Medical Aspects of Chemical Warfare (2008) - The Black Vault

Nerve Agentsand they were decreased or reversed by atropine (1.2mg, IV).In another study, 104 the EEG of a subject who wasseverely intoxicated with sarin was recorded afterthe loss of consciousness but before the onset of convulsions.The recording showed marked slowing ofactivity, with bursts of high-voltage, 5-Hz waves inthe temporofrontal leads. These waves persisted for 6days despite atropine administration.In one study 45 in which subjects were exposed tosmaller amounts of sarin, the EEG changes coincidedwith severity of symptoms. With mild symptoms, voltagewas slightly diminished. Irregularities in rhythm,variation in potential, and intermittent bursts of abnormalwaves (slow, elevated-voltage waves) occurredwith moderate symptoms. These changes persisted for4 to 8 days after the disappearance of symptoms anddecreased somewhat (decreases in voltage, in irregularfrequency and potential, and in slow waves) afteradministration of atropine (1 mg, IV).The effects of various anticholinesterase agents(nerve agents, other organophosphorus compounds,and carbamates) on EEG activity were reviewed andthe study authors proposed that a three-stage changeis produced in the normal EEG of animals or humansby progressively higher doses of these compounds. 105At Stage I an activation pattern is produced in theEEG that is characterized by a low amplitude desynchronizedpattern of mixed frequencies normally seenin alert subjects. This pattern is induced regardlessof the subject ’ s behavioral state when the anticholinesteraseis administered, and may last from minutesto several hours, depending upon the dose and thetype of compound. This pattern is associated with anapproximately 30% to 60% inhibition of RBC-AChE,which is comparable to levels of inhibition associatedwith minimal to mild signs or symptoms of exposure.This level of ChE inhibition may also be associatedwith some mild, short-term effect on REM sleep.The Stage II EEG pattern is marked by a continuationof the activation pattern seen during Stage I,with intrusions of high-voltage, slow-frequency(delta, theta) waves and an increased amount of highfrequency (beta) waves. The Stage II pattern is associatedwith mild to moderate signs or symptoms ofintoxication in both human and animal studies. TheseEEG changes may persist for hours or days, dependingupon the severity of the dose, and are associated withapproximately 60% to 80% inhibition of RBC-AChE.Such levels of exposure are also expected to producea moderate increase of REM.Stage III EEG changes are associated with the mostsevere levels of exposure and are represented byepileptiform activity in a variety of patterns. This istypically marked by very high-voltage waves, withlow-frequency delta waves being most prominent.There are marked signs of agent intoxication, as wellas seizure and convulsive activity, that require immediatepharmacological treatment. Animal studies showthat all nerve agents are potent convulsant compoundsthat can elicit prolonged seizure activity that has allthe clinical and electrophysiological features of statusepilepticus. 76,77,106,107 Seizure activity in human victimsof severe nerve agent exposure is typically of limitedduration, due to the rapid compromise in respiratorystatus and associated decrease in oxygenation.Following such severe exposures, EEG changesmay persist for months to years, depending upon theseverity of the initial insult and possibly upon the rapidityand effectiveness of pharmacological treatment.Long-term EEG effects show up as isolated spikes,sharp waves, or both during sleep or drowsiness, orwith hyperventilation. 46,103,108–110 Such severe EEG andneurobehavioral effects are associated with initiallevels of RBC-AChE inhibition greater than 70%.The effects of such severe exposures on REM sleepare prominent and can persist for weeks or monthsafter the exposure. In experimental animal studies,unchecked, nerve-agent–induced seizures can persistover a period of many hours, and can result in braindamage and long-term neurobehavioral changes. Boththe brain damage and neurobehavioral effects can beblocked or minimized by rapid treatment with appropriateanticonvulsant medications. 77,111Long-Term EffectsLong-term effects on the human CNS after poisoningwith nerve agents or organophosphorus insecticideshave been reported. 20,79,80,112,113 These reports arebased on clinical observations, occasionally supportedby psychological studies. In general, the behavioraleffects have not been permanent but have lastedweeks to several months, or possibly several years. 114A distinction needs to be made between these moretransient effects that represent reversible neurochemicalchanges of nerve agents on brain function and thosemore permanent effects described below.In the early 1980s, several laboratories reported thatanimals that survived high-dose exposure to nerveagents developed brain lesions. 115–117 Similar findingshad been reported by Canadian researchers in technicalreports in the 1960s. 118,119 Further studies confirmedthese initial findings and led to several hypotheses asto the cause of these brain lesions. First, some authorssuggested that the nerve agents may produce a directneurotoxic effect on brain neurons. 115,120 Second, thepattern of brain damage seen in these nerve-agent–177