Neuropathologic Effects of Chemical Warfare Agents

Nerve agents exert their effects through binding and irreversible inactivation of acetylcholinesterase, the enzyme that hydrolyzes acetylcholine (ACh), leading to a toxic accumulation of ACh at nicotinic (skeletal muscle and preganglionic autonomic) receptors, muscarinic (mainly postganglionic parasympathetic receptors), and central nervous system synapses. Exposure to symptomatic doses of these agents leads to characteristic neuropathologic effects that have been examined in a variety of animal models. In addition, it is becoming increasingly recognized that even lower levels of exposure to these agents, even in the absence of seizures or other manifestations of acute toxicity, may be associated with more subtle forms of toxicity. Historically, this has been of concern in organophosphate and carbamate insecticide exposure among farm workers; however, it is likely that use of nerve agents in civilian populations or against military personnel would likely result in a range of exposures that stem from both the proximity of various groups to the site of deployment as well as the persistence of residues of some agents in the environment. This chapter will describe what is known about the neuropathologic consequences of both symptomatic and asymptomatic exposure to these agents and touch upon underlying mechanisms that may account for some of the regional specificity of their effects in nervous tissues.