**1. Introduction**

Epilepsy is a brain disorder denoted by the predisposition to generate seizures accompanied by emotional and cognitive dysfunction [1]. Currently, there are estimated to be 50–70 million people worldwide suffering from epilepsy but only about 70% of them respond well to existing antiepileptic drugs [2, 3]. Furthermore, epileptic patients suffer deteriorating quality of life as they face limitations on their physical activities and daily life as well as being subjected to prejudice due to their seizures [4]. This calls for more research to seek for novel and effective therapies for the management and treatment of epilepsy, by first understanding the basis for the onset and progression of seizures.

The exact cause of epilepsy is still unknown, but there are mounting evidence showing that the development of epileptogenesis can be linked to a wide array of factors such as genetic predisposition, developmental disorders and neurological insults [5]. Neurological insults, which contribute towards up to 60% of epilepsy cases, include traumatic brain injuries (TBI), cerebrovascular accidents (CVA), central nervous system (CNS) infections and strokes, where inflammation is one of the key features of epileptogenesis [6]. However, the role of inflammation in epilepsy is still being actively studied, with various arguments on whether inflammation is the cause or consequence of epilepsy [7]. The blood-brain barrier (BBB), which functions as a protector of the central nervous system, has an important role in regulating the transfer of blood constituents in the brain extracellular space [8]. Increased BBB permeability or BBB leakage is said to be one of the earliest characteristics of the pathophysiology of epileptogenesis [9, 10]. BBB dysfunction may contribute to epileptogenesis via a cascade of events triggered by leakage of inflammatory mediators into the CNS which causes neuroinflammation [11, 12]. Here, we discuss briefly how neuroinflammation is involved in epileptogenesis as well as the status of inflammation in post-epileptic conditions; whether it is the cause or consequence of epilepsy, together with experimental evidences.

## **2. Inflammatory response in epilepsy**

Considering inflammation as one of the culprits of epileptogenesis, neuroinflammation occurs as a result of a cascade of inflammatory pathways. This involves inflammatory and anti-inflammatory molecules as a response to noxious stimuli or immune stimulation; targeted to defend against pathogenic threats. The activation of inflammatory mediators such as interleukins (ILs), interferons (IFNs), cyclooxygenase (COX)-2 and nuclear factor kappa B (NF-κB), and the surplus of downstream inflammatory mediators including IL-1β, IL-6, tumor necrosis factor (TNF)-α and prostaglandin E2 (PGE2) contribute to seizure progression [13, 14]. Inflammatory mediators are produced by the glia, neurons, endothelial cells of the BBB and peripheral immune cells. In the presence of noxious stimuli, cytokines are secreted by immunocompetent and endothelial cells as well as glial and neuronal cells in the CNS. In the presence of noxious stimuli, cytokines are released which enable effective communication between effector and target cells [7, 15].

Both innate and adaptive immunity is known to contribute in the generation of inflammation in the brain via the microglia, astrocytes and neurons [7]. In a non-epileptic condition, innate immunity activation occurs during infection and is instrumental for pathogen recognition as well as removal via homeostatic-type tissue inflammation [16]. In epileptic condition where pathogens are absent, innate immunity signaling is activated by damage-associated molecular patterns (DAMPs) which are secreted by injured or activated neurons, bringing about a phenomenon called 'sterile inflammation' [17]. The microglia and astrocytes recognize proteins such as high mobility group box 1 (HMGB1), S100 proteins, adenosine triphosphate (ATP), migration inhibitory factor-related protein 8 (MRP8), which makes are DAMPs, extracellular matrix degradation products and IL-1β to induce inflammation [17, 18]. On top of that, the inflammatory signaling disrupts the BBB integrity by inducing up-regulation of adhesion molecules as well as leukocyte recruitment. These processes reduces seizure threshold and contribute to epileptogenesis and seizure recurrence in epilepsy models [19, 20].

Clinically, it is observed that patients with autoimmune diseases such as systemic lupus erythematosus (SLE), Hashimoto's encephalopathy, Behcet's disease, and Sjogren's syndrome have an increased risk of developing epilepsy [5]. Another example of an autoimmune disease associated with a predisposition to seizures is Rasmussen encephalitis (RE), a rare inflammatory brain disease causing cerebral hemiatrophy, which progressively leads to severe seizures [21]. Patients of RE have higher levels of astrocytosis, proinflammatory mediators as well as lymphocytes and activated microglial cells in the brain [22, 23]. In these cases, usually, immunotherapies are more effective as compared to antiepileptic drugs in the management of epilepsy [24].

Moreover, a number of reports suggest that the onset and perpetuation of epilepsy can be driven by inflammation and is not caused by the autoimmune process.

**21**

*Inflammation: Cause or Consequence of Epilepsy? DOI: http://dx.doi.org/10.5772/intechopen.83428*

patients [27].

**3. Experimental models**

Upregulation of proinflammatory markers and inflammation-related microRNAs are found in patients of generalized seizures and temporal lobe epilepsy (TLE) [25, 26]. Butler, Li [27] reported a significantly greater inflammation intensity and spatial extent using positron emission tomography (PET) scan in post-seizure

Moving forward with the understanding on the clinical association of inflammation with epileptogenesis, researchers sought to decipher the role of inflammation and associated pathways in the genesis of a seizure in the brain. Experimental models of inflammation have been instrumental in understanding the role of inflammation in epilepsy. It is still an ongoing debate as there are two field of thoughts; (1) inflammation acts as the cause of seizures and (2) inflammation is the consequence of seizures [7]. Here, we discuss the different types of experimental models and the

Febrile seizures (FS) are common in children aged between 6 months and 5 years and occur in response to fever but without infection of the CNS. Fever is the elevation of the body temperature set point within the hypothalamus which results in an elevation of core temperature and is generated by inflammatory mediators such as cytokines and prostaglandins which then invokes a systemic inflammatory response [28, 29]. A widely used hyperthermia-induced seizure model for studying FS is one in which hyperthermia is induced using a regulated stream of mildly heated air to increase the body temperature of neonatal rats aged 10–13 days [30–32]. The brain development of rats between 10 and 15 postnatal days best corresponds to the development of brain in human infants when they are most susceptible to FS [30]. The 'ideal' increase of core temperature in the pups is around 2.9°C, which is reported to be parallel with the temperature increment observed in

In this model, seizures can be confirmed using electroencephalogram (EEG) [30]. The behaviors exhibited by the pups, such as biting tonic stiffening, and falling over, are similar to those observed after administration of convulsants. Generalized tonic seizures are rarely observed, however [30, 32]. In addition to biochemical analysis, behavioral tests such as the balance beam test and footprint test provide information on the severity and progression of seizures. Research has also shown that in this hyperthermic model, there is a remarkably high release of cytokines within the brain, specifically IL-1β within the hippocampus, and activation of astrocytes, which elevates the brain temperature. This finding is similar to

Systemic inflammation is believed to have several CNS manifestations, such as fever, locomotor activity reduction and behaviors that are associated with brain hyperactivity during peripheral inflammation [34]. In other words, the inflammatory response which can be observed during the manifestation of peripheral inflammatory diseases is similar to the inflammatory response generated in the

outcomes of the experimental work, summarized in **Table 1**.

**3.1 Inflammation increases seizure susceptibility**

*3.1.1 Hyperthermia-induced seizures*

children experiencing FS [33].

*3.1.2 Systemic inflammation*

those seen in children suffering from FS [31].

*Inflammation: Cause or Consequence of Epilepsy? DOI: http://dx.doi.org/10.5772/intechopen.83428*

Upregulation of proinflammatory markers and inflammation-related microRNAs are found in patients of generalized seizures and temporal lobe epilepsy (TLE) [25, 26]. Butler, Li [27] reported a significantly greater inflammation intensity and spatial extent using positron emission tomography (PET) scan in post-seizure patients [27].
