- Email: [email protected]
Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures
Epilepsy Research 31 (1998) 129 – 133
Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures Jukka Peltola a,c,*, Mikko Hurme c, Ari Miettinen b, Tapani Kera¨nen a,c b
a Department of Neurology, Tampere Uni6ersity Hospital, P.O. Box 2000, Fin-33101 Tampere, Finland Department of Clinical Microbiology, Tampere Uni6ersity Hospital, P.O. Box 2000, Fin-33101 Tampere, Finland c Medical School, Uni6ersity of Tampere, P.O. Box 607, Fin-33101 Tampere, Finland
Received 17 October 1997; received in revised form 17 March 1998; accepted 28 March 1998
Abstract Experimental animal studies suggest the involvement of cytokines in epilepsy. We measured increased concentrations of interleukin-6 in four out of 15 cerebrospinal fluid samples from unmedicated patients with newly developed tonic-clonic seizures; plasma levels were also increased but to a lesser extent. Although the significance of cytokine production in relation to epileptic seizures is not known, it might be important for neuronal survival. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Cytokines; Epilepsy; IL-6; Cerebrospinal fluid
1. Introduction Cytokines are a heterogeneous group of polypeptide mediators that have been associated classically with activation of the immune system and inflammatory responses, but they also exert diverse actions on the peripheral and central nervous system (Hopkins and Rothwell, 1995). Experimental studies suggest their involvement also in epilepsy. Convulsant-induced seizures increase
* Corresponding author.
messenger RNA synthesis of interleukins (IL)-1 and 6 and tumor necrosis factor a (TNFa) in the rat brain (Minami et al., 1991; De Bock et al., 1996) and have caused activation of cytokine regulatory factors in another rat model (Prasad et al., 1994). As cytokines have not been studied in patients with epileptic seizures, we decided to measure concentrations of IL-1b, IL-6 and TNFa in plasma and cerebrospinal fluid (CSF) from untreated patients with tonic-clonic seizures. The possible role of infections in this context was addressed by thorough clinical and laboratory evaluation.
0920-1211/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII S0920-1211(98)00024-2
130
J. Peltola et al. / Epilepsy Research 31 (1998) 129–133
2. Methods CSF and plasma samples were collected from 15 consecutive previously undiagnosed and untreated patients with recent (B72 h) primarily generalized or partial secondarily generalized tonic-clonic seizures (group I) and from 14 previously untreated patients suffering a seizure more than 2 weeks previously (group II). We excluded patients with seizures associated with electrolyte disturbances, metabolic causes, alcohol or drug withdrawal, acute brain disease and trauma, and those with a history of major psychiatric disease or known autoimmune disease. In group I, 8 out of 15 patients and in group II 8 out of 14 had isolated seizures. Four patients revealed later symptomatic epilepsy: one patient in group II had arteriovenous malformation, three patients in group I had brain tumours (patients 5, 8 and 9). There was no evidence of recent systemic or central nervous system infection in any patient. The patients were 15–60 years old. We also studied a control group of 22 patients of similar age range on whom lumbar puncture (LP) was performed to exclude neurological disease and who yielded normal neurological examination and laboratory findings. All patients were fully informed of the risks and potential benefits of the CSF examination, and informed consent was obtained from each subject. The study protocol was approved by the Ethics Committee of Tampere University Hospital. Lumbar CSF was obtained between 09:00 h and 14:00 h. The first 2 ml of CSF was used for routine examination and the next 1 ml for the present study. Blood was collected within 30 min of lumbar puncture in a Vacutainer EDTA vacuum tube and centrifuged at 3000 rpm for 10 min. The plasma and CSF were stored in small aliquots at −70°C in sterile Eppendorf tubes. The complete blood count (CBC) was determined using Coulter Counter Model S-Plus IV (Coulter, Hialeah, FL) and C-reactive protein (CRP) by immunoturbidimetry (Hitachi, Tokyo, Japan). Serum antibodies to streptolysin (AST) were measured by a standard nephelometric assay (Behringwerke, Hamburg, Germany). Antibodies to Salmonella, Campylobacter jejuni and Yersinia
were measured by in-house enzyme immunoassay (EIA) techniques. Antibodies to Varicella zoster and Herpes simplex virus were measured by EIA (Enzygnost, Behringwerke, Germany). IL-6 and TNFa were measured with enzymelinked immunosorbent assay (ELISA) kits (Pelikine Compact, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands). IL-1b was measured using ELISA kits obtained from R&D Systems (Minneapolis, MN). The assays were performed according to manufacturers’ instructions. The sensitivity of the IL-6 assay was 0.4 pg/ml; that for TNFa was 2 pg/ml and for IL-1b 1 pg/ml. Samples were considered positive if the level of the cytokine was higher than 2 S.D. (standard deviation) above the mean value for the control group.
3. Results In group I, the concentrations of IL-6 were \ 7.4 pg/ml (mean+ 2 S.D. for the control group) in four out of 15 CSF samples and \ 5.5 pg/ml (mean+ 2 S.D. for the control group) in three of the plasma samples. In contrast, none of the patients in group II had concentrations of IL-6\ 7.4 pg/ml in CSF; in two patients in this group the plasma concentrations of IL-6 were 5.7 pg/ml and 8.7 pg/ml, respectively. In the control group in one patient with acute headache the CSF concentration of IL-6 was 10 pg/ml and in another patient the plasma concentration of IL-6 was 8.1 pg/ml (Fig. 1a,b). All four patients in group I with elevated CSF levels of IL-6 had LPs performed within 15 h of the seizures (altogether six patients in group I had LPs obtained within 15 h of the last seizure). Two of these patients were the only ones with multiple seizures during one day. The highest TNFa level measured in CSF was only 2.2 pg/ml. In most CSF and plasma samples IL-1b was undetectable, the highest concentration measured in CSF being 2.18 pg/ml. For the evaluation of blood–brain barrier damage, ratios of CSF albumin to serum albumin were investigated, but none of the patients showed increased values (normalB 0.009).
J. Peltola et al. / Epilepsy Research 31 (1998) 129–133
131
Fig. 1. (a) CSF concentration of interleukin-6 in patients B 72 h from the last seizure (group I), more than 2 weeks from the last seizure (group II) and controls. (b) Plasma concentration of interleukin-6 in patients B 72 h from the last seizure (group I), more than 2 weeks from the last seizure (group II) and controls.
Table 1 shows cell counts, CRP, IL-6 levels and some clinical characteristics in group I. Slightly elevated AST levels were measured in three patients in group I. One of these patients also had elevated levels of IL-6 in CSF but not in plasma (patient 15). However, these patients had normal CRP and WBC counts and no clinical signs of streptococcal infection. Results of other antibody studies were unremarkable in all patients.
4. Discussion To our knowledge, this preliminary report is the first providing evidence of increased IL-6 levels in human CSF after epileptic seizures. Elevated CSF levels of IL-6 were detected in 27% of patients with seizures occurring within 72 h before sampling. Our results suggest that seizure-related IL-6 production occurs rapidly and is transitory: all the patients who had high IL-6 levels were studied within 15 h of the seizure. The rates of production and elimination of cytokines are
largely unknown. A pleiotropic cytokine transcription factor nuclear factor-kB expression was increased several days following convulsant-induced seizures (Prasad et al., 1994). In kainic acid- and pentylenetetrazol-induced seizures, maximal levels of IL-1b mRNA have been seen to be expressed in the brain 1.5–3.5 h after the seizures (Minami et al., 1990). Our earliest samples were drawn 10 h after the seizure and it is possible that IL-1 and TNFa with short half-lives had already peaked earlier. The severity of seizures may also be a predictive factor: both of the patients with multiple seizures had high CSF IL-6 levels. One out of two patients with brain tumors had an increased CSF IL-6 concentration. The cytokines measured in CSF can be either of peripheral or intrathecal origin. IL-6 is produced by a variety of cells, including fibroblasts, monocytes, T cells, B cells, microglia, endothelial cells and astrocytes (St. Pierre et al., 1996). Seizures may increase blood–brain barrier permeability (Ruth, 1984) and thus facilitate an influx of cytokines in the CSF. None of the four patients
J. Peltola et al. / Epilepsy Research 31 (1998) 129–133
132
Table 1 Clinical characteristics and laboratory parameters of patients with recent seizures (group I) Patient (age, sex)
CSF IL-6 (pg/ml)
P IL-6 (pg/ml)
Time interval (h)
CSF WBC (106/l)
WBC (109/l)
CRP (mg/l)
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
1.8 2.3 104 1.2 1.8 1.8 3.0 17.3 2.1 2.6 4.1 40.4 2.5 5.6 17.4
0.6 0.6 26.2 1.6 2.6 4.4 1.2 10.3 1.1 0.7 3.6 18.4 2.5 4.3 1.5
24 22 12 48 24 12 48 12 72 24 10 10 24 22 15
1 9 2 0 2 0 2 7 2 NA 1 6 2 2 0
9.5 4.8 16.3 7.8 8.3 5.3 6.5 14.8 7.5 2.8 8.5 12.6 9.4 10.8 7.1
5 6 6 7 6 7 7 6 6 5 8 88 7 9 6
(26,M) (16,M) (22,M) (38,F) (43,M) (57,F) (57,M) (21,M) (35,M) (43,M) (42,M) (29,M) (24,F) (28,M) (16,M)
M= male, F= female; CSF=cerebrospinal fluid; time interval =from seizure to lumbar puncture; P = plasma; IL-6 =interleukin-6; WBC= white blood cell; CRP =c-reactive protein; NA = not available.
with elevated IL-6 had elevated albumin CSF serum ratio, in favor of intact blood – brain barrier. In three of these patients, the plasma levels of IL-6 were also increased but to a lesser extent than in CSF. The patients in group I also had other signs of seizure-related immune activation such as mild CSF pleocytosis and peripheral blood leukocytosis. Pleocytosis following generalized tonic-clonic seizures has been reported as a transient phenomenon in patients with no other cause to account for the changes in CSF (Devinsky et al., 1988). Three patients with elevated plasma concentrations of IL-6 had an increased WBC count in the blood. Peripheral blood leukocytosis produced by a redistribution of the marginated granulocyte pool to the circulating granulocyte pool is a known consequence of convulsions (McKenzie, 1996). One patient with elevated IL-6 concentration and with multiple seizures and rhabdomyolysis had an increased concentration of CRP and another had elevated AST without any clinical symptoms or signs of infection. Furthermore, viral or bacterial antibody measurements did not point to recent infection. Earlier studies have suggested that subclinical infections might act as predisposing factors in patients with epileptic
seizures (Iivanainen et al., 1983), but our studies of bacterial and viral antibody levels were negative. The significance of cytokine production in relation to epileptic seizures is not known. Cytokines might be important for neuronal survival, and IL-1b and IL-6 have been shown to exert neuroprotective and neurotrophic effects (St. Pierre et al., 1996). Mice lacking TNF receptors show increased neuronal damage in response to kainic acid injection, implying that TNF could be neuroprotective (Bruce et al., 1996). IL-1, IL-6 and TNFa might be diffusible mediators of astrogliosis after CNS injury (Yong, 1996). The data available suggest a role for cytokines in epileptic processes and it is important to define this role in both experimental and human conditions.
References Bruce, A.J., Boling, W., Kindy, M.S., Peschon, J., Kraemer, P.H., Carpenter, M.K., Holtsberg, F.W., Mattson, M.P., 1996. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Med 2, 788 – 794. De Bock, F., Dornand, J., Rondouin, G., 1996. Release of TNFa in the rat hippocampus following epileptic seizures
J. Peltola et al. / Epilepsy Research 31 (1998) 129–133 and excitotoxic neuronal damage. NeuroReport 7, 1125– 1129. Devinsky, O., Nadi, S., Theodore, W.H., Porter, R.J., 1988. Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures. Ann Neurol 23, 402 – 403. Hopkins, S.J., Rothwell, N.J., 1995. Cytokines and the nervous system I: expression and recognition. Trends Neurosci 18, 83 – 88. Iivanainen, M., Hietala, J., Malkama¨ki, M., Waltimo, O., Valtonen, V.V., 1983. An association between epileptic seizures and increased serum bacterial antibody levels. Epilepsia 24, 584 – 587. McKenzie, S.B., 1996. Nonmalignant granulocyte and monocyte disorders. In: McKenzie, S.B. (Ed.), Textbook of Hematology. Williams and Wilkins, Baltimore, pp. 275295. Minami, M., Kuraishi, Y., Satoh, M., 1991. Effects of kainic acid on messenger RNA levels of IL-1a, IL-6, TNFa and LIF in the rat brain. Biochem Biophys Res Commun 176,
.
133
593 – 598. Minami, M., Kuraishi, Y., Yamaguchi, T., Nakai, S., Hirai, Y., Satoh, M., 1990. Convulsants induce interleukin-1b messenger RNA in rat brain. Biochem Biophys Res Commun 171, 832 – 837. Prasad, A.V., Pilcher, W.H., Joseph, S.A., 1994. Nuclear factor-kappa B in rat brain: enhanced DNA-binding activity following convulsant-induced seizures. Neurosci Lett 170, 145 – 148. Ruth, R.E., 1984. Increased cerebrovascular permeability to protein during systemic kainic acid seizures. Epilepsia 25, 259 – 268. St. Pierre, B.A., Merrill, J.E., Dopp, J.M., 1996. Effects of cytokines on CNS cells: glia. In: Ransohoff, R.M., Benveniste, E.N. (Eds.), Cytokines and the CNS. CRC Press, Boca Raton, FL, pp. 151 – 168. Yong, V.W., 1996. Cytokines, astrogliosis, and neurotrophism following CNS trauma. In: Ransohoff, R.M., Benveniste, E.N. (Eds.), Cytokines and the CNS. CRC Press, Boca Raton, FL, pp. 309 – 327.
.
Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures Jukka Peltola a,c,*, Mikko Hurme c, Ari Miettinen b, Tapani Kera¨nen a,c b
a Department of Neurology, Tampere Uni6ersity Hospital, P.O. Box 2000, Fin-33101 Tampere, Finland Department of Clinical Microbiology, Tampere Uni6ersity Hospital, P.O. Box 2000, Fin-33101 Tampere, Finland c Medical School, Uni6ersity of Tampere, P.O. Box 607, Fin-33101 Tampere, Finland
Received 17 October 1997; received in revised form 17 March 1998; accepted 28 March 1998
Abstract Experimental animal studies suggest the involvement of cytokines in epilepsy. We measured increased concentrations of interleukin-6 in four out of 15 cerebrospinal fluid samples from unmedicated patients with newly developed tonic-clonic seizures; plasma levels were also increased but to a lesser extent. Although the significance of cytokine production in relation to epileptic seizures is not known, it might be important for neuronal survival. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Cytokines; Epilepsy; IL-6; Cerebrospinal fluid
1. Introduction Cytokines are a heterogeneous group of polypeptide mediators that have been associated classically with activation of the immune system and inflammatory responses, but they also exert diverse actions on the peripheral and central nervous system (Hopkins and Rothwell, 1995). Experimental studies suggest their involvement also in epilepsy. Convulsant-induced seizures increase
* Corresponding author.
messenger RNA synthesis of interleukins (IL)-1 and 6 and tumor necrosis factor a (TNFa) in the rat brain (Minami et al., 1991; De Bock et al., 1996) and have caused activation of cytokine regulatory factors in another rat model (Prasad et al., 1994). As cytokines have not been studied in patients with epileptic seizures, we decided to measure concentrations of IL-1b, IL-6 and TNFa in plasma and cerebrospinal fluid (CSF) from untreated patients with tonic-clonic seizures. The possible role of infections in this context was addressed by thorough clinical and laboratory evaluation.
0920-1211/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII S0920-1211(98)00024-2
130
J. Peltola et al. / Epilepsy Research 31 (1998) 129–133
2. Methods CSF and plasma samples were collected from 15 consecutive previously undiagnosed and untreated patients with recent (B72 h) primarily generalized or partial secondarily generalized tonic-clonic seizures (group I) and from 14 previously untreated patients suffering a seizure more than 2 weeks previously (group II). We excluded patients with seizures associated with electrolyte disturbances, metabolic causes, alcohol or drug withdrawal, acute brain disease and trauma, and those with a history of major psychiatric disease or known autoimmune disease. In group I, 8 out of 15 patients and in group II 8 out of 14 had isolated seizures. Four patients revealed later symptomatic epilepsy: one patient in group II had arteriovenous malformation, three patients in group I had brain tumours (patients 5, 8 and 9). There was no evidence of recent systemic or central nervous system infection in any patient. The patients were 15–60 years old. We also studied a control group of 22 patients of similar age range on whom lumbar puncture (LP) was performed to exclude neurological disease and who yielded normal neurological examination and laboratory findings. All patients were fully informed of the risks and potential benefits of the CSF examination, and informed consent was obtained from each subject. The study protocol was approved by the Ethics Committee of Tampere University Hospital. Lumbar CSF was obtained between 09:00 h and 14:00 h. The first 2 ml of CSF was used for routine examination and the next 1 ml for the present study. Blood was collected within 30 min of lumbar puncture in a Vacutainer EDTA vacuum tube and centrifuged at 3000 rpm for 10 min. The plasma and CSF were stored in small aliquots at −70°C in sterile Eppendorf tubes. The complete blood count (CBC) was determined using Coulter Counter Model S-Plus IV (Coulter, Hialeah, FL) and C-reactive protein (CRP) by immunoturbidimetry (Hitachi, Tokyo, Japan). Serum antibodies to streptolysin (AST) were measured by a standard nephelometric assay (Behringwerke, Hamburg, Germany). Antibodies to Salmonella, Campylobacter jejuni and Yersinia
were measured by in-house enzyme immunoassay (EIA) techniques. Antibodies to Varicella zoster and Herpes simplex virus were measured by EIA (Enzygnost, Behringwerke, Germany). IL-6 and TNFa were measured with enzymelinked immunosorbent assay (ELISA) kits (Pelikine Compact, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands). IL-1b was measured using ELISA kits obtained from R&D Systems (Minneapolis, MN). The assays were performed according to manufacturers’ instructions. The sensitivity of the IL-6 assay was 0.4 pg/ml; that for TNFa was 2 pg/ml and for IL-1b 1 pg/ml. Samples were considered positive if the level of the cytokine was higher than 2 S.D. (standard deviation) above the mean value for the control group.
3. Results In group I, the concentrations of IL-6 were \ 7.4 pg/ml (mean+ 2 S.D. for the control group) in four out of 15 CSF samples and \ 5.5 pg/ml (mean+ 2 S.D. for the control group) in three of the plasma samples. In contrast, none of the patients in group II had concentrations of IL-6\ 7.4 pg/ml in CSF; in two patients in this group the plasma concentrations of IL-6 were 5.7 pg/ml and 8.7 pg/ml, respectively. In the control group in one patient with acute headache the CSF concentration of IL-6 was 10 pg/ml and in another patient the plasma concentration of IL-6 was 8.1 pg/ml (Fig. 1a,b). All four patients in group I with elevated CSF levels of IL-6 had LPs performed within 15 h of the seizures (altogether six patients in group I had LPs obtained within 15 h of the last seizure). Two of these patients were the only ones with multiple seizures during one day. The highest TNFa level measured in CSF was only 2.2 pg/ml. In most CSF and plasma samples IL-1b was undetectable, the highest concentration measured in CSF being 2.18 pg/ml. For the evaluation of blood–brain barrier damage, ratios of CSF albumin to serum albumin were investigated, but none of the patients showed increased values (normalB 0.009).
J. Peltola et al. / Epilepsy Research 31 (1998) 129–133
131
Fig. 1. (a) CSF concentration of interleukin-6 in patients B 72 h from the last seizure (group I), more than 2 weeks from the last seizure (group II) and controls. (b) Plasma concentration of interleukin-6 in patients B 72 h from the last seizure (group I), more than 2 weeks from the last seizure (group II) and controls.
Table 1 shows cell counts, CRP, IL-6 levels and some clinical characteristics in group I. Slightly elevated AST levels were measured in three patients in group I. One of these patients also had elevated levels of IL-6 in CSF but not in plasma (patient 15). However, these patients had normal CRP and WBC counts and no clinical signs of streptococcal infection. Results of other antibody studies were unremarkable in all patients.
4. Discussion To our knowledge, this preliminary report is the first providing evidence of increased IL-6 levels in human CSF after epileptic seizures. Elevated CSF levels of IL-6 were detected in 27% of patients with seizures occurring within 72 h before sampling. Our results suggest that seizure-related IL-6 production occurs rapidly and is transitory: all the patients who had high IL-6 levels were studied within 15 h of the seizure. The rates of production and elimination of cytokines are
largely unknown. A pleiotropic cytokine transcription factor nuclear factor-kB expression was increased several days following convulsant-induced seizures (Prasad et al., 1994). In kainic acid- and pentylenetetrazol-induced seizures, maximal levels of IL-1b mRNA have been seen to be expressed in the brain 1.5–3.5 h after the seizures (Minami et al., 1990). Our earliest samples were drawn 10 h after the seizure and it is possible that IL-1 and TNFa with short half-lives had already peaked earlier. The severity of seizures may also be a predictive factor: both of the patients with multiple seizures had high CSF IL-6 levels. One out of two patients with brain tumors had an increased CSF IL-6 concentration. The cytokines measured in CSF can be either of peripheral or intrathecal origin. IL-6 is produced by a variety of cells, including fibroblasts, monocytes, T cells, B cells, microglia, endothelial cells and astrocytes (St. Pierre et al., 1996). Seizures may increase blood–brain barrier permeability (Ruth, 1984) and thus facilitate an influx of cytokines in the CSF. None of the four patients
J. Peltola et al. / Epilepsy Research 31 (1998) 129–133
132
Table 1 Clinical characteristics and laboratory parameters of patients with recent seizures (group I) Patient (age, sex)
CSF IL-6 (pg/ml)
P IL-6 (pg/ml)
Time interval (h)
CSF WBC (106/l)
WBC (109/l)
CRP (mg/l)
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
1.8 2.3 104 1.2 1.8 1.8 3.0 17.3 2.1 2.6 4.1 40.4 2.5 5.6 17.4
0.6 0.6 26.2 1.6 2.6 4.4 1.2 10.3 1.1 0.7 3.6 18.4 2.5 4.3 1.5
24 22 12 48 24 12 48 12 72 24 10 10 24 22 15
1 9 2 0 2 0 2 7 2 NA 1 6 2 2 0
9.5 4.8 16.3 7.8 8.3 5.3 6.5 14.8 7.5 2.8 8.5 12.6 9.4 10.8 7.1
5 6 6 7 6 7 7 6 6 5 8 88 7 9 6
(26,M) (16,M) (22,M) (38,F) (43,M) (57,F) (57,M) (21,M) (35,M) (43,M) (42,M) (29,M) (24,F) (28,M) (16,M)
M= male, F= female; CSF=cerebrospinal fluid; time interval =from seizure to lumbar puncture; P = plasma; IL-6 =interleukin-6; WBC= white blood cell; CRP =c-reactive protein; NA = not available.
with elevated IL-6 had elevated albumin CSF serum ratio, in favor of intact blood – brain barrier. In three of these patients, the plasma levels of IL-6 were also increased but to a lesser extent than in CSF. The patients in group I also had other signs of seizure-related immune activation such as mild CSF pleocytosis and peripheral blood leukocytosis. Pleocytosis following generalized tonic-clonic seizures has been reported as a transient phenomenon in patients with no other cause to account for the changes in CSF (Devinsky et al., 1988). Three patients with elevated plasma concentrations of IL-6 had an increased WBC count in the blood. Peripheral blood leukocytosis produced by a redistribution of the marginated granulocyte pool to the circulating granulocyte pool is a known consequence of convulsions (McKenzie, 1996). One patient with elevated IL-6 concentration and with multiple seizures and rhabdomyolysis had an increased concentration of CRP and another had elevated AST without any clinical symptoms or signs of infection. Furthermore, viral or bacterial antibody measurements did not point to recent infection. Earlier studies have suggested that subclinical infections might act as predisposing factors in patients with epileptic
seizures (Iivanainen et al., 1983), but our studies of bacterial and viral antibody levels were negative. The significance of cytokine production in relation to epileptic seizures is not known. Cytokines might be important for neuronal survival, and IL-1b and IL-6 have been shown to exert neuroprotective and neurotrophic effects (St. Pierre et al., 1996). Mice lacking TNF receptors show increased neuronal damage in response to kainic acid injection, implying that TNF could be neuroprotective (Bruce et al., 1996). IL-1, IL-6 and TNFa might be diffusible mediators of astrogliosis after CNS injury (Yong, 1996). The data available suggest a role for cytokines in epileptic processes and it is important to define this role in both experimental and human conditions.
References Bruce, A.J., Boling, W., Kindy, M.S., Peschon, J., Kraemer, P.H., Carpenter, M.K., Holtsberg, F.W., Mattson, M.P., 1996. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Med 2, 788 – 794. De Bock, F., Dornand, J., Rondouin, G., 1996. Release of TNFa in the rat hippocampus following epileptic seizures
J. Peltola et al. / Epilepsy Research 31 (1998) 129–133 and excitotoxic neuronal damage. NeuroReport 7, 1125– 1129. Devinsky, O., Nadi, S., Theodore, W.H., Porter, R.J., 1988. Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures. Ann Neurol 23, 402 – 403. Hopkins, S.J., Rothwell, N.J., 1995. Cytokines and the nervous system I: expression and recognition. Trends Neurosci 18, 83 – 88. Iivanainen, M., Hietala, J., Malkama¨ki, M., Waltimo, O., Valtonen, V.V., 1983. An association between epileptic seizures and increased serum bacterial antibody levels. Epilepsia 24, 584 – 587. McKenzie, S.B., 1996. Nonmalignant granulocyte and monocyte disorders. In: McKenzie, S.B. (Ed.), Textbook of Hematology. Williams and Wilkins, Baltimore, pp. 275295. Minami, M., Kuraishi, Y., Satoh, M., 1991. Effects of kainic acid on messenger RNA levels of IL-1a, IL-6, TNFa and LIF in the rat brain. Biochem Biophys Res Commun 176,
.
133
593 – 598. Minami, M., Kuraishi, Y., Yamaguchi, T., Nakai, S., Hirai, Y., Satoh, M., 1990. Convulsants induce interleukin-1b messenger RNA in rat brain. Biochem Biophys Res Commun 171, 832 – 837. Prasad, A.V., Pilcher, W.H., Joseph, S.A., 1994. Nuclear factor-kappa B in rat brain: enhanced DNA-binding activity following convulsant-induced seizures. Neurosci Lett 170, 145 – 148. Ruth, R.E., 1984. Increased cerebrovascular permeability to protein during systemic kainic acid seizures. Epilepsia 25, 259 – 268. St. Pierre, B.A., Merrill, J.E., Dopp, J.M., 1996. Effects of cytokines on CNS cells: glia. In: Ransohoff, R.M., Benveniste, E.N. (Eds.), Cytokines and the CNS. CRC Press, Boca Raton, FL, pp. 151 – 168. Yong, V.W., 1996. Cytokines, astrogliosis, and neurotrophism following CNS trauma. In: Ransohoff, R.M., Benveniste, E.N. (Eds.), Cytokines and the CNS. CRC Press, Boca Raton, FL, pp. 309 – 327.
.