According to the WHO Dictionary of Epilepsy status epilepticus (SE) occurs “when a seizure persists for a sufficient length of time or is repeated frequently enough to produce a fixed or enduring epileptic condition”⁶

Self limited seizure type:

Generalized seizures:-Tonic-clonic seizures(includes variations beginning with a clonic or myoclonic phase),Without tonic feature, Typical absence seizures, Atypical absence seizures, Myoclonic absence seizures, Tonic seizures, Spasms, Myoclonic seizures, Eyelid myoclonia, Without absences, With absences, Myoclonic atonic seizures, Negative myoclonus.^4-5

Focal seizures:-Focal sensory seizures: with elementary sensory symptoms(e.g. occipital and parietal lobe seizures) with experiential sensory symptoms(e.g., temporo parieto occipital junction seizures),Focal motor seizures: with elementary clonic motor signs, with asymmetrical tonic motor seizures(e.g.,supplementary motor seizures),with typical(temporal lobe) automatisms(e.g.,mesial temporal lobe seizures) with hyperkinetic automatisms, with focal negative myoclonus, with inhibitory motor seizures,Gelastic seizures,Hemiclonic seizures.^4-5

Continuous seizure types:

Generalized status epilepticus:- Generalized tonic-clonic status epilepticus, Clonic status epilepticus, Absence status epilepticus, Tonic status epilepticus, Myoclonic status epilepticus.^7-12

Focal status epilepticus:- Epilepsia partialis continua of Kojevnikov, Aura continua, Limbic status epilepticus (psychomotor status), Hemi convulsive status.^7-12

Ionic pumps in epilepsy:

Gradients between intracellular and extracellular ion concentrations are the basis for electrical signaling in the nervous system by means of transmembrane ion currents.^13-14 The Pumps are present in the plasma membrane of the cell to maintain the chemical and electrical gradients, such as the sodium-potassium ATPase, raising the possibility that an abnormality in these pumps could facilitate seizures. Indeed, blockade of the sodium-potassium ATPase can lead to seizure activity in experimental preparations,¹⁵ suggesting a role in epilepsy.¹⁶ The sodium-potassium pump is very interesting because it does not develop in the rodent until several days after birth, and this may contribute to the greater risk of seizures in early life.^17-18 In development, transporter expression changes, and this has led to evidence that one of the transporters, NKCC1, may explain seizure susceptibility early in life.¹⁹

Glial cells in epilepsy:

Besides neurons, glial cells constitute of brain cells and are of four types: (i) ependymocytes, (ii) microgliocytes, (iii) oligodendrocytes and (iv) astrocytes. Astrocytes are the more abundant glial cells, and they have numerous functions including their contribution to neurogenesis^20-22 and synaptogenesis.^23-27 Astrocytes are also involved in the control of synaptogenesis.^28-29,30-33 Astrocytes participate in neurotransmission by regulating concentrations of ions and neurotransmitters in the synaptic cleft, thereby controlling synaptic efficacy.^{29, 21,34-36}Astrocytes contribute to the control of neurotransmission using additional mechanisms: (i) they synthesize a glia-derived soluble acetylcholine-binding protein (AChBP), which is a naturally occurring analog of ligand-binding domains of the nicotinic acetylcholine receptors (nAChRs).²⁰ (ii) astrocytes produce a protein, the tumor necrosis factor alpha (TNFα), which enhances synaptic efficacy by increasing surface of AMPA receptors.²¹ In addition, the active roles of extrasynaptic neurotransmitter receptors and their relevance to neurovascular coupling, and of exocytosis of neurotransmitters from astrocytes, have recently been reviewed^36,37-39 and the implication of these roles in epilepsy have been evoked.^40-42

Synaptic transmission:

Gamma amino butyric acid (GABA):

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the CNS. GABAergic inhibition can be presynaptic (release of GABA from the GABAergic nerve terminal into presynaptic nerve terminals causing a reduction of neuro-transmitter release) or postsynaptic (caused by the interaction of GABA with specific postsynaptic receptors). GABA released from GABAergic nerve terminals binds to two distinct types of GABA receptors GABA_A and GABA_B receptors to produce neuronal inhibition.⁴³ GABA is catabolized postsynaptically by GABA-transaminase. Dysfunction of the GABA-system can be caused by defects of synaptic GABA release, or of the postsynaptic GABA receptor. Low GABA and high glutamate values have been demonstrated in the cerebrospinal fluid of epileptic dogs.⁴⁴

Sex hormones influence the regulation of GABAergic transmission in the CNS. Animal models have shown that the infusion of estrogens , lower the threshold for experimentally provoked seizures, and that this effect of estrogen is intensified if a cortical lesion is already present. Progesterone has been shown to possess an inhibitory effect on spontaneous and experimentally provoked seizures.^45-46

Nitric acid:

It has been demonstrated that NO is released upon of receptors for N-methyl-D-aspartic acid (NMDA), an excitatory amino acid considered to play an important role in excitability, and exerts proconvulsant effects.^47-49 It has been postulated that NO can directly activate GABA_A receptors through the interaction with their _2 subunits.⁵⁰ NO has been found to increase release of GABA from the cerebral cortex,⁵¹ hippocampus⁵² and striatum.⁵³ Additionally, it has been observed that NOS inhibitors decreased release of GABA from cortical and striatal synaptosomes.⁵¹

Neuropeptide Y (NPY):

David Woldbye⁵⁴ shown the icv administration of NPY inhibits limbic seizures activity induced by kainic acid or electrical hippocampal stimulation.

Adenosine:

Adenosine and its analogues are active against different types of seizures. For instance, adenosine protects seizure-prone mice from audiogenic convulsions,⁵⁵ R-PIA (an receptor agonist protects rats from leptazol seizures,⁵⁶ other agonists are effective in antagonizing picrotoxin convulsions,⁵⁷ NECA and R-PIA reduce the severity of amygdaloid-kindled seizures in rats.⁵⁸ It turns out that both A and A receptors are involved in the protection 1 2A from seizures, as selective A and A receptor agonists 1 2A dose-dependently reduce pentylenetetrazole-induced convulsions⁵⁹ and audiogenic seizures in DBA/2 mice.⁶⁰

Calcineurin:

Calcineurin (CaN), also known as protein phosphatase 2B, is a calcium/ calmodulin - dependent phosphatase highly enriched in neural tissue.³⁶ CaN enzymatic activity has been related to epileptic seizures in several animal models. The increased intracellular calcium associated with status epilepticus could be responsible for activating CaN above its normal physiological level, because status epilepticus induces a loss of function of the endoplasmic reticulum Mg2+/Ca2+ ATPase.⁶¹ Furthermore, CaN may play a role in regulating the long-term changes that lead to epileptogenesis. CaN inhibitors may acutely potentiate GABAergic transmission – thus transiently increasing the picrotoxin seizure threshold11 – but when excessive excitatory activity induces massive Ca2+ entry through NMDA or Ca2+- permeable AMPA receptors, CaN may be also involved in the activation of long-term molecular cellular mechanisms that lead to the sustained recurrent excitatory activity, which induces late spontaneous seizures.The increase in CaN activity observed after the in vivo microperfusion of latrunculin A in the rat hippocampus may be related to cytoskeletal re-organisation induced by F-actin depolymerisation followed by an increase in NMDA-receptor activation, with implications for epileptogenesis.⁶²

Connexins:

Sohl et al.⁶³ studied expression and localization of Cx30, Cx32, Cx36, and Cx43 in two rat models of temporal lobe epilepsy (kindling and kainate treatment).While they found a large increase in glial fibrillary acidic protein (GFAP) mRNA and protein associated gliosis in rats 4 weeks after kainate treatment, no change in Cx30 or Cx43 mRNA or protein was found.⁶³ They did find a 44% decrease in Cx36 mRNA with a smaller reduction in Cx36 protein, effects possibly attributable to neuronal cell death. Following kainite induced seizures in rats, Condorelli et al. found a region specific regulation (increase, decrease, or no change) in Cx30 mRNA and protein levels⁶⁴ and unclear regulation of other connexins.⁶⁵

Non-synaptic transmission:

The distinction between synaptic and non-synaptic transmission is a general property of amino acid and other neurotransmitter systems in the mammalian brain. In recent years it has been increasingly evident that glutamate, GABA and glycine receptors, in addition to their subsynaptic localisation, are also expressed extra synaptically.⁶⁶ The NMDA receptor subunit NR2B predominates at non-synaptic sites in hippocampal neurons. In cerebellar Golgi cells, the NMDA receptor subunit NR2D seems to be restricted to non-synaptic sites. Interestingly, incorporation of this subunit into various subunit composition NMDA receptors may cause loss of targeting to the post-synaptic membrane, suggesting that the actual balance between synaptic/nonsynaptic NMDA receptor functions can be regulated by specific subunit expression.⁶⁷Extrasynaptic GABA_A and GABA_Breceptors have been also unequivocally recognised. The single-channel properties of extrasynaptic GABA_Areceptors have been shown to be different from those within the synapse, and the δ-subunit-containing GABA_A receptors that mediate tonic inhibition are found only in extrasynaptic membranes.⁶⁸

Intra cellular signaling pathway:

Recent evidence shows that activation of extracellular regulated kinase (ERK) and p38α mitogen-activated protein kinase (p38) pathways play a critical role in some forms of human epilepsy. The ERK kinases are abundantly expressed in the central nervous system, and are activated in response to various physiological stimuli associated with synaptic activity and plasticity, most notably calcium influx and neurotrophins, but also during pathological events such as brain ischaemia and epilepsy^.69-71 ERK and p38 are involved in hippocampal seizure tolerance,⁷²and ERK activation appears to be sufficient to trigger epilepsy in some animal models.^71-72 Pre-treatment with the ERK inhibitor PD98059 and the p38 inhibitor SB203580 selectively reduces seizure elicited activation of ERK and p38, respectively, and significantly reduces priming seizure-induced protection of CA3 neurons.⁶⁹ For instance, deregulated mobility caused by alterations in receptor subunit composition, protein kinases/phosphatases or cytoskeletal proteins is likely to be involved in hyperexcitability leading to epileptic seizures.⁷³

Network control of excitability:

In 1964, Matsumoto and Ajmone-Marsan⁷⁴ found that the electrographic events recorded at the cortical surface during seizures corresponded to paroxysmal depolarization shifts (PDS) of cortical pyramidal cells occurring synchronously. These studies led to efforts to understand how neurons begin to fire in concert when normally they do not. Glutamatergic interconnections are one example of a mechanism that can lead to synchronization. Indeed, studies of the PDS suggested that the underlying mechanism was a “giant” excitatory postsynaptic potential, ⁷⁵ although it was debated widely at that time if this was the only cause.

DISCUSSION:

Thus, the mechanisms that allow the CNS to develop into a complex structure and the mechanisms that provide plasticity, which are so important to its ability to function in a changing environment, do not come without risk—the risk of epileptogenesis. Even though many of these issues are still unsolved, gone years have witnessed substantial progress, largely resulting from the interplay between clinical and basic research in epilepsy.

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Received on 19.12.2012

Modified on 25.12.2012

Accepted on 08.01.2013

Research J. Pharmacology and Pharmacodynamics. 5(1): January –February 2013, 01-05