This article describes neurologic effects of various biological and chemical agents used as biowarfare or bioterrorism agents. Pathogenesis and pathophysiology as well as clinical manifestations of the important agents are described. Management is focused on botulism as an example of biological agents and organophosphates as chemical agents, particularly sarin. Neurologic manifestations can be acute, and there are some late sequelae in survivors. Management consists of diagnostic and preventive measures, which are mostly investigational for organophosphate poisoning.
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• Chemicals, toxins, and biological agents used in warfare have adverse neurotoxic effects.
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• Important examples are sarin gas (an organophosphate) and botulinum toxin.
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• Pathomechanisms of neurotoxicity of these agents have been studied.
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• Preventive measures and diagnosis are important.
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• Treatment is helpful, and examples are atropine for sarin poisoning and botulinum antitoxin in the early stages of botulinum poisoning.
Historical note and terminology
Instances of the use of biological and chemical agents for causing harm are documented throughout human history. Biological weapons include replicating agents, such as live organisms or spores, as well as non-replicating agents, such as toxins. Modern attempts to use biological toxins such as botulinum and ricin were preceded by curare and amphibian-derived toxins as arrow poisons by aboriginal South Americans using Neolithic technology (13). One of the earliest reported uses occurred in the 6th century BCE, with the Assyrian practice of poisoning enemy wells with rye ergot. The modern development of biological agents as weapons has paralleled advances in microbiology and chemistry and industrial scale to produce large quantities of pathogens and toxins. Neurologic manifestations of toxins have also been documented. A detailed clinical description of botulism was provided in 1817 by Justinus Kerner, a German neurologist (16). The episode of "anthrax letters" in the United States in 2001 indicates that use of biological weapons is not limited to the battlefield but can extend into civilian everyday life. Anthrax can affect the nervous systems, although few reported deaths were due to pulmonary complications resulting from inhalation of anthrax powder.
Bioterrorism is defined as the intentional use of biological, chemical, nuclear, or radiological agents to cause disease, death, or environmental damage, and involvement of the nervous system, including diagnosis as well treatment, is referred to as “neuroterrorism” (07). Agents used as biowarfare or bioterror weapons can be divided into biological agents, chemical agents, and toxins (see Table 1). The use of nuclear or radiological agents is not included in this article. In the last century, poisonous warfare agents were used for the first time on the battlefields almost all over the world. After World War II, new types of organophosphorus chemical warfare agents were developed, and Novichoks were only one of them. Despite the Chemical Weapons Convention, entered into force in 1997, there is still real threat of use of chemical weapons (24). Novichok use has become a symbol for chemical substances use to carry out political assassinations by both states and transnational terrorist organizations, as in the case of a Russian dissident who was evacuated in a comatose condition to Germany after being poisoned in August 2020 and was treated at Charite Hospital in Berlin. The diagnosis of Novichok was confirmed, but the case has not yet been published in scientific literature.
Table 1. Biological and Chemical Agents Used as Weapons of Mass Destruction
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• Bacillus anthracis (inhalation anthrax)
• Brucella suis
• Francisella tularensis
• Rickettsia prowazeki (typhus fever)
• Salmonella typhi (typhoid fever)
• Shigella species
• Vibrio cholerae
• Yersinia pestis (plague)
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• Encephalomyelitis viruses
• Engineered viruses
• Viral hemorrhagic fevers
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• Blood gas: hydrogen cyanide
• Mustard gases
• Nerve agents (organophosphates): eg, sarin, soman, VX, VR, and Novichok
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• Epsilon toxin of Clostridium perfringens
• Staphylococcal enterotoxin B
• T-2 mycotoxins
The Centers for Disease Control and Prevention lists bioterrorism agents and diseases into 3 categories (https://emergency.cdc.gov/agent/agentlist.asp):
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• Category A includes high-priority agents, such as organisms that pose a risk to national security because they can be easily disseminated or transmitted from person to person. These are anthrax, botulism, plague, smallpox, tularemia, and viral hemorrhagic fevers.
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• Category B includes the second highest priority agents that are moderately easy to disseminate. These are brucellosis, epsilon toxin of Clostridium perfringens, food-borne infections such as Salmonella, glanders, melioidosis, psittacosis, Q fever, ricin toxin, Staphylococcal enterotoxin B, typhus fever, and viral encephalitis.
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• Category C includes emerging pathogens that could be engineered for mass dissemination in the future, such as Nipah virus and hantavirus.
Chemical agents such as mustard gases can affect the skin, eyes, respiratory system, and gastrointestinal system. They leave affected persons at risk for long-term effects and are less attractive for use in war or terrorist attacks in which the aim is to disable or kill rapidly. For the latter purpose, nerve agents such as sarin are used. The Aum Shinrikyo sect in Japan prepared the chemical warfare agent “sarin” for an attack on a Tokyo subway in 1995.
The term “toxin” refers to a toxic substance of biological origin, usually bacterial, although simple toxins can be synthesized in the laboratory or produced by genetic modification in other species. Types of toxins are endotoxins, exotoxins, and myotoxins. Endotoxins are lipopolysaccharide toxins in the cell walls of certain gram-negative bacteria. An exotoxin is a toxin that an organism releases into the environment. A myotoxin is produced by a fungus.
As chemical products of living organisms, toxins are at times considered to be biological warfare agents. As a result, they are sometimes grouped with chemical warfare agents because they exhibit important similarities and differences relative to each group. The toxins occupy an ill-defined “no-man’s land” between chemical warfare and biological warfare agents. From a pharmacological and toxicological point of view, toxins could be considered chemical weapons, but most experts and the United States Army classify toxins as biological weapons. Examples of toxin action are (03):
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• Ricin causes multiorgan toxicity by blocking protein synthesis.
• Conotoxins block potassium and sodium channels in neurons.
• Shigatoxins inhibit protein synthesis and induce apoptosis.
• Saxitoxin and tetrodotoxin inhibit sodium channels in neurons.
• Botulinum toxin blocks acetylcholine in the peripheral nervous system, leading to muscle paralysis.
The best known toxin is botulinum toxin, a product of gram-positive anaerobic bacterium Clostridium botulinum. It is feasible to deliver botulinum toxin as an aerosolized biological weapon. The focus of this article is on 2 agents that produce neurologic manifestations--botulinum toxin and organophosphates (eg, sarin).