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

Neuroprotection as a Treatment for Nerve Agent SurvivorsINTRODUCTIONOrganophosphorus nerve agents are the principalchemical warfare agents known to produce braininjury. They block hydrolysis of the neurotransmitteracetylcholine by inhibiting the enzyme acetylcholinesterase,resulting in greatly increased postsynapticacetylcholine levels. This causes a spectrum of effects,including miosis, excess secretions, nausea, vomiting,and muscle fasciculations. At moderate to high doses,nerve agents also cause seizures and associated convulsions.If left untreated, seizures rapidly progress tostatus epilepticus (SE) and cause irreversible seizurerelatedbrain damage (SRBD). 1,2 The InternationalClassification of Epileptic Seizures defines SE as anyseizure lasting at least 30 minutes or intermittent seizureslasting longer than 30 minutes between whichthe patient does not regain consciousness. 3,4For over a decade acute therapy has effectively savedthose poisoned by nerve agents on the battlefield, 5 afteraccidental exposures, 6 and in terrorist attacks, as in theJapan subway attacks in 1994 and 1995. One lessonlearned from the 1995 Tokyo attack was that, lackingacute antidotal treatment, many survivors arrived athospitals in convulsive SE. The Tokyo experience illustratesthe necessity of acute antidotal therapy, such asthe regimen adopted by the US military. This regimenis aimed primarily at treating cholinergic crisis witha postexposure anticholinergic (atropine sulfate) andan oxime reactivator (2-pralidoxime [2-PAM Cl]). Inspecific intelligence-driven situations, pyridostigminebromide (PB) pretreatment is added. Although thesemedications greatly reduce morbidity and mortality,they do not always prevent seizures and brain damagein nerve agent casualties; therefore, the regimen nowincludes the anticonvulsant diazepam. 2Even with diazepam, however, the treatment regimenhas limitations. The decision to include diazepamwas based on animal data showing that it couldterminate nerve-agent–induced seizures and convulsionsand enhance survival when given in conjunctionwith the acute therapy described above. 7–11 However,the therapeutic window for arresting seizures andSE with diazepam is less than an hour following onset;after that, both are refractory to anticonvulsanttherapy. 7,8,10–19Early use of an anticonvulsant does not guaranteethat seizures, once stopped, will not return. The recurrenceof seizures is often observed in animal studies inseveral species and is of concern in human exposures.Although neuropathology is reduced in diazepamtreatedanimals, the incidence and degree of protectionafforded by diazepam is not complete. 9,20–23 Moreover,switching the fielded anticonvulsant to another benzodiazepine,such as midazolam or lorazepam, does notentirely solve the problem of refractory SE.Seizures and SE are key causes of brain damage resultingfrom nerve agent poisoning, and their preventionor alleviation should be the primary objective. 24–26However, because of the refractory nature of seizuresand especially SE, prevention and alleviation becomeincreasingly difficult as more time elapses beforetherapy begins. Also, there is high probability thatseizures will return when anticonvulsants wear off.Therefore, it is reasonable to anticipate a high incidenceof brain damage connected to the increased survivalrate of nerve agent victims.Casualties exhibiting seizures and SE can be anticipatednot only from terrorist attacks but also frombattlefield scenarios involving troops who were notin full protective ensemble at the time of the attack. 27In the confusion following a terrorist attack or on thebattlefield, prompt treatment of nerve agent casualtiescan be expected to be problematic, and some victimsundergoing seizures may not receive anticonvulsantsinside the antiseizure therapeutic window. It is alsopossible that some victims may undergo nonconvulsiveSE, a state of continuous seizures withoutobservable clinical movement. 28 For these victims,treatment might be inadvertently delayed beyond thetherapeutic window. Under the Small Business InnovativeResearch Program, the US Army funds efforts tofield a far-forward, simple seizure detector to identifythese casualties.This chapter presents a detailed overview of nerveagent–inducedneuropathology and explains the mechanismsof action of candidate neuroprotectants that haveshown promise in various animal and human studies,especially those that have received US Food and DrugAdministration (FDA) approval for other indications.Neuropathology And The Mechanism Of Nerve-Agent–Induced DamageAlthough there is little neuropathological datafrom patients who have survived nerve agent attacks,abundant evidence is available from animal models,many of which involve persistent SE. The profoundbrain damage produced by nerve agents was firstdescribed by Petras 29 ; Lemercier et al 30 ; and McLeodet al. 31 Since then, numerous studies have greatly enhancedthe understanding of neuropathology resultingfrom nerve agent intoxication. 23,32–38 These studies haveestablished that prolonged seizures and SE resulting223