In this dissertation I searched togerher with my collaborators for evidence of an association between cytokine network activation and seizures both in patients with acute seizures and chronic epilepsy. We studied the circulating levels of cytokines in cerebrospinal fluid and plasma after tonic-clonic seizures with different time-windows in order to assess the significance of recent seizures in relation to cytokine production. In these patients with acute seizures we measured a set of indicators of inflammation in order to study the potential consequences of the activation of the cytokine network. In patients with refractory chronic epilepsy we evaluated the source of cytokines with comparing the plasma levels of cytokines with the production of cytokines by blood cells. We also studied cytokine gene polymorphism in patients with refractory chronic epilepsy in order to assess the potential genetic contribution. CSF and plasma samples were collected from 37 patients with recent seizures (<72 hours) previously undiagnosed and untreated and from 14 patients suffering a seizure more than 2 weeks previously. The control samples for this acute study were obtained from 40 adult patients on whom lumbar puncture was performed to exclude neurological disease and who yielded normal neurological examination and laboratory findings. The concentrations of IL-6 were significantly higher in the group with recent seizures both in CSF and plasma as compared with patients at more than 2 weeks from the seizure and controls. There was some indication of increased IL-1RA production both in CSF and plasma in the patients with recent seizures. There was no difference in concentrations of IL-1b, TNFa or NGF between patients and controls. All increased concentrations of IL-6 were observed from patients sampled within 24 hours of the seizure. These studies demonstrate an increased and temporary production of IL-6 after tonic-clonic seizures with some indication of activation of the IL-1 system. We were able to correlate the indicators of inflammation with plasma IL-6 levels after recent tonic-clonic seizures. The mean peripheral blood and CSF-leukocyte counts were significantly higher in patients compared with controls; there was some indication of increased concentration of C-reactive protein in patients with seizures but no difference in haptoglobin levels. A consequent point for patient care is that, CSF pleocytosis and increase in some indicators of inflammation should not automatically be attributed to systemic or CNS infections in patients with acute seizures. We studied the plasma levels of IL-1b, IL-1RA and IL-6 as well as the spontaneous and exogenously stimulated production of these cytokines from peripheral blood mononuclear cells (PBMC) from 10 patients with refractory localization-related epilepsy compared with healthy controls. Highly pro-inflammatory cytokine profile (high IL-6, low IL-1RA and low IL-1RA/IL-1â ratio) was observed in plasma from patients with epilepsy. Spontaneous and LPS stimulated cytokine release was similar in PBMC cultures of patients and control subjects, whereas there was evidence of decreased production of these cytokines when stimulated. These results suggest that the altered plasma levels are not derived from peripheral blood, and the most likely origin for these cytokines is the brain. Formally, cytokine production by sessile cells of lymphoid organs is not excluded. This explanation would imply that there would exist a systemic disease causing proneness to seizures, that would be revolut! ionary to current thinking. In the genetic study of 48 patients with refractory localization-related epilepsy compared with 400 healthy blood donors the frequencies of the IL-1a allele 1 and IL-1b allele 2 were significantly higher in patients compared with controls, whereas there were no differences in IL-1RA allele frequencies. The combination of IL-1b (-511) A 2+ /IL-1RA (VNTR)A2- was more prevalent in patients than in control subjects. The significance of cytokine production in relation to epileptic seizures is not yet fully known. However, there is an increasing amount of consistent experimental data suggesting a role for cytokines as modulators of seizure activity and brain plasticity. IL-1b is proconvulsant and neurotoxic in animal models, whereas IL-1RA antagonist acts as an anticonvulsant and neuroprotectant. The significance of TNFá and IL-6 is less well established, but IL-6 may be proconvulsant and local TNFá anticonvulsant. We have now presented clinical data on the association between the activation of the cytokine network both in acute seizures and chronic epilepsy as well evidence of genetic association. The available data suggests a role for cytokines in epileptic processes, and it is important to define this role better in the future in both experimental and human studies.
