Trends in Neurosciences
OpinionInflammatory pathways of seizure disorders
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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