Abstracts

Rationale: Over the last few decades, literature is expanding to support the role of inflammation in ongoing seizures and their long-term consequences of epilepsy. However the role of inflammation is not clear in epileptogenesis and it is difficult to know whether the inflammatory changes precede epileptogenesis or are secondary to the seizures.Aim: To investigate the role of intrathecal inflammation using cerebrospinal fluid (CSF) cytokines and chemokines in paediatric epilepsy subgroup patients with frequent daily seizures. Methods: We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with frequent daily seizures caused by Febrile infection-related epilepsy syndrome (FIRES)/ FIRES related disorders (FRD)(n=6), febrile status epilepticus (FSE)(n=8), afebrile status epilepticus (ASE) (n=8), new onset explosive focal seizures (NOEFS, n=10), infantile spasms (n=19), chronic epilepsy [genetic epileptic encephalopathy (GEE, n=11) and genetic generalised epilepsy (GGE, n=10)] and compared with encephalitis (n=43) and non-inflammatory neurological controls (n=20). We also performed serial CSF cytokine/chemokine studies in 3 cases with FIRES/FRD. Results: Children in FIRES/FRD, FSE, ASE, GEE and spasms (Med range 0.5yr-3.1yr), were younger compared to the NOEFS (Med 6yr) and GGE (Med 4yr) at the onset of seizures (p=(p=<0.001). Median CSF timing from onset of seizures was longer in NOEFS (10 days), spasms (28 days), GGE (0.7yrs) and GEE (5.25yrs) whereas FIRES, FSE and ASE had within 1-2 days of onset of seizures (p=<0.001). The elevation of cytokine/chemokines was higher in FIRES followed by FSE and NOEFS when compared to non-inflammatory neurological controls and other epilepsy subgroups. Th1 associated cytokines (TNF alpha, CXCL9, CXCL10, CXCL11), Th17 (IL-6, IL-8) and CCL2, CCL19 and CXCL1 (p<0.05) were elevated in FIRES in contrast to the elevation of a broader network of cytokines/chemokines in encephalitis. The median concentrations of these cytokine/chemokines rapidly declined during the course of illness in all three FIRES/FRD cases.The cytokine/chemokines (CXCL9, CXCL10, CXCL11, and CCL19) were elevated in FSE when compared to ASE despite the similar median seizure duration and timing of CSF from seizures. Infantile spasm, GGE and GEE generally lacked significant elevation of cytokines/chemokines despite frequent daily seizures.Figure 1:The elevated CSF cytokine/ chemokines in the CSF of patients with epilepsy subgroups compared to non-inflammatory neurological controls (n=20)Figure 2: Longitudinal CSF cytokines/chemokines in children with FIRES/FRD and acute encephalopathy with biphasic seizures and reduced diffusion (AESD)  Conclusions: The prominent elevation of CSF cytokines and chemokines in FIRES/FRD and to a lesser extent, FSE group compared to other epilepsy subgroups with frequent daily seizures highlights the importance of etiology in causing measurable CNS inflammation, rather than inflammation being secondary to the seizures themselves. The acute phase of FIRES/FRD may provide a therapeutic window for early anti-inflammatory therapy targeting cytokines thereby limiting epileptogenesis. Funding: This work was supported by scholarship from Petre Foundation, Australian Postgraduate award, and Multiple Sclerosis Research Australia.