convulsions, CSF AVP concentrations were comparable to those in nonfebrile groups. There was no difference in the AVP levels
Table 1 Description of the children in different groups Group
Febrile convulsive ~ nonconvulsive b Nonfebrile convulsive c nonconvulsive a
Number of cases
Mean age (range) (years)
Female/male
29 18
1.9 (0.9-6.7) 5.4 (0.6-11.4)
7 18
3.5 (0.7-8.7) 7.1 (0.3-14.3)
Drugs Antipyretic agents n (%)
Benzodiazepines n (%)
11/ 18 9/9
25 (86) 13 (72)
15 (52) 6 (33)
4/3 9/9
1 (14) 3 (16)
6 (86) 4 (22)
Diagnoses: a upper respiratory tract infections (1 I), pneumonia (5), exanthem subitum (5), gastroenteritis (4), viral infections (3), pyelonephritis (1); b upper respiratory tract infections (9), acute leukemia without cytotoxic chemotherapy or neuroleukemia (4), viral infections (2), pyelonephritis (1), plexus neuritis (1), sepsis with malignant lymphoma before cytotoxic chemotherapy (1); c complex partial seizures (3), status epilepticus (1), tonic-clonic seizure (1), infantile spasm (2); ~ acute leukemia without cytotoxic chemotherapy or neuroleukemia (9), vertigo (2), neck pain (2), malignant mediastinal lymphoma without cytotoxic chemotherapy (I), suspected neurological symptoms or delay in development (4).
112
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o 0 265 270 2 7 5 2 0 285 2 0 2=5" CSF-OSMOLALITY(mOmTt/kgH20)
Fig. 1. The correlation between cerebrospinal fluid osmolality and arginine-vasoprcssin concentration. The equation of the regression line is y = 0.01 x - 2.92, r = 0.33, P = 0.02 (Pearson's correlation analysis). Symbols: • one observation. [] two overlapping observations.
in the CSF between the children with simple (0.72 + 0.08 pmol/1, n = 21) and those with complicated febrile convulsions (0.70 + 0.09 pmol/I, n = 8). CSF AVP correlated with CSF osmolality (Fig. 1). None of the following factors had any statistically significant effect on CSF or plasma AVP levels: age, gender, maximal body temperature during the febrile illness, duration of the fever or the seizure, interval between the seizure and CSF sampling, use of benzodiazepines or antipyretic analgetics, or the time of day when the CSF samples were taken. No statistical differences in the levels of plasma AVP between groups could be found (Table 2). The concentration of AVP in plasma did not correlate with plasma osmolality.
4. D I S C U S S I O N The CSF vasopressin concentrations measured in the present study were within the range reported earlier for children [16]. There was no correlation between the age of the children and the level of AVP in CSF, consistent with earlier studies in adults [2,17] and children [16]. In the present study the concentration of AVP in CSF of febrile nonconvulsive children was lower than that of nonfebrile nonconvulsive children. In previous works, vasopressin has been shown to influence thermoregulation in several animal species [9,18-28]. Earlier studies indicate that AVP is released both centrally [20] and peripherally [16] during fever and hyperthermia. The stimulus for AVP release may be complex as both pyrogenic and thermal stimuli seem to be involved [24]. In febrile animals, the peak AVP level in CSF has been documented to occur 3 - 4 h after initiation of an endotoxin-induced fever [20]. AVP administered into ventricles has been shown to induce an antipyretic action lasting for 30 min in rats [27]. Although no elevated AVP values were detected in our patients at the time of CSF sampling, the animal experiments suggest that AVP release may have occurred at the beginning of the fever. The release of AVP could explain our earlier finding that CSF osmolality is significantly decreased in febrile children [29]. The mechanism behind these changes cannot be resolved by this study. We do not know which is the primary phenomenon, decrease of osmolality or primarily a release of AVP in the first phase of fever. Based on earlier data and our findings it is probable that low levels of electrolytes in CSF might be secondary to the initial release of
AVP leading further to a decrease of AVP concentration by a feedback mechanism. The antidiuresis evoked by the elevated AVP plasma concentration during the initial phase of fever would thus alleviate the decrease in plasma volume which accompanies fever and preserve the water supply needed to compensate for evaporative heat loss [18]. The difference in CSF AVP concentration between the febrile and nonfebrile nonconvulsive children supports the hypothesis that vasopressin might have a role in physiological phenomena associated with febrile diseases, in thermoregulation or in the regulation of fluid balance of CNS. This last alternative is supported by our observation that CSF osmolality and AVP concentration correlated with each other. In animal studies, increases in CSF osmolality are followed by an increase in CSF AVP concentration [30]. The changes of fluid and electrolyte fluxes between plasma, brain, and CSF influence the regulation of brain ionic environment and volume homeostasis. It has been suggested that centrally released vasopressin is involved in this regulation through its effects on the composition of CSF [3,6,8,31]. The increase in the levels of AVP in plasma [32] and CSF found in children with bacterial meningitis has been proposed to be an additional factor in the pathogenesis of cerebral edema in these children [33]. It has been proposed that AVP could be one of the agents responsible for inducing convulsions during fever in animals [12,13]. The absence of AVP in the brain of Brattleboro rats, or neutralization of central AVP by intracerebroventricularly administered antiserum, has allowed animals to reach higher body temperature before experiencing convulsions, or has even prevented totally the convulsions [12]. If AVP does play a role as a mediator in febrile convulsions [12,13], the lower CSF AVP concentrations could be beneficial in the protection against seizures during febrile diseases. No data on the level of CSF AVP after epileptic seizures in children have been published before. In plasma, prolonged epileptic convulsions have been shown to increase transiently AVP levels in adults [34]. We did not find such change in the group of nonfebrile convulsive children, probably due to the small number of patients and different etiologies of their clinical symptoms. Our finding that these children had lower AVP levels in CSF should therefore also be considered preliminary, requiring further confirmation. Plasma AVP concentrations in febrile children have been found to be normal [32] or elevated [ 16]. We could not detect any statistically significant changes in plasma AVP concentrations between the febrile and nonfebrile groups. The discrepancy in the results between the CSF and blood samples can be explained by the fact that AVP entering the CSF may be derived, at least in part, from a different population of neurons from those secreting AVP into the blood [35]. Another explanation for the dissimilarity can be the time interval between the CSF and blood samples. In this study we excluded children with meningitis or encephalitis and thus the difference in the diagnosis of the children could partly explain the higher AVP concentrations in plasma found by Sharpies and coworkers [16]. The influence of AVP on body fluid balance could not be evaluated by measurement of urine osmolality and volume in the present study, because the time the children spent in hospital was usually limited to only a few hours. Our study reveals simultaneous changes in CSF AVP and osmolality in febrile diseases, providing support for the concept of synchronous regulation of osmolality and AVP in CSF. CSF
T. Kiviranta et al. / Brain & Development 1996: 18:110-113
A V P concentrations were lower in febrile nonconvulsive children than in nonfebrile nonconvulsive patients. A normal C S F A V P concentration in children with FCs may be indicative of a difference in the release of A V P in C S F and theoretically be associated with the susceptibility to seizures during fever. The difference between the groups o f febrile children was, however, small and needs later investigations to resolve in greater detail the mechanisms underlying febrile convulsions.
ACKNOWLEDGEMENTS The study has been supported by grants from the Arvo and Lea Ylppb Foundation, the North-Savo Fund of the Finnish Cultural Foundation and the Academy of Finland, Research Council for Medicine.
16.
17.
18. 19.
20.
21. REFERENCES I. Wang BC, Goetz KL. Volume influences on the plasma osmolality plasma vasopressin relationship mediated by cardiac receptors. In: Schrier RW, ed. Vasopressin. New York: Raven Press, 1985:221-8. 2. SeJrensen PS. Studies of vasopressin in the human cerebrospinal fluid. Acta Neurol Scand 1986; 74: 81-102. 3. Raichle ME, Grubb RL Jr. Regulation of brain water permeability by centrally-released vasopressin. Brain Res 1978; 143: 191-4. 4. Reeder RF, Nattie EE, North WG. Effect of vasopressin on cold-induced brain edema in cats. J Neurosurg 1986; 64: 941-50. 5. Jolkkonen J, Tuomisto L, van Wimersma Greidanus TB, L ~ E, Riekkinen P. Effects of osmotic stimuli on vasopressin levels in the CSF of rats. Peptides 1988; 9:109-11. 6. DePasquale M, Patlak CS, Cserr HF. Brain ion and volume regulation during acute hypernatremia in Brattleboro rats. Am J Physiol 1989; 256: FI059-66. 7. Faraci FM, Mayhan WG, Heistad DD. Effect of vasopressin on production of cerebrospinal fluid: possible role of vasopressin (V~)receptors. Am J Physiol 1990; 258: R94-8. 8. Szmydynger-Chodobska J, Szczepanska-Sadowska E, Chodobski A. Effect of arginine vasopressin on CSF composition and bulk flow in hyperosmolar state. Am J Physiol 1990; 259: RI250-8. 9. Kasting, NW. Criteria for establishing a physiological role for brain peptides. A case in point: the role of vasopressin in thermoregulation during fever and antipyresis. Brain Res Rev 1989; 14: 143-53. 10. Hauser WA. The natural history of febrile seizures. In: Nelson KB, Ellenbcrg JH, eds. Febrile seizures. New York: Raven Press, 1981: 5-17. 11. Wallace SJ. The child with febrile seizures. London: Wright, 1988. 12. Kasting NW, Veale WL, Cooper KE, Lederis K. Vasopressin may mediate febrile convulsions. Brain Res 1981; 213: 327-33. 13. Veale WL. Cooper KE, Ruwe WD. Vasopressin: its role in antipyresis and febrile convulsion. Brain Res Bull 1984; 12: 161-5. 14. Jolkkonen J, Helkala E-L, Kutvonen R, Lehtinen M, Riekkinen RJ. Vasopressin levels in CSF of Alzheimer patients: correlations with monoamine metabolites and neuropsychological test performance. Psychoneuroendocrim)logy 1989; 14: 89-95. 15. Pesonen U, Jolkkonen J, Huupponen R, Koulu M. Differential hypothalamic arginine vasopressin response to glucocorticoid receptor
22.
23. 24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
113
antagonism in lean and obese zucker rats. Neuroendocrinology 1992; 56: 271-7. Sharpies PM, Seckl JL, Human D, Lightman SL, Dunger DB. Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever. Arch Dis ChiM 1992; 67: 998-1002. Gold PW, Kaye W. Robertson GL. Ebert M. Abnormalities in plasma and cerebrospinal-fluid axginine vasopressin in patients with anorexia nervosa. N EnglJ Med 1983: 308:I117-23. Zeisberger E. Role of vasopressin in fever regulation and suppression. TIPS 1985; 6: 428-30. Veale WL, Kasting NW, Cooper KE. Arginine vasopressin and endogenous antipyresis: evidence and significance. Fed Proc 1981: 40: 2750-3. Kasting NW, Carr DB, Martin JB, Blume H, Bergland R. Changes in cerebrospinal fluid and plasma vasopressin in the febrile sheep. Can J Physiol Pharmacol 1983; 61:427-3 I. Ruwe WD. Electrical stimulation of the paraventrieular nucleus attenuates pyrogen fever in the rabbit. Brain Res 1992: 588: 181-90. Naylor AM, Ruwe WD, Veale WL. Antipyretic action of centrally administered arginine vasopressin but not oxytocin in the cat. Brain Res 1986; 385: 156-60. Kasting NW, Wilkinson MF. Vasopressin /'unctions as an endogenous antipyretic in the newborn. Biol Neonate 1987: 51: 249-54. Landgraf R, Malkinson TJ, Veale WL, Lederis K, Pittman QJ. Vasopressin and oxytocin in rat brain in response to prostaglandin fever. Am J Physiol 1990; 259: R1056-62. Cridland RA, Kasting NW. A critical role for central vasopressin in regulation of fever during bacterial infection. Am J Physiol 1992; 263:R1235-40. Federico P, Veale WL, Pittman QJ. Vasopressin-induced antipyresis in the medial amygdaloid nucleus of conscious rats. Am J Physiol 1992; 262: R901-8. Kovacs GL, Baars AM, De Wied D. Antipyretic effect of central arginine-vasopressin treatment: V~ receptors specifically involved? L(fe &'i 1992; 50: 1625-30. Roth J, Schulze K, Simon E, Zeisberger E. Alteration of endotoxin fever and release of arginine vasopressin by dehydration in the guinea pig. Neuroendocriru~h)gy 1992; 56: 680-6. Kiviranta T, Tuomisto L, Airaksinen EM. Osmolality and electrolytes in cerebrospinal fluid and serum of febrile children with and without seizures. Eur J Pediatr, in press. Nilsson C, Lindvall-Axelsson M, Owman C. Neuroendocrine regulatory mechanisms in the choroid plexus-cerebrospinal fluid system. Brain Res Rev 1992; 17:109-38. Ludwig M, Landgraf R. Does the release of vasopressin within the supraoptic nucleus of the rat brain depend upon changes in osmolality and Ca"" / K + ? Brain Re,~ 1992; 576:231 - 4. Kaplan SL, Feigin RD. The syndrome of inappropriate secretion of antidiuretic hormone in children with bacterial meningitis. J Pediatr 1978; 92: 758-61. Garcia H, Kaplan SL, Feigin RD. Cerebrospinal fluid concentration of arginine vasopressin in children with bacterial meningitis. J Pediatr 1981: 98: 67-70. Meierkord H, Shorvon S, Lightman SL. Plasma concentrations of prolactin, noradrenaline, vasopressin and oxytocin during and after a prolonged epileptic seizure. Acta Neurol Scaml 1994; 90: 73-7. Wang BC. Share L. Goetz KL. Factors influencing the secretion of vasopressin into cerebrospinal fluid. Fed Prm" 1985; 44: 72-7.
•
~"
f'
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•
y,
..7.
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ELSEVIER
Brain & Development 1996; 18: 110-113
Original article
Vasopressin in the cerebrospinal fluid of febrile children with or without seizures Tuula Kiviranta
a,*,
Leena Tuomisto b, Jukka Jolkkonen c, Eila M. Airaksinen
a
a Department ofPaediatrics, Kuopio University tto,spital, P.O. Box 1777, FIN-7021/Kuopio. Finland b Department of Pharmacology and Toxwology. University of Kuopio, FIN-70211 Kuopio, Finland c Department of Neurology, University of Kuopio, FIN-70211 Kuopio, Finland Received 3 August 1995; accepted 12 November 1995
Immaturity in water and electrolyte balance in the brain has been considered to increase the susceptibility of young animals and children to febrile convulsions (FCs). Arginine-vasopressin (AVP) is involved in the regulation of several centrally mediated events such as modulation of fever and the ease with which water permeates into and out of the brain. To evaluate the possible role of AVP in the control of water balance and susceptibility to convulsions during fever we measured the AVP concentration in the cerebrospinal fluid (CSF) and plasma of febrile children with or without convulsions. The febrile population consisted of 47 children, of whom 29 experienced seizures during fever• Seven children with epileptic symptoms and 18 children without seizures were included as nonfebrile controls. The CSF AVP concentration in febrile children without seizures and in nonfebrile convulsive children was significantly lower (0.60 + 0.07 p m o l / l , mean + SEM, P < 0.01 and 0.65 + 0.19 p m o l / I , P < 0.05, respectively) than in nonfebrile children without convulsions (0.83 + 0 . 0 6 p m o l / I ) . However, the levels of CSF AVP were not significantly different in children with FCs (0.71 + 0.06 p m o l / I ) compared with other groups. CSF AVP correlated with the CSF osmolality (r= 0.33, P = 0.02). No statistical differences in plasma AVP levels between the groups could be found. The present data provide support for the hypothesis of synchronous regulation of osmolality and AVP concentration in CSF. During fever the concentration of CSF AVP was lower in nonconvulsive children compared with nonfebrile nonconvulsive children• CSF AVP levels were not affected in febrile children by convulsions. Keywords: Vasopressin; Febrile convulsion; Fever; Seizure; Cerebrospinal fluid
1. I N T R O D U C T I O N Arginine vasopressin (AVP) has generally been regarded as a peripheral regulator of water balance and vasoconstriction [I]. AVP is predominantly synthesized in two hypothalamic nuclei, the paraventricular (PVN) and supraoptic nuclei (SON), transported into the neural lobe of the pituitary and secreted from there into the circulation [2]. On the other hand, AVP released from the PVN or extrahypothalamic projections ('central pool') has been suggested to play an important role in the regulation of brain water permeability and intracranial pressure [2-8]. AVP has
• Corresponding author. Taivallahdentie 7, FIN-70620 Kuopio, Finland. Fax: (358) (71) 262 6696. 0387-7604/96/$15.00 © 1996 Elsevier Science B.V. All fights reserved SSDI 03 87-7604(95)001 46-8
also been demonstrated to have a physiological role as an endogenous antipyretic in the regulation of fever in several mammalian species [9]. Convulsions occur frequently in conjunction with febrile diseases during childhood: 2 - 5 % of all children will experience febrile convulsions (FCs) before the age of 5 years [10,11]. AVP has been proposed to be one of the agents responsible for inducing convulsions during fever in animals [12,13]. To our knowledge, there are no earlier studies published of cerebrospinal fluid (CSF) AVP measurements in children with febrile convulsions. To evaluate how fever and convulsions, alone or in combination, affect the vasopressinergic system, we measured the concentrations of AVP in CSF and plasma of febrile and nonfebrile children with or without convulsions.
I11
T. Kiviranta et al./Brain & Development 1996; 18:110-113
2. P A T I E N T S
Table 2 Concentrations of CSF and plasma vasopressin o? children in
AND METHODS
different groups
The study population consisted of 72 children admitted to the Department of Pediatrics at Kuopio University Hospital (Table 1). When clinical indications existed, CSF samples were taken after obtaining informed consent from the parents. The study protocol was accepted by the ethical committee of the Kuopio University Hospital. The body temperature was recorded immediately before lumbar puncture. Forty-two of the children had received antipyretic analgetics during the last 24 h (Table 1). Diazepam or other benzodiazepines were used as anticonvulsant or sedative drugs before the lumbar puncture, when needed. Clinical signs of dehydration were not found in any of the children. There was no significant difference in the mean temperature of febrile convulsive and nonconvulsive children (38.7°C and 38.8°C, respectively) before the lumbar puncture. The group of febrile children consisted of 47 children, 29 of whom had had febrile seizures before admission to the hospital. A single seizure lasting less than 15 min without focal features in children under 5 years was defined as a simple febrile convulsion. Febrile seizures were considered complicated if they did not fulfil the above criteria. Twenty-one of the children (72%) had simple seizures and eight children (28%) were classified as having complicated convulsions. The CSF samples were taken shortly after the patients' admission to the hospital, on average 4 h (range 1.5-20 h) after the convulsive attacks. The nonconvulsive febrile group consisted of 18 children with a variety of acute infectious illnesses, but not having seizures. Patients with meningitis or encephalitis were excluded. The nonfebrile group without seizures consisted of 18 children. Seven children with nonfebrile seizures formed the nonfebrile convulsive group. The duration of the convulsions varied from a few seconds (repeated in series such as in infantile spasms) to status epilepticus lasting for 30 min. Also in this group, the CSF samples were obtained on average 4 h after the last epileptic fit (range 2 - 8 h).
2.1. Sample collection and analysis CSF samples (3.5 ml) were taken by lumbar puncture. Plasma samples for AVP determination were taken within 2 h of the CSF samples ( n - 18), or during the next 10 h if the patient was admitted to the hospital during the night (n = 30). AVP was
Group Febrile convulsive nonconvulsive Non febrile convulsive nonconvulsive
Vasopressin (pmol/1) CSF
Plasma
0.71 _+0.06 (29) 0.60=0.07(18) " "
1.70 + 0.33 (24) 2.53_+0.93(10)
0.65 + 0.19 (7) " 0.83:t:0.06 (18)
0.75 _+0. I I (5) 3.41 _+ 1.16(9)
Statistical significance compared with nonfebrile, nonconvulsive children, • " P < 0.01, " P < 0.05 (KruskaI-Wallis test). Values are expressed as mean + SEM with the number of patients in parentheses.
measured by a specific radioimmunoassay as described previously for CSF [14] and for plasma [15]. The detection limit of the assay was 0.35 p m o l / l , which was used in the data analysis as the lowest value for those measurements below that level. Osmolality was analyzed by the freezing point depression method (Advanced Instruments Model 3).
2.2. Statistical methods Kruskal-Wallis analysis was used to test the differences of CSF and plasma AVP concentrations in the various diagnosis groups. Student's t-test was used to study the effects of sex and the use of benzodiazepines or antipyretic analgetics on CSF and plasma AVP levels. Correlations between variables were determined by Pearson's correlation analysis. All results are presented as the mean + SEM.
3. R E S U L T S CSF and plasma AVP concentrations are presented in Table 2. The concentration of AVP in CSF of febrile children without seizures and in nonfebrile children with convulsions was significantly lower than that of nonfebrile children without convulsions ( P < 0.01 and P < 0.05, respectively). In children with febrile convulsions, CSF AVP concentrations were comparable to those in nonfebrile groups. There was no difference in the AVP levels
Table 1 Description of the children in different groups Group
Febrile convulsive ~ nonconvulsive b Nonfebrile convulsive c nonconvulsive a
Number of cases
Mean age (range) (years)
Female/male
29 18
1.9 (0.9-6.7) 5.4 (0.6-11.4)
7 18
3.5 (0.7-8.7) 7.1 (0.3-14.3)
Drugs Antipyretic agents n (%)
Benzodiazepines n (%)
11/ 18 9/9
25 (86) 13 (72)
15 (52) 6 (33)
4/3 9/9
1 (14) 3 (16)
6 (86) 4 (22)
Diagnoses: a upper respiratory tract infections (1 I), pneumonia (5), exanthem subitum (5), gastroenteritis (4), viral infections (3), pyelonephritis (1); b upper respiratory tract infections (9), acute leukemia without cytotoxic chemotherapy or neuroleukemia (4), viral infections (2), pyelonephritis (1), plexus neuritis (1), sepsis with malignant lymphoma before cytotoxic chemotherapy (1); c complex partial seizures (3), status epilepticus (1), tonic-clonic seizure (1), infantile spasm (2); ~ acute leukemia without cytotoxic chemotherapy or neuroleukemia (9), vertigo (2), neck pain (2), malignant mediastinal lymphoma without cytotoxic chemotherapy (I), suspected neurological symptoms or delay in development (4).
112
7: Kiviranta et a l . / Brain & Development 1996; 18:110-113 1.6
~
1.4 1.2
v
z
1
~. 1
0.8
•
•
k&
~- 0.2
~
o 0 265 270 2 7 5 2 0 285 2 0 2=5" CSF-OSMOLALITY(mOmTt/kgH20)
Fig. 1. The correlation between cerebrospinal fluid osmolality and arginine-vasoprcssin concentration. The equation of the regression line is y = 0.01 x - 2.92, r = 0.33, P = 0.02 (Pearson's correlation analysis). Symbols: • one observation. [] two overlapping observations.
in the CSF between the children with simple (0.72 + 0.08 pmol/1, n = 21) and those with complicated febrile convulsions (0.70 + 0.09 pmol/I, n = 8). CSF AVP correlated with CSF osmolality (Fig. 1). None of the following factors had any statistically significant effect on CSF or plasma AVP levels: age, gender, maximal body temperature during the febrile illness, duration of the fever or the seizure, interval between the seizure and CSF sampling, use of benzodiazepines or antipyretic analgetics, or the time of day when the CSF samples were taken. No statistical differences in the levels of plasma AVP between groups could be found (Table 2). The concentration of AVP in plasma did not correlate with plasma osmolality.
4. D I S C U S S I O N The CSF vasopressin concentrations measured in the present study were within the range reported earlier for children [16]. There was no correlation between the age of the children and the level of AVP in CSF, consistent with earlier studies in adults [2,17] and children [16]. In the present study the concentration of AVP in CSF of febrile nonconvulsive children was lower than that of nonfebrile nonconvulsive children. In previous works, vasopressin has been shown to influence thermoregulation in several animal species [9,18-28]. Earlier studies indicate that AVP is released both centrally [20] and peripherally [16] during fever and hyperthermia. The stimulus for AVP release may be complex as both pyrogenic and thermal stimuli seem to be involved [24]. In febrile animals, the peak AVP level in CSF has been documented to occur 3 - 4 h after initiation of an endotoxin-induced fever [20]. AVP administered into ventricles has been shown to induce an antipyretic action lasting for 30 min in rats [27]. Although no elevated AVP values were detected in our patients at the time of CSF sampling, the animal experiments suggest that AVP release may have occurred at the beginning of the fever. The release of AVP could explain our earlier finding that CSF osmolality is significantly decreased in febrile children [29]. The mechanism behind these changes cannot be resolved by this study. We do not know which is the primary phenomenon, decrease of osmolality or primarily a release of AVP in the first phase of fever. Based on earlier data and our findings it is probable that low levels of electrolytes in CSF might be secondary to the initial release of
AVP leading further to a decrease of AVP concentration by a feedback mechanism. The antidiuresis evoked by the elevated AVP plasma concentration during the initial phase of fever would thus alleviate the decrease in plasma volume which accompanies fever and preserve the water supply needed to compensate for evaporative heat loss [18]. The difference in CSF AVP concentration between the febrile and nonfebrile nonconvulsive children supports the hypothesis that vasopressin might have a role in physiological phenomena associated with febrile diseases, in thermoregulation or in the regulation of fluid balance of CNS. This last alternative is supported by our observation that CSF osmolality and AVP concentration correlated with each other. In animal studies, increases in CSF osmolality are followed by an increase in CSF AVP concentration [30]. The changes of fluid and electrolyte fluxes between plasma, brain, and CSF influence the regulation of brain ionic environment and volume homeostasis. It has been suggested that centrally released vasopressin is involved in this regulation through its effects on the composition of CSF [3,6,8,31]. The increase in the levels of AVP in plasma [32] and CSF found in children with bacterial meningitis has been proposed to be an additional factor in the pathogenesis of cerebral edema in these children [33]. It has been proposed that AVP could be one of the agents responsible for inducing convulsions during fever in animals [12,13]. The absence of AVP in the brain of Brattleboro rats, or neutralization of central AVP by intracerebroventricularly administered antiserum, has allowed animals to reach higher body temperature before experiencing convulsions, or has even prevented totally the convulsions [12]. If AVP does play a role as a mediator in febrile convulsions [12,13], the lower CSF AVP concentrations could be beneficial in the protection against seizures during febrile diseases. No data on the level of CSF AVP after epileptic seizures in children have been published before. In plasma, prolonged epileptic convulsions have been shown to increase transiently AVP levels in adults [34]. We did not find such change in the group of nonfebrile convulsive children, probably due to the small number of patients and different etiologies of their clinical symptoms. Our finding that these children had lower AVP levels in CSF should therefore also be considered preliminary, requiring further confirmation. Plasma AVP concentrations in febrile children have been found to be normal [32] or elevated [ 16]. We could not detect any statistically significant changes in plasma AVP concentrations between the febrile and nonfebrile groups. The discrepancy in the results between the CSF and blood samples can be explained by the fact that AVP entering the CSF may be derived, at least in part, from a different population of neurons from those secreting AVP into the blood [35]. Another explanation for the dissimilarity can be the time interval between the CSF and blood samples. In this study we excluded children with meningitis or encephalitis and thus the difference in the diagnosis of the children could partly explain the higher AVP concentrations in plasma found by Sharpies and coworkers [16]. The influence of AVP on body fluid balance could not be evaluated by measurement of urine osmolality and volume in the present study, because the time the children spent in hospital was usually limited to only a few hours. Our study reveals simultaneous changes in CSF AVP and osmolality in febrile diseases, providing support for the concept of synchronous regulation of osmolality and AVP in CSF. CSF
T. Kiviranta et al. / Brain & Development 1996: 18:110-113
A V P concentrations were lower in febrile nonconvulsive children than in nonfebrile nonconvulsive patients. A normal C S F A V P concentration in children with FCs may be indicative of a difference in the release of A V P in C S F and theoretically be associated with the susceptibility to seizures during fever. The difference between the groups o f febrile children was, however, small and needs later investigations to resolve in greater detail the mechanisms underlying febrile convulsions.
ACKNOWLEDGEMENTS The study has been supported by grants from the Arvo and Lea Ylppb Foundation, the North-Savo Fund of the Finnish Cultural Foundation and the Academy of Finland, Research Council for Medicine.
16.
17.
18. 19.
20.
21. REFERENCES I. Wang BC, Goetz KL. Volume influences on the plasma osmolality plasma vasopressin relationship mediated by cardiac receptors. In: Schrier RW, ed. Vasopressin. New York: Raven Press, 1985:221-8. 2. SeJrensen PS. Studies of vasopressin in the human cerebrospinal fluid. Acta Neurol Scand 1986; 74: 81-102. 3. Raichle ME, Grubb RL Jr. Regulation of brain water permeability by centrally-released vasopressin. Brain Res 1978; 143: 191-4. 4. Reeder RF, Nattie EE, North WG. Effect of vasopressin on cold-induced brain edema in cats. J Neurosurg 1986; 64: 941-50. 5. Jolkkonen J, Tuomisto L, van Wimersma Greidanus TB, L ~ E, Riekkinen P. Effects of osmotic stimuli on vasopressin levels in the CSF of rats. Peptides 1988; 9:109-11. 6. DePasquale M, Patlak CS, Cserr HF. Brain ion and volume regulation during acute hypernatremia in Brattleboro rats. Am J Physiol 1989; 256: FI059-66. 7. Faraci FM, Mayhan WG, Heistad DD. Effect of vasopressin on production of cerebrospinal fluid: possible role of vasopressin (V~)receptors. Am J Physiol 1990; 258: R94-8. 8. Szmydynger-Chodobska J, Szczepanska-Sadowska E, Chodobski A. Effect of arginine vasopressin on CSF composition and bulk flow in hyperosmolar state. Am J Physiol 1990; 259: RI250-8. 9. Kasting, NW. Criteria for establishing a physiological role for brain peptides. A case in point: the role of vasopressin in thermoregulation during fever and antipyresis. Brain Res Rev 1989; 14: 143-53. 10. Hauser WA. The natural history of febrile seizures. In: Nelson KB, Ellenbcrg JH, eds. Febrile seizures. New York: Raven Press, 1981: 5-17. 11. Wallace SJ. The child with febrile seizures. London: Wright, 1988. 12. Kasting NW, Veale WL, Cooper KE, Lederis K. Vasopressin may mediate febrile convulsions. Brain Res 1981; 213: 327-33. 13. Veale WL. Cooper KE, Ruwe WD. Vasopressin: its role in antipyresis and febrile convulsion. Brain Res Bull 1984; 12: 161-5. 14. Jolkkonen J, Helkala E-L, Kutvonen R, Lehtinen M, Riekkinen RJ. Vasopressin levels in CSF of Alzheimer patients: correlations with monoamine metabolites and neuropsychological test performance. Psychoneuroendocrim)logy 1989; 14: 89-95. 15. Pesonen U, Jolkkonen J, Huupponen R, Koulu M. Differential hypothalamic arginine vasopressin response to glucocorticoid receptor
22.
23. 24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
113
antagonism in lean and obese zucker rats. Neuroendocrinology 1992; 56: 271-7. Sharpies PM, Seckl JL, Human D, Lightman SL, Dunger DB. Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever. Arch Dis ChiM 1992; 67: 998-1002. Gold PW, Kaye W. Robertson GL. Ebert M. Abnormalities in plasma and cerebrospinal-fluid axginine vasopressin in patients with anorexia nervosa. N EnglJ Med 1983: 308:I117-23. Zeisberger E. Role of vasopressin in fever regulation and suppression. TIPS 1985; 6: 428-30. Veale WL, Kasting NW, Cooper KE. Arginine vasopressin and endogenous antipyresis: evidence and significance. Fed Proc 1981: 40: 2750-3. Kasting NW, Carr DB, Martin JB, Blume H, Bergland R. Changes in cerebrospinal fluid and plasma vasopressin in the febrile sheep. Can J Physiol Pharmacol 1983; 61:427-3 I. Ruwe WD. Electrical stimulation of the paraventrieular nucleus attenuates pyrogen fever in the rabbit. Brain Res 1992: 588: 181-90. Naylor AM, Ruwe WD, Veale WL. Antipyretic action of centrally administered arginine vasopressin but not oxytocin in the cat. Brain Res 1986; 385: 156-60. Kasting NW, Wilkinson MF. Vasopressin /'unctions as an endogenous antipyretic in the newborn. Biol Neonate 1987: 51: 249-54. Landgraf R, Malkinson TJ, Veale WL, Lederis K, Pittman QJ. Vasopressin and oxytocin in rat brain in response to prostaglandin fever. Am J Physiol 1990; 259: R1056-62. Cridland RA, Kasting NW. A critical role for central vasopressin in regulation of fever during bacterial infection. Am J Physiol 1992; 263:R1235-40. Federico P, Veale WL, Pittman QJ. Vasopressin-induced antipyresis in the medial amygdaloid nucleus of conscious rats. Am J Physiol 1992; 262: R901-8. Kovacs GL, Baars AM, De Wied D. Antipyretic effect of central arginine-vasopressin treatment: V~ receptors specifically involved? L(fe &'i 1992; 50: 1625-30. Roth J, Schulze K, Simon E, Zeisberger E. Alteration of endotoxin fever and release of arginine vasopressin by dehydration in the guinea pig. Neuroendocriru~h)gy 1992; 56: 680-6. Kiviranta T, Tuomisto L, Airaksinen EM. Osmolality and electrolytes in cerebrospinal fluid and serum of febrile children with and without seizures. Eur J Pediatr, in press. Nilsson C, Lindvall-Axelsson M, Owman C. Neuroendocrine regulatory mechanisms in the choroid plexus-cerebrospinal fluid system. Brain Res Rev 1992; 17:109-38. Ludwig M, Landgraf R. Does the release of vasopressin within the supraoptic nucleus of the rat brain depend upon changes in osmolality and Ca"" / K + ? Brain Re,~ 1992; 576:231 - 4. Kaplan SL, Feigin RD. The syndrome of inappropriate secretion of antidiuretic hormone in children with bacterial meningitis. J Pediatr 1978; 92: 758-61. Garcia H, Kaplan SL, Feigin RD. Cerebrospinal fluid concentration of arginine vasopressin in children with bacterial meningitis. J Pediatr 1981: 98: 67-70. Meierkord H, Shorvon S, Lightman SL. Plasma concentrations of prolactin, noradrenaline, vasopressin and oxytocin during and after a prolonged epileptic seizure. Acta Neurol Scaml 1994; 90: 73-7. Wang BC. Share L. Goetz KL. Factors influencing the secretion of vasopressin into cerebrospinal fluid. Fed Prm" 1985; 44: 72-7.