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

Medical Aspects of Chemical Warfareexposed animals was similar to that seen after hypoxicencephalopathy. Because nerve-agent–exposed animalsexhibit varying durations of respiratory distress, severalauthors hypothesized that nerve-agent–inducedhypoxia was primarily responsible for producing theselesions. 116,118,119 A third hypothesis was that the lesionswere the consequence of the prolonged seizures experiencedby the animals during the intoxication. 121Subsequent work both in vivo 122 and in vitro 123 hasfailed to demonstrate support for the hypothesis thatnerve agents are directly neurotoxic. Likewise, theoverwhelming evidence that effective treatment ofnerve-agent–induced seizures can block or significantlyreduce the extent of brain lesions argues againstthe direct neurotoxicity hypothesis. 77There is conflicting evidence regarding the possiblerole of hypoxia as an etiologic factor in brain damagefollowing seizure activity, whether nerve agents orother chemoconvulsants cause this seizure activity.Rats given bicuculline convulsed for 2 hours undercontrolled conditions. Those given a lower percentageof oxygen in their inspired air to keep the partialpressure of arterial oxygen close to 50 mm Hg didnot have brain lesions, whereas those with normal airintake and partial pressure of arterial oxygen higherthan 128 mm Hg developed brain lesions. 124 Althoughthis evidence does not eliminate the possibility oflocalized hypoxic areas in the brain as a factor innerve-agent–induced damage, it does suggest thatsystemic hypoxia is not a factor. On the other hand, asimilar study 125 (hypoxic rats with bicuculline-inducedconvulsions that lasted 2 h) suggested that there wereslightly more brain lesions in the hypoxic animals thanin normoxic animals.The hypothesis that prolonged seizure activity isprimarily responsible for nerve-agent–induced braindamage in experimental animals has now becomewell accepted. 77 Studies in rats have shown that braindamage development requires a minimum durationof continuous seizure activity. 124,125 Seizures terminatingbefore 10 minutes have elapsed resulted inno observable damage. In animals that seized for 20minutes before seizures were stopped, about 20% experiencedmild amounts of damage in restricted foci.In contrast, in animals that experienced 40 minutesof seizure before seizures were stopped, over 80%experienced damage, and this damage was moresevere and widespread than the 20-minute-treatmentgroup. Studies in nonhuman primates confirm thatdelay in seizure control increases subsequent brainpathology. 126,127 Studies with effective drugs that canstop nerve agent seizures (benzodiazepines, anticholinergics,N-methyl-d-aspartate antagonists) by manyresearch groups have overwhelmingly demonstratedthat seizure control protects experimental animals(rats, guinea pigs, nonhuman primates) from developingbrain damage. 107,128–137There are, however, experimental studies that showthat convulsion development following nerve agentexposure does not invariably lead to brain damageand, conversely, that some animals that never displayconvulsions develop brain lesions. All of these studiesused observational procedures to determine presenceof convulsive/seizure activity following nerve agentexposure. While nonconvulsive/nonseizure-mediatedneuropathology may have been observed followingexposure to nerve agents, the exact neuropharmacologicalmechanism(s) that might produce this damagehas yet to be described.In addition to having morphologically detectablebrain lesions, animals surviving severe nerve agentintoxication have been shown to have decrements inperformance, as measured on a variety of behavioraltests. 136–140 These decrements were apparent in somestudies for at least 4 months, when the last survivorswere sacrificed. These animals, mostly rats, are reportedto display other persistent behavioral changes(hyperresponsiveness, difficulties regulating bodyweight, spontaneous convulsions) that can also beconsidered consequences of the brain lesions.In general, in untreated or inadequately treatednerve-agent–poisoned animals, convulsive (and seizure)activity usually stops shortly after respirationbecomes compromised. Some of these animals diewhile others recover after some degree of apnea, andelectrographic seizure activity, as monitored on theEEG, can resume while overt motor convulsions mayno longer be apparent. Motor movements (fingertwitches, repetitive arm/leg movements, nystagmus)become more subtle, of smaller amplitude, andintermittent. These bear all the same clinical characteristicsas described for late-stage status epilepticusin humans. 141 In some of the reported cases of severenerve agent intoxication in humans, 20,66,104 convulsiveactivity has also been brief and medical treatmentwas promptly available to prevent further convulsiveepisodes. There are several reports, however, from theAum Shinrikyo terrorist attacks of individuals exhibitingprolonged seizure activity before adequate therapycould be delivered. 110,142 It is not known whether thesevictims suffered brain damage similar to that describedin experimental animals, but two individuals experiencedprofound retrograde amnesia, one of which stilldisplayed high-amplitude epileptiform waves in theEEG 1 year after the exposure.Interpreting clinical studies in light of experimentalresults is difficult largely because the role of hypoxiais very hard to separate from any seizure-mediated178