Traditionally, chemically-induced seizures have received little detailed emphasis in general neurology literature. The few articles that describe correlations between seizures and chemical exposure(s) usually focus on clinical effects rather than underlying pathophysiological mechanisms. Conclusions of studies from various biological disciplines are discussed in order to convey a global understanding of chemically-induced seizure mechanisms. Theoretical mechanisms underlying the progression from a seizure occurring only with external induction to a seizure occurring spontaneously (epilepsy) are also discussed. A generally accepted model of epileptogensis is that of kindling, in which the clinical manifestations of seizures increase as seizures are repeatedly induced. Recent studies are beginning to reveal just how this kindling phenomenon might occur through permanent genetic and microneuroanatomic alterations induced by aberrant excessive electrical impulse activity, via direct physiologic injury, or through unintended adverse consequences of repair mechanisms. Largescale genomic studies are beginning to reveal that many genes likely contribute to seizure induction and the loss of synaptic plasticity observed in epilepsy. Examples of mechanisms underlying specific chemically-induced seizures are discussed including those caused by cyanide, carbon monoxide, and chemical nerve agents. Further research and understanding of fundamental seizure mechanisms will likely lead to the discovery of novel and more effective methods by which to treat and ultimately prevent seizure or epilepsy development. To this end, a review of the basic principles of relevant microscopic neuroanatomy, neuroelectrophysiology, neurotoxicology, and molecular genetics, is presented along with specific examples of chemicals known to elicit seizures.

Until more recently, the effects of exposure to chemical warfare agents were a remote area of clinical practice, which concerned military specialists, microbiologists, and toxicologists. Since the World Trade Center attack in New York City in September 2001, there has been real concern about the possible impact of nerve agents (NA) released by terrorists on civilian population. In the pre- and intra-hospital settings, anesthesiologists have since become more involved in the preparedness of such potential mass casualty events together with administrative officials. The former create protocols to improve casualty rescue, management, and outcome, while the latter building up medical contingents, drilling interventional and logistic protocols and provide early and late medical and psychological life support to the care providers and the population.

Exposure to warfare NA intoxicants can cause brain damage, long-term cognitive and behavioral deficits, and even death. In the acute phase of the intoxication, brain damage is primarily caused by intense seizure activity induced by these agents. Also, hypoxia and asphyxia are associated with seizures; however, these may be pre-terminal conditions.

This review will elaborate in detail pre-hospital and intra-hospital management of NA in terms of seizures. Other aspects of medical and administrative attendance associated with these chaotic situations are reviewed elsewhere and will be refereed accordingly. Pathophysiology and clinical management of current trends of life support will be addressed.

Acute organophosphate (OP) intoxication is associated with many symptoms and clinical signs, including potentially life-threatening seizures and status epilepticus. Instead of being linked to the direct cholinergic toxidrome, OP-related seizures are more probably linked to the interaction of OPs with acetylcholineindependent neuromodulation pathways, such as GABA and NMDA. The importance of preventing, or recognizing and treating OP-related seizures lies in that, the central nervous system (CNS) damage from OP poisoning is thought to be due to the excitotoxicity of the seizure activity itself rather than a direct toxic effect. Muscular weakness and paralysis occurring 1-4 days after the resolution of an acute cholinergic toxidrome, the intermediate syndrome is usually not diagnosed until significant respiratory insufficiency has occurred; it is nevertheless a major cause of OP-induced morbidity and mortality and requires aggressive supportive treatment. The condition usually resolves spontaneously in 1-2 weeks.

Treatment of OP intoxication relies on prompt diagnosis, and specific and immediate treatment of the lifethreatening symptoms. Since patients suffering from OP poisoning can secondarily expose care providers via contaminated skin, clothing, hair, or body fluids. EMS and hospital caregivers should be prepared to protect themselves with appropriate protective equipment, isolate such patients, and decontaminate them. After prompt decontamination, the initial priority of patient management is an immediate ABCDE (A : airway, B : breathing, C : circulation, D : dysfunction or disability of the central nervous system, and E : exposure) resuscitation approach, including aggressive respiratory support, since respiratory failure is the usual ultimate cause of death. The subsequent priority is initiating atropine therapy to oppose the muscarinic symptoms and diazepam to prevent or control seizures, with oximes added to enhance acetylcholinesterase (AChE) activity recovery. Large doses of atropine and oximes may be necessary for poisoning due to suicidal ingestions of OP pesticides.

The current medical countermeasures for organophosphate (OP) poisoning are effective to a reasonable extent, yet, there is room for improvement. In this review, suspected causes of acute and long term-effects of OPexposure and possible interventions will be discussed, in relation to the type of nerve agent and different exposure routes. Inhibition of AChE by organophosphates leads to excessive buildup of released acetylcholine (ACh) at cholinergic synapses resulting in a failure of neuromuscular transmission and leads to seizures followed by status epilepticus. Eventually, poisoning with OPs is likely to result in death or long-term neuronal deficits.

Although, the OP nerve agents soman and VX act via a similar mechanism, that is inhibition of AChE, the toxicological impact following exposure shows to be quite different. Whereas, toxic signs upon sc exposure to soman in general develop very rapidly with the presence of seizures, pc exposure to VX animals shows delayed development of clinical signs compared to sc soman exposure. Such differences in agent behavior put special demands on treatment.

Another important conclusion of the present study is that an effective life-saving treatment at short term, may not be sufficient to prevent long term cognition deficits. This implies that a more thorough understanding of the cause of such deficits is needed to design improved treatment strategies. Suppression of the inflammatory processes in seizure initiation and continuation and restoring impaired neurogenesis, the latter proposed as a cause of cognition deficits following soman exposure, could be starting points for improved treatment.

Soman, a potent acetylcholinesterase inhibitor, induces accumulation of acetylcholine at the neural synapses resulting in overstimulation of the cholinergic system. At lethal concentrations, Soman-induced seizures progress rapidly into status epilepticus, which if not terminated, will lead to eventual death or profound brain damage amongst survivors. The current diazepam anticonvulsant could stop seizures when administrated early but its efficacy diminishes rapidly when applied late post seizures. Increasing diazepam dosage to compensate for reduction in anticonvulsant potency enhances nerve agent-induced respiratory depression. Research is on-going to identify alternate neuroprotection options for managing established and refractory status epilepticus without increasing respiratory difficulties amongst nerve agent casualties. In this chapter, a review of the various neuroprotection options that have been investigated as alternatives to diazepam in the last decade is presented. In addition, we have also provided a comprehensive report on neuroprotective actions achieved with a combined administration of clonidine and atropine sulfate in Soman poisoned animals with status epilepticus. Clonidine, an α2-adrenergic agonist, acts on post-synaptic heteroreceptors to exert pre-synaptic inhibition on release of acetylcholine while atropine sulphate, as a muscarinic antagonist, blocks cholinergic activation of post-synaptic muscarinic receptors. By targeting the central cholinergic system with this synergistic drug combination, besides enhancing animal survival, rapid seizure arrest was achieved with early administration while functional neuroprotection was observed in animals undergoing established status epilepticus. Interestingly, neuroprotection was achieved despite the continued presence of seizures, when it was applied during established status epilepticus and its effect was much higher than that afforded by diazepam. Inclusion of clonidine was vital for preventing atropine induced lethal ventricular arrhythmias in hypoxic animals when treatment was given late. This finding may be useful for reviewing the current perceived roles of central cholinergic and glutamatergic systems in maintaining established status epilepticus, which has directed much of current research for new neuroprotection options towards the glutamate system.

Absence epilepsy is a group of syndromes with generalized non-convulsive seizures that are characterized by synchronous spike-and-wave discharges (SWDs) on the electroencephalogram (EEG). Animal models of absence epilepsy generally mimic this non-convulsive type of the absence seizure with SWDs on the EEG. In the literature, there are several experimental in vitro and in vivo models of the absence epilepsy displaying the spike-and-wave activity induced by different approaches (electrical, chemical, genetic manipulations). All these models have provided valuable insights into the underlying mechanisms and treatment of the disease. The aim of this chapter is to review commonly used in vivo animal models of absence seizures that are induced by the administration of chemicals. In these chemical models, SWD activity is induced in an otherwise normal brain.

By the systemic (i.p., s.c., or i.v.) or local intracerebral injection of kainic acid (KA) into different regions of the brain of experimental animals, status epilepticus and brain damage are induced. After a latent period, progressive neuronal loss, axon sprouting and rewiring, and spontaneously recurrent seizures occurred, which are similar to the pathogenesis of the human temporal lobe epilepsy. Hence, KA models have been considered to be suitable for clarifying the mechanism of onsets of spontaneously recurrent seizures in human and for evaluating or screening anti-epileptic drugs. In this paper, we will review different seizure models induced by KA and its relevant neuropathological changes, discuss possible mechanisms for seizure generation and summarize current therapeutic approaches to control seizures and neuropathological changes. Hopefully, it will shed light on better understanding the mechanism of epiletogenesis in patients with temporal lobe epilepsy, and provide some clues for the development of novel therapeutic approaches to effectively control human intractable epilepsy.

Cholinergic nerve agents remain a realistic terrorist threat due to its combination of high lethality, demonstrated use and relative abundance of un-destroyed stockpiles around the world. While current fielded antidotes are able to mitigate acute poisoning, effective neuroprotection in the field remains a challenge amongst subjects with established status epilepticus (SE) following nerve agent intoxication. Due to ethical, safety and chemical security related issues, extensive preclinical and clinical research on cholinergic nerve agents is not possible. This may have been a contributory factor for the slow progress in uncovering uncovering new neuroprotectants for nerve agent casualties with established status epilepticus. To overcome this challenge, comparative research with surrogate chemicals that produce similar hypercholinergic toxicity but with less security concerns would be a useful approach forward. In this paper, we will systemically compare the mechanism of seizure generation, neuropathological, Genomic and neurobehavioral changes reported with pilocarpine, soman, and sarin challenged animal models. This review will be an important first step in closing this knowledge gap between two closely related models of neurotoxicity. Hopefully, it will spur further efforts in using surrogate cholinergic models by the wider scientific community to expedite the development of a new generation of antidotes that are better able to protect against delayed neurological effects inflicted by nerve agents.