Trends in Neurosciences
Volume 37, Issue 2, February 2014, Pages 55-65
Journal home page for Trends in Neurosciences

Opinion
Inflammatory pathways of seizure disorders

https://doi.org/10.1016/j.tins.2013.11.002Get rights and content

Highlights

  • Traditional and novel anti-epileptic treatments encompass immunomodulatory effects.

  • Acute and chronic immunological triggers contribute to acute and chronic seizures.

  • Etiological factors of seizure disorders include brain and peripheral proinflammatory changes and their interplay.

  • The blood–brain barrier (BBB) is a dynamic interface between the central nervous system (CNS) and the periphery.

  • The BBB reacts to pro-inflammatory stimuli from either the brain or periphery.

Epilepsy refers to a cluster of neurological diseases characterized by seizures. Although many forms of epilepsy have a well-defined immune etiology, in other forms of epilepsy an altered immune response is only suspected. In general, the hypothesis that inflammation contributes to seizures is supported by experimental results. Additionally, antiepileptic maneuvers may act as immunomodulators and anti-inflammatory therapies can treat seizures. Triggers of seizure include a bidirectional communication between the nervous system and organs of immunity. Thus, a crucial cellular interface protecting from immunological seizures is the blood–brain barrier (BBB). Here, we summarize recent advances in the understanding and treatment of epileptic seizures that derive from a non-neurocentric viewpoint and suggest key avenues for future research.

Section snippets

Seizures and epilepsy

A seizure is a paroxysmal event due to an excessive, hypersynchronous (see Glossary) discharge from central nervous system (CNS) neurons or neuronal networks. This abnormal electrical activity causes a range of clinical/behavioral manifestations, ranging from dramatic convulsions often associated with loss of consciousness to experiential phenomena not readily discernible by an observer [1]. The term seizure should be carefully distinguished from epilepsy. Epilepsy is a syndrome of two or more

Inflammatory mechanisms involved in BBB disruption

If BBBD is responsible for loss of CNS homeostasis and abnormal neuronal firing, how and when do BBB cells lose their physiological function? Owing to its intravascular location, the BBB is prone to incursions by circulating inflammatory signals 9, 27, 43, 44, 45, 46. These attacks could be facilitated by increased expression of adhesion molecules on endothelial cells seen in epileptic brain [47]. In addition to leukocyte–endothelial interactions, BBBD may also result from other factors. These

How does inflammation affect neuronal behavior?

One of the most remarkable features of the mammalian BBB is its ability to maintain ionic and osmotic gradients between brain and blood (recently reviewed in [37]). Consequences of BBBD all seem to conspire towards increased neuronal firing 36, 37. Although the following paragraphs focus on the role of potassium homeostasis, other mechanisms are also crucial to ictogenesis after BBBD 39, 41, 42. Conclusive evidence that BBBD can cause seizures was derived from the experimental or clinical

Clinical evidence linking inflammation to seizures

The first description of epilepsy due to inflammation dates back to 1958 when Theodore Rasmussen from the Montreal Neurological Institute described a few children operated on for intractable focal seizures and progressive hemiparesis, and in whom the pathology of the brain tissues demonstrated hemispheric inflammatory changes [68]. Neuropathology clarified that the brain inflammation in what is now termed Rasmussen encephalitis (RE) is dominated by T cells (granzyme B positive CD8+ cells), by

Pharmacological evidence linking inflammation to seizures

Epilepsy is a complex disease and the pharmacology of AEDs is comparably multifaceted. Because the ultimate goal of AEDs is to prevent or abort the abnormal electrical firing of neurons, their mechanism of action has traditionally been ascribed to blockade of excitatory neurons and ion currents or to augmentation of inhibitory interneurons and ionic conductances. Thus, two broad categories of AEDs can be described, drugs reducing sodium, calcium, or glutamate receptor-mediated ion currents or

Communication between peripheral and neuroinflammation: possible role in seizure disorders

Seizures do not only impact the cerebral cortex but can spread to nuclei involved in autonomic regulation and neuroendocrine function. Conversely, peripherally generated nervous or chemical signals can impact brain physiology [43]. The integration of these signals may influence seizure threshold. A broad range of stress stimuli (e.g., social, physical, consequent to mood disorders) activate the hypothalamic–pituitary–adrenal (HPA) and the sympathetic–adrenal–medullary (SAM) axes. Both pathways

Concluding remarks, important caveats, and future directions

Despite the increasing evidence supporting inflammatory processes triggering or sustaining seizures (Table 3), a number of questions remain unresolved. For example, whether brain inflammation is the initiator or the consequence of systemic inflammatory processes is not a purely academic question. From the therapeutic point of view, if systemic inflammation is to be targeted, then issues of trans-BBB drug delivery are mute therapeutic implications [84]. Conversely, selective direct targeting of

Acknowledgments

Supported by R01NS078307 (N.M. and D.J.), R01NS43284, R41MH093302, R21NS077236, R42MH093302, UH2TR000491, and R21HD057256 (D.J.).

Glossary

Cryptogenic, idiopathic, and symptomatic epilepsy
a cryptogenic or idiopathic disease is a disease with unknown etiology. In the case of epilepsy, these terms refer to patients where no genetic or metabolic disorder is identified and imaging (MRI) of the cortex and hippocampus does not reveal detectable abnormalities. The term symptomatic epilepsy is, by contrast, used to define an epileptic disorder due to a structural or metabolic condition, genetic or acquired, that has been demonstrated to

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