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

Medical Aspects of Chemical Warfareloss of striations of myofibers can be observed by lightmicroscopy in the motor endplate regions as early as2 hours after administration of the organophosphate,and the lesion is fully developed in 12 to 24 hours. Inaffected fibers, the sarcolemma remains intact and isthe focus of later repair of the fiber. Recovery begins in2 days and is complete by 2 weeks. The lesion can beprevented or lessened by denervation or by administrationof atropine and oxime within the first 2 hours;the lesion is more severe in muscles of high activity,such as the diaphragm, and in type II fast-twitchmuscle fibers. 90Muscle necrosis was seen in the diaphragm of a manwho died after drinking parathion. No cholinesterasecould be demonstrated in the myoneural junctions ofany muscle, but necrosis was limited to the diaphragm.Each focus involved one to four sarcomeres of bothtypes of myofibers, varying from acute swelling tovacuolar disintegration of the fibers. The nerve endingsin the segmental necrotic zones were degenerated. 91Nerve AgentsThe circumscribed muscular necrosis seen withinsecticides has also been seen after sarin 92,93 andtabun 94 administration to experimental animals. Somanproduced necrosis in one study, 95 but not in another. 94On stimulation of the nerve, the muscle was unableto sustain a tetanic contraction at frequencies of 100and 200 Hz. 93Intermediate SyndromeInsecticidesA second type of delayed neurological manifestationof organophosphate insecticide poisoning is the “intermediatesyndrome.” In a series of 200 consecutivecases of organophosphate insecticide poisoning, 36patients developed a weakness of the proximal musclesof the limbs, cranial nerve weaknesses, bilateral pyramidaltract signs, and areflexia. 96 This disturbancebegan 12 to 84 hours after hospital admission. In mostcases, the cholinergic crisis had resolved, and the 21patients who survived recovered completely by 96hours. The lesion was unresponsive to large amountsof atropine; 2-PAM Cl was not available. The authorsof the report 96 divided the signs of organophosphateintoxication into two groups, which they called typeI and type II. According to these authors, type I signswere muscarinic in nature and were amenable to atropinetherapy, whereas type II signs were nicotinicin nature, appeared 12 to 48 hours after exposure, andwere resistant to atropine therapy.Ten additional cases were later described. 97 Thesepatients received atropine (up to 40 mg every 24 h)and 2-PAM Cl (1 g every 12 hour for 24 to 48 h) duringthe cholinergic-crisis phase. About 24 to 96 hours afterpoisoning, the 10 patients developed a syndrome thatincluded palsies of cranial nerves III, IV, VI, VII, andX; weakness of the respiratory muscles (four patientsrequired immediate intubation and assisted ventilationat the onset of the syndrome); weakness of theproximal limb muscles; and pyramidal tract signs.Recovery occurred in 5 to 18 days. Electromyographyin limb muscles and nerve conduction were normal.Tetanic stimulation of the abductor pollicis brevisshowed a marked fade with no posttetanic facilitation.The authors of the report 45 called this conditionthe “intermediate syndrome,” meaning that it is intermediatebetween the acute cholinergic effects andthe later, well-recognized delayed polyneuropathy.Consequently, the term intermediate syndrome, ratherthan type II signs, has been adopted.Two additional cases of this syndrome were reportedseveral years later; both patients required ventilatorysupport during the paralytic phase. 98 In another series,29 of 90 patients with organophosphate poisoninghad the intermediate syndrome. 99 Tetanic fade with noposttetanic facilitation was maximal between days 4 and6, and the response to electrical stimulation had returnedto normal by 8 to 10 days. The author suggested that aneuromuscular junction defect was responsible for thelesion. Other cases have since been reported 100–103 andin some, the weakness or paralysis lasted for days toweeks. Lack of early oxime therapy had been thoughtto contribute to the development of the syndrome, 104 butit has occurred with adequate amounts of oxime. 100,101,105The cause of this neuromuscular dysfunction has notbeen elucidated, nor has an animal model been described.Intermediate syndrome may be related to themyopathy seen at the neuromuscular junction.Nerve AgentsThe occurrence of the intermediate syndrome followingnerve agent exposure is not well characterized.106 In one experiment, single fiber electromyographywas used to examine the syndrome in volunteersexposed to a low level of sarin. 107 Significant, albeitsmall, changes in single fiber electromyography wereobserved at 3 hours and at 3 days following exposure.However, the electromyographic changes did not accompanyclinical neuromuscular symptoms. The smallchanges observed were resolved when the volunteerswere evaluated 2 years later.Another study examined the delayed neurotoxiceffects of repeated sarin inhalation in mice. 108 Female318