Neurological Aspects of Chemical Terrorism

Transcription

1 NEUROLOGICAL PROGRESS Neurological Aspects of Chemical Terrorism David A. Jett, PhD This review describes the neurological aspects of chemical terrorism with a focus on the civilian perspective. This review defines chemical threats as highly toxic chemicals that could be used in a terrorist attack, or those that could be released at toxic levels from transportation vehicles and storage facilities during an accident or natural disaster. Chemical threats can be categorized based on the target tissues and types of primary acute effects they produce (Table). Probably the most easily recognizable chemical terrorism threats are the traditional chemical warfare agents (CWAs) developed during the first and second World Wars. These include the organophosphorus (OP) nerve agents, such as sarin and VX, and the mustard blister agents. As a consequence of previous state-sponsored CWA programs, several stockpiles remain around the world. Sulfur mustard and OP nerve agents were used against Iraqi Kurdish villages in the late 1980s, and more recently, the OP nerve agents were used by the Japanese cult organization Aum Shinrikyo in two separate attacks against civilians in Japan. 1 The United States also produces and uses more than 80,000 chemicals, many of which are highly toxic and lethal at relatively low doses. Chemical agents in this broad category include the toxic industrial chemicals (TICs) manufactured and stored in large volume at industrial facilities and transported across the nation for various uses. Whereas the threat from CWAs is mitigated by restricted access, difficulty in synthesis of purified agent, and international treaties against their use, the TICs are not regulated as strictly, and many chemicals are readily available or stored in large enough amounts to pose a serious threat to human health if released by accident, natural disaster, or a deliberate act of terror. One of the most deadly industrial accidents occurred in Bhopal, India, where methyl isocyanate was released from an industrial storage tank killing 5,000 people and injuring thousands more, some with long-term effects. 2 More recent fatal accidents involving large-scale chlorine gas releases during transportation in the United States have brought national attention to the hazards associated with TICs. 3 Organophosphorus Nerve Agents The OP nerve agents belong to a chemically diverse group of organic compounds that have in common at least one carbon atom bound to a phosphorous atom. They are sometimes referred to as nerve gases because of the high volatility of some of the specific agents, but in fact, they are clear, colorless liquids at room temperature. The OP nerve agents were derived from OP pesticides during World Ward II by the Nazis to be used as CWAs against the allied forces. Traditional OP nerve agents fall into two groups, the G- and the V-series, based on their chemical and physical properties. The G-series nerve agents (GA, tabun; GB, sarin; GD, soman; and others) are volatile liquids at room temperature that can be deadly when inhaled as a vapor or from percutaneous exposure to the vapor. V-series agents (VX and others) have a consistency similar to oil and do not evaporate rapidly. V-series agents can remain on clothing and other surfaces for a long time, and they pose a greater risk from dermal exposure or by ingestion. Agents in the V-series are approximately 10- to 100-fold more toxic than those in the G-series. OP nerve agents inhibit the catalytic function of acetylcholinesterase (EC ; AChE) by phosphorylating the esteratic site of the enzyme. 4 This removes the capacity of the enzyme to catalyze its endogenous substrate acetylcholine (ACh). As a consequence, the hydrolysis of ACh is prevented, leading to accumulation of ACh in the synaptic cleft and overstimulation and subsequent desensitization of muscarinic and nicotinic ACh receptors at cholinergic synapses in the brain, glands, and skeletal and smooth muscles. The OP nerve agents are more toxic than the related OP pesticides still in use today, and they bind irreversibly to AChE and interact at several other molecular sites at low doses. 5 They are lethal at minute doses. For example, the median lethal dose (LD 50 ) of VX for a 70kg person is only 10mg. The acute effects of OP nerve agents and pesticides are well characterized 4 and include a progression from miosis, excessive secretions, and muscle fasciculation to epileptic seizures, muscle From the National Institutes of Health, National Institute of Neurological Disorders and Stroke, Office of Technology Development, Bethesda, MD. Received Nov 28, Accepted for publication Dec 4, The information in this article is provided for educational purposes only and does not necessarily represent endorsement by, or an official position of, the National Institute of Neurological Disorders and Stroke or any other Federal agency. Published online Jan 29, 2007 in Wiley InterScience ( DOI: /ana Address correspondence to Dr Jett, National Institutes of Health, NINDS, 6001 Executive Boulevard, NSC, Room 2177, MSC 9527, Bethesda, MD jettd@ninds.nih.gov 2007 American Neurological Association 9 Published by Wiley-Liss, Inc., through Wiley Subscription Services

2 Table. Syndromic Classification of Potential Chemical Threats Category Examples a Properties Exposures Acute Effects Nervous system agents Metabolic and cellular poisons Sarin, VX, saxitoxin, botulinum toxin, fentanyl Cyanide, arsine High- or low-volatility liquids, natural or synthetic peptides, drugs Volatile liquids and gases, cyanogen salts percutaneous, ingestion ingestion Miosis, anxiety, confusions, excess secretions, muscle fasciculations, bronchoconstriction, paralysis, cardiorespiratory depression, convulsions and seizures, coma, death Convulsions, hemolysis, coma, respiratory and renal failure, bradycardia, cardiac arrest Pulmonary agents Chlorine, phosgene Volatile gases Inhalation Cough, dyspnea, pulmonary edema, respiratory failure Eye, skin and mucous membrane agents Sulfur and nitrogen mustards, lewisite Oily liquids more volatile at higher temperatures percutaneous Tearing, burning eyes, rhinorrhea, sneezing, cough, erythema, corneal damage, dyspnea, pulmonary edema, vesication a For many of these examples, there is considerable overlap among the four categories. For example, cyanide is classified as a metabolic poison, but it also significantly affects the nervous system. paralysis, cardiorespiratory depression, and death caused by respiratory failure (see the Table). Acute poisonings with OP nerve agents and pesticides are treated with atropine sulfate to inhibit central muscarinic effects, and an oxime, usually pralidoxime (2-PAM) chloride, to reactivate AChE. Atropine blocks muscarinic cholinergic receptors in the parasympathetic nervous system to reduce excessive secretions and smooth muscle contraction. It does not have a significant therapeutic effect for central nervous system toxicity, and it does not appear to work well at cholinergic synapses on skeletal muscle. Atropine works well as an antidote to OPs, but it can have significant side effects if dosing is not monitored carefully. Other cholinergic drugs and drugs that interact with other neurotransmitter systems are under development that may be more selective and have fewer side effects. The oxime 2-PAM chloride removes OP nerve agents and pesticides from AChE by virtue of its highly nucleophilic oxime moiety, and it appears to have its most significant effect at nicotinic cholinergic synapses on skeletal muscle. 4 Both OP pesticides and nerve agents undergo a deacylation process called aging, during which the bond strength between the OP and AChE increases significantly, and after which oximes are ineffective. Once aging has occurred, the AChE is essentially destroyed and enzyme activity can be restored only by de novo resynthesis. Aging times vary according to the nerve agent and range from fast with soman (2 minutes) to much slower with sarin (3 4 hours) and longer for others. Research programs on improved AChE reactivators focus on increasing activity within the central nervous system and increasing the therapeutic window, especially for fast-aging nerve agents. Atropine and 2-PAM chloride are packaged together for civilian use in the Strategic National Stockpile s CHEMPACK and in MARK I spring-powered autoinjectors used by the US military. Other treatment strategies for OP nerve agents include sequestration or inactivation of the agent systemically. This approach uses endogenous or modified proteins to bind free nerve agents stoichiometrically or the introduction of enzymes with high catalytic activity to remove the nerve agent from circulation before it reaches the target site. Organophosphorus-Induced Seizures and Long-Term Effects The OP nerve agents cause epileptic seizures at sufficient doses. Prolonged seizure activity after nerve agent exposure has been shown in animals to cause neuropathological lesions in the central nervous system that are associated with long-term impairment of cognitive function and other behaviors. 6,7 Seizures can begin in various cortical and subcortical regions and spread throughout the brain. They can cause lesions in a number of areas, including the cortex, hippocampus, thalamus, and amygdala. 6,8,9 Neurological damage from seizures is a particular concern when respiration and tissue oxygenation are compromised. The neural mechanisms that underlie OP nerve agent induced seizures and resultant neuropathology involve an initial cholinergic trigger and hyperstimulation of cholinergic receptors that is initially treatable with anticholinergic drugs. 9 If left unchecked, seizures proceed to the next phase during which other neurotransmitter systems are 10 Annals of Neurology Vol 61 No 1 January 2007

3 recruited, at which point anticholinergic drugs become less effective. The last phase involves stimulation of the glutamatergic system, causing eventual excitotoxicity, calcium accumulation, increased catabolic activity, and cell death. 10 Research in the area of antiglutamatergic drugs and prevention of excitotoxicity is being pursued, because in many cases, first responders may not be able to administer any treatment until this latter excitotoxic phase. Alone, the atropine and 2-PAM treatment regimen is not effective against OP-induced seizures once they are established, but these antidotes are crucial to the effectiveness of anticonvulsants, and the dose of atropine influences the effectiveness of anticonvulsants. 11 The benzodiazepine diazepam is an anticonvulsant used for treatment of exposure to OP nerve agents, and it is included in 10mg doses in the antidote treatment regimen used by the US military (Convulsant Antidote, Nerve Agent [CANA]). It is also included in the civilian CHEMPACK stockpile. Diazepam is an effective treatment for the seizures associated with nerve agent exposure, but it has limited bioavailability when administered intramuscularly, and there is a loss in efficacy after prolonged seizure activity. As with most drugs that suppress central nervous system activity, the potential for oversedation and respiratory depression exists with diazepam, especially in cases where patients may already be suffering from paralysis or hypoxia from the nerve agent. This last point regarding OPinduced paralysis is also important when considering the diagnosis of seizure activity and appropriate treatments. The muscular effects of OP nerve agents may mask or mimic signs of seizure activity. A field deployable electroencephalograph suitable for use by firstresponder medical personnel could be used to detect potential nonconvulsive seizures during a chemical event. Animal data clearly suggest that most of the neuropathology associated with exposure to nerve agents is directly related to seizure activity, and an effective dosage and timing of anticonvulsant administration protects against most of the brain pathology. 6,7,12,13 However, many of these studies have used a military exposure paradigm that employs pretreatment with a prophylactic drug (pyridostigmine bromide) and atropine administration within minutes after nerve agent exposure. This may not accurately reflect a civilian scenario where neither pretreatment nor immediately posttreatment therapies are possible. This experimental paradigm also allows for survival at higher doses that would be lethal to civilians without pretreatment or rapid administration of atropine. Newer models that better reflect civilian exposure scenarios are under development. Notwithstanding these caveats from animal studies, emerging human data do support the notion that long-term neurological effects occurred in humans exposed to nerve agent during the Tokyo subway attack, 1,14,15 and this is further supported by Yamasue and colleagues 16 clinical investigation that is reported in this issue of Annals. It is unknown whether seizures occurred in all of these patients, or whether they were controlled with anticonvulsants at the time of the incident. This raises the question of whether mechanisms unrelated to seizures may be responsible for some of the long-term effects of nerve agents. Some of these long-term effects could be related to subconvulsive exposures to nerve agent. It does appear in animal studies that subtle transient cognitive and physiological effects may occur after nonconvulsive doses of nerve agents, 17,18 but there is not any definitive evidence to support this theory. Clearly, more work is needed on the effects of both acute and chronic exposures to low levels of OP nerve agents. 19 Concerns related to long-term damage to the nervous system by nerve agents emphasize the importance of another class of therapeutics called neuroprotectants. Neuroprotectants are drugs that prevent or halt the process of cell damage and death, and they are currently being developed to treat such conditions as stroke and traumatic brain injury. They could be an important component of the treatment strategy for OP nerve agents because as better antidotes are developed that reduce lethality, there will be more survivors that could potentially develop long-term neuropathology. Other Chemical Threats with Neurological Effects Among the TICs with greatest impact on the nervous system is the metabolic poison cyanide. Cyanide is ultimately toxic in its ionic form (CN ), which can be released from hydrogen cyanide or cyanogen chloride gases. It can also come from sodium, potassium, and calcium salts that when mixed with acid, release highly toxic hydrogen cyanide vapor. In addition to its deliberate use, cyanide can come from industrial, natural, and even iatrogenic sources, such is the case with the use of sodium nitroprusside as an antihypertensive medication. The CN ions bind to positively charged iron atoms in the cytochromes within the mitochondrial electron transport chain, ultimately blocking electron transfer from cytochrome oxidase to molecular oxygen. This compromises oxidative phosphorylation and anaerobic metabolism, and results in lactic and metabolic acidosis, histotoxic hypoxia, and profound effects on critical functions especially in high-demand areas such as the brain and cardiovascular systems. Neurological symptoms after acute exposure to cyanide usually include headache, vertigo, and seizures, followed by coma, respiratory failure, cardiac arrest, and death (see Table). The rapidity of progression to lifethreatening effects can be within minutes if high levels of hydrogen cyanide are inhaled, but somewhat slower Jett: Neurological Aspects of Chemical Terrorism 11

4 if exposed to lower concentrations in vapor form or via ingestion of cyanide salts. Long-term effects from sublethal acute exposures to cyanide have not been studied extensively in humans. However, patients who survive an acute intoxication develop a delayed Parkinsonism and dystonia that can develop into a Parkinson s disease like state. 20,21 Chronic exposures to cyanide have also been linked to several chronic neurological diseases such as tobacco amblyopia, retrobulbar neuritis, Leber s optic atrophy, and tropical ataxia neuropathy. 22 Cyanide may cause neurodegeneration by its effect on mitochondrial respiration, but there is evidence that other molecular mechanisms may be involved, such as excitotoxicity and interaction with inhibitory neurotransmitters. 23 Because of the short therapeutic window for cyanide poisoning, antidotes must be administered rapidly, and they must reach effective concentrations at the target site within minutes. Two strategies are used to treat victims of cyanide poisoning. First, amyl and sodium nitrites are given intravenously to form methemoglobin. CN ions have a higher affinity for the Fe 3 atoms in methemoglobin and are sequestered and removed from circulation. This approach is effective but needs careful monitoring because methemoglobin itself is toxic. The second approach is to facilitate metabolic detoxification by administering sulfur donors. Sodium thiosulfate donates sulfur to rhodanese that converts cyanide into thiocyanate and sulfite, which are then excreted by the kidneys. Most cyanide poisoning victims are given oxygen therapy in conjunction with the specific antidotes. Both civilian and military antidote kits contain amyl nitrite, sodium nitrite, and sodium thiosulfate. Rapid diagnosis of cyanide poisoning is important because of the risks associated with using specific antidotes, especially the methemoglobin formers that may have serious side effects. Also, symptoms of cyanide poisoning may be confused with exposure to OP nerve agents, botulinum toxin, and other neurotoxic chemicals. Naturally occurring toxins have been used as tools in neurological research for many decades, and some of these toxins serve a dual use by also posing a threat as a terrorist weapon by virtue of their high potency at critical molecular targets within the nervous system. Toxins in this category include those derived from marine life such as conotoxin (cone snail), brevitoxin (dinoflagellates), and saxitoxin (shellfish); plants such as castor beans (ricin); amanita mushroom toxin; trichothecene mycotoxin; or the bacterium Clostridium botulinum. Because most of these are derived from biological sources, some (eg, ricin and botulinum) have been considered more a biological rather than chemical threat and have been reviewed elsewhere. 24 The botulinum toxins block ACh release at neuromuscular junctions and cause paralysis. There are current antitoxins, and next-generation therapies are under development for botulinum poisoning. The conotoxins act at several receptor and ion channel sites depending on the specific protein. Saxitoxin blocks sodium channels, and the brevitoxins and ciguatoxins activate Na channels. These toxins can cause a variety of neurological symptoms ranging from numbness and tingling to respiratory paralysis and death (see Table). High doses of sulfur mustard can also cause neurological symptoms, and some evidence exists that there were long-term neurological complications in Iranian veterans exposed to this agent. 25 Some incapacitating drugs have been described as potential chemical threats as well. This category includes amphetamine stimulants; depressants such as fentanyl that was reportedly used in the Moscow siege incident in 2002; psychedelic drugs such as lysergic acid (LSD); and deliriants such as quinuclidinyl benzilate (BZ), which was once considered for use in chemical warfare. Conclusions and Future Directions Preparing for chemical terrorism represents a new challenge to civilian health care professionals and researchers, because this has historically been confined to military research and medicine. Unlike the military, civilians have a more diverse demographic, and the focus is on postexposure treatments, rather than protective measures for a soldier being prepared for the battlefield. Among the chemical threats that cause neurological complications, the types that have been studied most extensively include the OP nerve agents, cyanide, natural neurotoxins, and some drugs. Specific antidotes are available for many of these agents, but they will need to be administered rapidly because of a relatively small therapeutic window. In addition to laboratories engaged in basic research and drug discovery, research exploring alternate indications, routes of administration, and formulations of approved therapies is under way. Research efforts also focus on animal models that simulate the variation in disease susceptibility of the civilian demographic, including prenatal and neonatal casualties, the young, the elderly, and segments of the general population that are more sensitive to chemical threats because of genetic or other predispositions. Improved rapid diagnostic techniques and technologies are also needed that could be used in the field by first responders, who themselves need effective medical prophylactic treatments and protective equipment before entering a contaminated site. References 1. Yanagisawa N, Morita H, Nakajima T. 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