Introduction

The pivotal role of immunity and inflammatory processes in epilepsy is increasingly recognized. To discuss the developments in this field, we convened a brain-storm meeting on Immunity and Inflammation in Epilepsy between basic science investigators and clinicians on September 16–18, 2010 at the Mario Negri Institute for Pharmacological Research, Milano, Italy (Fig. 1). The meeting was generously supported by the Commission on European Affairs of the International League Against Epilepsy (CEA-ILAE), the American Epilepsy Society (AES), and Agencia Italiana del Farmaco (AIFA). We are especially grateful to UCB Pharma, Basel, Switzerland; Sanofi-Aventis, Milano, Italy; and Questcor Union City, CA, U.S.A. for their support, which was instrumental for the realization of this meeting. Participants in the first meeting on Immunity and Inflammation in Epilepsy. The following articles summarize the major meeting outcomes by highlighting the state-of-art knowledge in this field, the emerging consensus on the type of epileptic disorders and syndromes in which immunity and inflammation may play an etiopathogenic role, the remaining challenges for future experimental and clinical research, and the therapeutic interventions envisaged for targeting immune/inflammatory mechanisms in epilepsy. Inflammation is defined as a homeostatic phenomenon induced by various types of tissue injuries, and consists of the rapid production of molecules with proinflammatory or antiinflammatory properties by cells of the immune system, including both innate and adaptive immunity cell types. Typically, this process is triggered to defend tissues against pathogen invasion during infections, but it can be also activated by endogenous “danger signals” released by threatened cells (Bianchi, 2007). In the brain, inflammation occurs as a result of activation of both resident parenchymal cells, such as microglia, astrocytes, and neurons constituting major players of innate immunity mechanisms, as well as via production of inflammatory mediators by leukocytes, which may penetrate the brain through the blood–brain barrier (these cell types include both components of peripheral innate immunity such as macrophages and granulocytes, and T and B cells as part of adaptive immunity). Several endogenous mechanisms have been identified to resolve inflammation after its first occurrence to prevent this phenomenon from becoming detrimental for tissue. When these regulatory mechanisms fail, inflammation may become chronic or last long enough to provoke tissue damage or dysfunction; therefore, a strict control of both the extent of inflammation and its permanence in tissue are considered important determinants of beneficial rather than pathologic outcomes. Long-lasting brain inflammation has been described after ischemic stroke, traumatic brain injury, or during chronic neurodegenerative diseases, and in all these conditions inflammation appears to contribute to the evolution of the pathology (Nguyen et al., 2002; Allan et al., 2005; Glass et al., 2010). In the last decade increasing research was directed to elucidate the possible role of immune and inflammatory processes in the etiopathogenesis of seizures in various types of epilepsy (Aarli, 2000; Palace & Lang, 2000; Choi et al., 2009; Vezzani et al., 2011). The first insights into the potential role of immunity and inflammation in human epilepsy raised from the evidence of anticonvulsant activity of adrenocorticotropic hormone (ACTH) and steroids in some infancy and childhood epilepsies (Low, 1958; Wirrell et al., 2005; Wheless et al., 2007). More recently, steroids have been administered in selected cases of refractory status epilepticus with variable efficacy (Bonati et al., 2006; Robakis & Hirsch, 2006; Shorvon et al., 2008; Kramer et al., 2009). Additional evidence came from febrile seizures and seizure aggravation upon infection (Dubé et al., 2007), since both phenomena coincides with or are caused by increased proinflammatory molecules (Dinarello, 2004). Chronic and progressive brain inflammation was first identified in Rasmussen’s encephalitis, an epileptic syndrome associated with unilateral progressive destruction of the brain precentral region accompanied by epilepsia partialis continua and cognitive decline (Rasmussen et al., 1958). Although there is little doubt about the inflammatory nature of this disorder (Bien et al., 2002; Pardo et al., 2004), the exact immune and inflammatory mechanism(s) possibly involved in disease onset and its progression still remain largely unknown. Immune system activation has been demonstrated in some patients with seizure disorders by the discovery of circulating autoantibodies that recognize membrane or intracellular neuronal antigenic epitopes, such as in limbic encephalitis or encephalomyelitis, as well as from the higher incidence of seizures in several autoimmune diseases. These findings opened a new field of investigation in epilepsy because these antibodies might be causally involved in the occurrence of severe seizures in these disorders (Bien et al., 2007; Dalmau et al., 2007; Irani & Lang, 2008; Vincent et al., 2010). Accordingly, immunosuppressive and immunomodulatory treatments can successfully suppress seizures, likely by removing the pathogenic antibodies and/or reducing inflammatory processes associated with the underlying autoimmune disorder (Irani & Lang, 2008; Vincent et al., 2010; Wong et al., 2010). However, the pathogenetic role of these autoantibodies is not clearly elucidated yet and is, therefore, under extensive investigation. More recently, histologic evidence in surgically resected specimens from patients with drug-resistant temporal lobe epilepsy or epilepsy associated with malformations of cortical development showed a number of inflammatory mediators in epileptogenic tissue. These molecules are produced mainly by activated microglia and astrocytes, as well as by neurons. Evidence of peripheral immune cells invading brain tissue was reported in some of these specimens (for review see Choi et al., 2009; Vezzani et al., 2010). The novel finding that brain inflammation occurs also in epilepsies not apparently linked to immunologic dysfunctions raised the possibility that inflammatory processes are intrinsic pathologic features of epilepsy independently on the etiology. Consequent to these findings, imaging techniques [i.e. magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET)] are now under development to image brain inflammation in epilepsy, and biologic fluid markers of brain inflammation are being investigated, which would help to identify the patient population that could best benefit from antiinflammatory therapeutic approaches. Experimental evidence from animal models of seizures shed light on the reciprocal link between epileptic activity and brain inflammation, highlighting the possibility that inflammation can be both a consequence as well as a cause of seizures, and may contribute to the development of epilepsy after an initial precipitating event (Vezzani et al., 2010). In particular, experimental studies showed that recurrent seizures are powerful inducers of brain inflammation in microglia, astrocytes, neurons, and endothelial cells of the blood–brain barrier (BBB), also in the absence of progressive brain pathology. Reciprocally, systemic or central nervous system (CNS) inflammation induced in neonatal or adult rodents, as well as brain injuries (e.g. trauma, ischemia/hypoxia, prolonged febrile seizures), decrease seizure threshold in animals and worsen neuropathology (Vezzani et al., 2008; Heida et al., 2009). Long-term changes in neuronal excitability are also induced in rodents by inflammatory challenges in early life (Riazi et al., 2010). The causal link between activation of specific proinflammatory pathways in brain and seizure precipitation and their recurrence has been demonstrated in various models of acute and chronic seizures. For example, pharmacologic blockade or genetic inactivation of proinflammatory cytokines such as interleukin (IL)-1β or tumor necrosis factor (TNF)-α (Vezzani et al., 2008; Heida et al., 2009) or Toll-like receptor signaling pathways (Maroso et al., 2010), and in some instances of cyclooxygenase (COX)-2 (Kulkarni & Dhir, 2009), mediate powerful anticonvulsant effects. Conversely, mimicking of brain inflammation by brain application of proinflammatory molecules or complement system activation exacerbates or provokes seizure activity (Jankowsky & Patterson, 2001; Vezzani et al., 2008). Very recently, neuroprotective effects mediated by activation of one class of prostaglandin receptor subtypes have been shown in one model of epilepsy (Jiang et al., 2010), thereby highlighting the complex role of inflammatory mediators in the epileptic pathology, and the need to specifically reduce some inflammatory pathways while sparing others. A simplified schema is displayed in Fig. 2 to summarize the interplay between inflammation, seizures, and epilepsy. Simplified schema summarizing the interplay between inflammation, seizures and epilepsy. On the basis of these premises, the aim of the meeting on Immunity and Inflammation in Epilepsy was to bring together for the first time international clinical and basic science investigators with longstanding background and experience in this field of research to report and discuss the related current state of knowledge. The main questions that were initially put forth and that were addressed during the presentations are summarized below: Is brain inflammation a cause or a consequence of seizures, or both? Which are the cell types contributing to brain inflammation, and under which circumstances (e.g., parenchymal brain cells such as neurons, microglia, and astrocytes versus leukocytes)? Does inflammation contribute to the generation and recurrence of seizures? Does inflammation contribute to the development of epilepsy after an initial precipitating event? Under which circumstances may inflammation become detrimental for brain tissue? Are inflammatory mechanisms involved at all stages of the epileptic process? Which are the mechanisms underlying the actions of inflammatory mediators in epilepsy? Do all patients have a similar degree of brain inflammation? Do sources of inflammatory mediators differ among epilepsy types? Are there biomarkers (i.e., circulating molecules or antibodies, imaging techniques) that could be used to detect brain inflammation for diagnostic, prognostic, and therapeutic purposes? Can we envisage new antiinflammatory therapy for drug-resistant epilepsies, and could all etiologies associated with inflammation be targeted therapeutically? The following articles report the summary of the key issues emerging in the various scientific sessions of this meeting. Chapters will also report suggestions for future directions of clinical and experimental research, in order to prime and foster interactions between clinicians and basic scientists for translational purposes. Dr. Rüegg received unconditional research grants from UCB; honoraria from serving on the scientific advisory boards of Eisai, GSK, and UCB; and honoraria from serving as a consultant for Eisai, GlaxoSmithKline, Janssen-Cilag, Pfizer, Novartis, and UCB. Dr. Vezzani owns intellectual property on a patent on the use of ICE inhibitors in epilepsy issued from Vertex Pharmaceuticals, Cambridge U.S.A., that does not involve any financial interest or profit.