who can complete this by 11:30pm tonight?
Topic: Nerve Gas and Acetocholinesterase Inhibition
Write a one-page summary as single-spaced and font 12pt on the article attached.
Acu
t
e and long-term consequences of exposure to
organophosphate nerve agents in humans
Taiza H. Figueiredo, James P. Apland¥, Maria F. M. Braga, and Ann M. Marini*,§
*Department of Neurology, Department of Anatomy, Physiology and Genetics; Uniformed
Services University of the Health Sciences, Bethesda, Maryland 20814
¥Neuroscience Program, US Army Medical Research Institute of Chemical Defense, Aberdeen
Proving Ground, MD 21010, United States
Nerve agents are organophosphate (OP) compounds and among the most powerful poisons known
to man. A terrorist attack on civilian or military populations causing mass casualties is a real
threat. The OP nerve agents include soman, sarin, cyclosarin, tabun and VX. The major
mechanism of acute toxicity is the irreversible inhibition of acetylcholinesterase (AChE). AChE
inhibition results in the accumulation of excessive acetylcholine levels in synapses leading to
progression of toxic signs including hypersecretions, tremors, status epilepticus, respiratory
distress and death. Miosis and rhinorrhea are the most common clinical findings in those
individuals acutely exposed to OP nerve agents. Prolonged seizures are responsible for the
neuropathology. The brain region that shows the most severe damage is the amygdala followed by
the piriform cortex, hippocampus, cortex, thalamus, and caudate/putamen. Current medical
countermeasures are only modestly effective in attenuating the seizures and neuropathology.
Anticonvulsants such as benzodiazepines decrease seizure activity and improve outcome but their
efficacy depends upon the administration time post-exposure to the nerve agent. Administration of
benzodiazepines may increase the risk for seizure recurrence. Recent studies document long-term
neurologic and behavior deficits while technological advances demonstrate structural brain
changes on magnetic resonance imaging.
Keywords
organophosphate nerve agents; acetylcholinesterase; human; acute effects; long-term effects
§Address correspondence to: Ann M. Marini, Ph.D., M.D., Department of Neurology, Uniformed Services University of the Health
Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814, Ann.marini@usuhs.edu, Phone number: 301-295-9686.
Disclosure of Conflicts of Interes
t
The authors have no conflicts of interest.
Ethical Publication
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent
with those guidelines.
HHS Public Access
Author manuscript
Epilepsia. Author manuscript; available in PMC 2019 October 01.
Published in final edited form as:
Epilepsia. 2018 October ; 59(Suppl 2): 92–99. doi:10.1111/epi.14500.
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Background
Organophosphate (OP) G-series nerve agents were synthesized in the 1930s by German
scientists.1 An accidental spill in a laboratory where synthetic production of nerve agents
was being conducted highlighted the extreme toxicity of these compounds.2 These
compounds quickly and efficiently penetrate the human body via the skin, inhalation, and
through the bloodstream. OP nerve agent use during war is particularly advantageous given
that they cause mass casualties by inducing status epilepticus and incapacitating organ
systems in the body that may result in death. These compounds were deployed during the
Iraq-Iran war3 and on Kurdish people in Northern Iraq.4 In 2013, sarin was dropped in
Damascus killing over 1400 Syrians,5,6 including 426 children;5,7 sarin gas was suspected to
have been deployed again outside of Damascus in 2016 (http://www.telegraph.co.uk/news/
2016/05/17/assads-forces-have-used-sarin-nerve-gas-for-the-first-time-since/).
The recent death of a high profile figure by VX, a V-series nerve agent that exerts higher
toxicity in comparison with some other G-series nerve agents possibly due to the inability of
phosphorylphosphatases to break the phosphorous-sulfur bond in the bloodstream,8 at an
international airport (http://www.bbc.com/news/world-asia-39096172) demonstrates facile
concealment, accessibility, mobility and immediate deployment of OP nerve agents. Similar
but more widespread human intoxication occurred in June of 1994 when sarin gas was
surreptitiously released at midnight while people slept in the city of Matsumoto, Japan and
again in March 1995 when sarin gas was deployed in the Tokyo subway where thousands of
individuals were intoxicated and nineteen died.9 These events illustrate the versatility and
destructive capability of chemical warfare agents i.e., killing one person versus incurring
mass casualties.
Acetylcholinesterase
Nerve agents have the ability to irreversibly inhibit the enzyme AChE in central and
peripheral nervous system synapses. In the mammalian brain, AChE, located in membranes
of postsynaptic neurons10, exists mostly as a four subunit enzyme of 70 kDa. The catalytic
subunits are linked together by disulfide bonds to the hydrophobic subunit P. Subunit P is
required for localization at the cell surface11. The acetylcholinesterase gene is transcribed by
alternative splicing at the carboxyl terminal with peptide sequences of R (readthrough), H
(hydrophobic). or T (tail) catalytic subunit isoforms that determine post-translational
processing, quaternary associations and anchoring12. The soluble and cell membrane-
localized acetylcholinesterase forms are generated from the AChER form. AChEH is a
glycosylphosphatidylinositol-anchored dimer that is primarily expressed in red blood cells
and liver. Perhaps the most interesting, diverse and dynamic isoform is the AChET form
because it produces monomers, dimers and the collagen-and hydrophobic-tailed forms and
soluble forms13. The “T’ peptide directs the assembly of tetramers of AChE14 and the
product of this specific transcript is the synaptic form of AChE that is expressed
predominately in the CNS and muscle tissue15. Inducers of the readthrough AChE transcript
include stress i.e. forced swim, continued use and toxic concentrations of AChE inhibitors
and inflammation16–19. The molecular diversity of AChE leading to three isoforms serves
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http://www.telegraph.co.uk/news/2016/05/17/assads-forces-have-used-sarin-nerve-gas-for-the-first-time-since/
http://www.telegraph.co.uk/news/2016/05/17/assads-forces-have-used-sarin-nerve-gas-for-the-first-time-since/
http://www.bbc.com/news/world-asia-39096172
the functional range and location of this enzyme as soluble monomers, dimers, and tetramers
that are anchored in membranes, amphiphilic dimers, hydrophobic- and collagen-tailed
tetramers13.
Mechanism of Action
Exposure to nerve agents results in rapid absorption of agent into the bloodstream from
every route, including percutaneous, inhalation and oral administration8,20. Nerve agents
selectively target and irreversibly inhibit acetylcholinesterase (AChE), the enzyme that
breaks down the excitatory neurotransmitter acetylcholine. In the central nervous system,
acetylcholinesterase inhibition results in the overactivation of muscarinic receptors leading
to the initiation of status epilepticus whereas other types of toxic signs are observed in the
peripheral nervous system (
). Miosis and rhinorrhea are the most common clinical
signs of exposure to OP nerve agents.9,21,22 Excessive synaptic acetylcholine levels cause a
massive release of glutamate which in turn, sustains and maintains status epilepticus23,24
resulting in hypoxic-ischemic neuronal cell death via N-methyl-D-aspartate (NMDA)
receptor-mediated excitotoxicity.23, 25–28
Status epilepticus is a serious complication of nerve agent exposure and is defined as a
prolonged seizure or continuous seizures lasting more than five minutes without regaining
consciousness.29 It is well-established that prolonged seizures cause the neuropathology.
30–32 Neurodegeneration occurs most frequently in the amygdala, followed by the piriform
cortex, hippocampus, cerebral cortex, thalamus, and caudate/putamen.30,33, 34–37
Some characteristics of OP nerve agents
Sarin belongs to the same class of G-series OP nerve agents as tabun, soman and cyclosarin.
The OP nerve agents are volatile liquids and persist for a short time in the environment.38
Nerve agents are clear, and odorless liquids at room temperature. The vapor pressures of the
nerve agents (2.9 mm Hg (sarin), 0.4 mm Hg (soman), 0.07 mm Hg (tabun) and 0.044 mm
Hg (cyclosarin)) are high and the lethal vapor risk follows in descending order with sarin
exhibiting the highest lethal vapor risk39. The higher the vapor pressure, the higher the
volatility of the organophosphate nerve agent at any given temperature. The vapor/aerosol
state enters the body through the respiratory tract and eyes, and the liquid state enters the
body through eyes, skin and mouth. While it has been reported that nerve agents that exhibit
low volatility do not cause miosis as an initial symptom40, the Center for Disease Control,
the Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institutes
of Health all list miosis and other symptoms including diarrhea on their websites as
symptoms following exposure to organophosphate nerve agents regardless of route of
administration (https://www.atsdr.cdc.gov/MMG/MMG.asp?id=523&tid=93; https://
emergency.cdc.gov/agent/nerve/tsd.asp; https://chemm.nlm.nih.gov/nerveagents.htm).
Clinical examination of any patient exposed to an organophosphate nerve agent regardless of
route of administration (oral, systemic, dermal, inhalation) should include evaluation of all
signs of acetylcholinesterase inhibition within the sympathetic and parasympathetic system.
In particular, evaluation of miosis is rapid and easy to recognize during the examination. A
thorough examination of individuals thought or confirmed to be exposed to organophosphate
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https://www.atsdr.cdc.gov/MMG/MMG.asp?id=523&tid=93
https://emergency.cdc.gov/agent/nerve/tsd.asp
https://emergency.cdc.gov/agent/nerve/tsd.asp
https://chemm.nlm.nih.gov/nerveagents.htm
nerve agents will minimize oversight of even an uncommon symptom that may otherwise
result in respiratory failure and death.
Evaluation after OP nerve agent exposure
Exposure to OP nerve agents requires immediate evaluation and treatment because vapor
and systemic exposure in particular can result in the rapid development of symptoms leading
to death. It is extremely important for personnel caring for individuals exposed to OP nerve
agents to keep in mind that these agents can emanate from clothing. Liquid droplets from an
OP nerve agent that are absorbed by clothing can cross contaminate the skin of personnel
that in turn can result in local signs initially such as sweating and fasciculations but more
progressive signs of toxicity will occur as the nerve agent is absorbed and carried
systemically throughout the body leading to generalized signs of toxicity including status
epilepticus, defecation, miosis, bronchospasm, bronchorrhea, paralysis and respiratory
failure40. If dermal exposure is suspected, multiple clinical examinations may be important
in detecting delayed systemic signs and symptoms. Dermal exposure via touching
contaminated clothing can result in devastating consequences if the contaminated skin like
the fingers rub the eyes as ocular contact results in rapid local and systemic toxic effects40.
A highly organized and coordinated effort must be in place after dissemination of an OP
nerve agent. Tents with showers should be set up in the field and victims must be
decontaminated with copious amounts of water. A basic outline of the exposure levels,
clinical signs and symptoms and treatments is shown in
.
At the hospital, a detailed history and examination of individuals suspected of OP nerve
agent exposure need to be performed as the rapid development of symptoms could lead to
death depending upon the specific agent, route of exposure, and the amount of agent and
time of exposure. Taking advantage of easily recognized clinical signs such as sweating,
fasciculations and miosis helps to arrive at the correct diagnosis and provide urgent and life-
saving treatment.
It is incumbent upon emergency department staff to be properly prepared if victims
suspected of OP nerve agent exposure are expected to arrive at the hospital. Medical staff
were not wearing the proper equipment in the emergency department while triaging sarin
victims after the subway attack in Tokyo and were exposed to sarin vapor leading to signs
and symptoms of exposure9. All personnel involved with the care of nerve agent victims
need to wear personal protective equipment, and air supplied respirators. Butyl rubber
gloves and aprons are protective against dermal exposure. This equipment is required until
the patient is decontaminated; air purifying respirators and double latex gloves are not
protective41. In addition to protecting staff and caring for victims urgently, it should be
emphasized that chemical weapons inflict mass casualties. The deployment and
dissemination of OP nerve agents cause chaos in the field as well as in the emergency
department due to the overwhelming number of critically ill patients that need urgent
treatment. If a significant amount of an OP nerve agent is deployed in a small but crowded
area, one can expect that first responders will not be able to administer life-saving
countermeasures within minutes of the deployment. Under these circumstances, it is not
unreasonable to predict that status epilepticus in some if not many victims may continue for
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up to an hour before currently approved medical countermeasures can be administered to
these victims.
In summary, cognizance of the possibility of OP nerve agent exposure requires an organized,
carefully crafted and coordinated plan involving local hazmat teams, police, fire and experts
in the field as well as a network of medical centers where well-trained and equipped staff are
prepared to further decontaminate and urgently treat the expected large number of victims.
Treatment
Standard-of-care treatment for OP nerve agent acute exposure includes atropine, a
muscarinic antagonist, pralidoxime (2-PAM), an oxime that regenerates acetycholinesterase
activity in those molecules that are not aged, and diazepam, a benzodiazepine to stop/
attenuate seizures.8,25 Repeated administration of atropine five minutes after the first
injection may be necessary to reduce secretions, difficulty breathing and improve
ventilation. It is critical to thoroughly wash the eyes for 5–10 minutes to limit eye injury
after exposure to liquid OP nerve agents; decontamination of eyes is of no use when
individuals are exposed to the vapors of OP nerve agents41. Inhibition of AChE activity by
OP nerve agents is initially reversible but over time the covalent bond between the active site
and the OP nerve agent stabilizes by removal of an alkyl group, a process called aging42, and
results in irreversible AChE inhibition.
Current medical countermeasures are only modestly effective when given post-exposure in a
mass casualty situation because it is anticipated that large crowds or a crowded areas of
limited space would delay administration of life-saving medical countermeasures. Thus, it
will take some time for first responders to identify survivors that need urgent treatment with
medical countermeasures while victims are being decontaminated. The use of
benzodiazepines is relatively ineffective when given thirty minutes or longer after OP nerve
agent exposure and may increase seizure recurrence.43–45 Given the expected number of
victims and the time it will take for first responders to identify and treat critically ill victims,
it is not inconceivable that victims may be in status epilepticus for at least 30 minutes prior
to administration of currently approved medical countermeasures.
Long-term effects after exposure to OP nerve agents
Years after exposure to sarin, victims of the Tokyo subway attack presented with significant
declines in psychomotor and memory functions,46,47 signifying long-term cognitive
impairment. An active duty soldier exposed to low-dose sarin while deployed to Iraq six
years prior to evaluation exhibited poor informational processing speed, difficulties with
speed-related bilateral manual motor coordination, poor attention, reduced memory and
recall.48 In a recent article, 344 adults who were children at the time they were exposed to
mustard gas and sarin in the Kurdish city of Halabja and surrounding areas deployed by
Iraqi forces in 1988, participated in a study investigating the long-term effects of chemical
warfare agents. Eighteen participants were excluded from the study after their forms were
lost in transit. Participants exposed to chemical warfare agents were children (10 years or
younger) at the time of chemical warfare exposure. The mean age of the group at the time of
exposure was 4.9 years and the mean age of subjects when they were examined was 20
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years. There were 202 females and 142 males in the study. Only four participants received
emergency treatment within 24 hours of exposures; the remainder received treatment
between 24 hours and more than one week after chemical warfare exposure. There was no
mention whether anyone received currently approved medical countermeasures. Current or
previous smokers, anyone who had a medical condition that affected organs relevant to the
study or had a history of occupational dust exposure were excluded from the study.
Documentation of both acute and long-term effects of chemical warfare agents was
conducted in the subjects fourteen to twenty-two years after exposure. Among the maladies
at the time of examination by investigators, seventy-four percent of subjects had
neurological symptoms. Twenty percent of subjects had convulsions while ninety percent
exhibited signs of anxiety/restlessness/muscular cramps. Additional clinical neurologic signs
that were found in the subjects included ataxia (31%), paralysis (4%), fasciculations (7%),
confusion (38%), dysarthria (22%), headaches (43%) and coma (38%)49.
People exposed to OP pesticides also exhibit long-term effects. Sheep farmers exposed to
low-level OP pesticides demonstrated significant cognitive impairment on working, verbal
and visual memory testing, response speed, fine motor control, mental flexibility and
strategy making. In contrast, other cognitive domains such as visuospatial, verbal abilities
and verbal reasoning were not impaired. Two different control groups were used in this
study to ensure that there was no selection bias.50 Depression is a major neuropsychiatric
disorder found in individuals exposed to either intoxicating or low-dose OP nerve agents,
deployed veterans exposed to nerve agents,51,52 individuals of the terrorist attack in the
Tokyo subway53 as well as those exposed to OP pesticides,50, 54–58 particularly women.59
Post-traumatic stress disorder (PTSD), an anxiety disorder, was reported in human studies
following exposure to OP nerve agents despite administration of standard-of-care drugs to
promote survival and stop the nerve agent-induced seizures.60,61 Anxiety in the absence of
PTSD has also been found in individuals exposed to OP pesticides.50,57,62
The long-term effects of OP nerve agent exposure in humans are similar to results reported
in rodents exposed to OP nerve agents demonstrating neuropathological changes in several
brain regions following soman exposure63,64. Neuronal damage continues for days and
weeks after OP exposure in rodents despite lifesaving treatment with an oxime, atropine and
diazepam.65–67 Learning and memory deficits and depressive-like behavior are also
associated with soman-induced brain damage.64–69 In summary, long-term neuropsychiatric
deficits have been reported in humans exposed to either low or intoxicating levels of OP
nerve agents. A recent report in children exposed to chemical warfare agents suggests that
exposure to chemical warfare agents can lead to long-term neurological and
neuropsychiatric deficits. Animal models of OP nerve agents replicate many of the adult
human cognitive deficits.
Structural brain changes on magnetic resonance imaging after OP nerve agent exposure
Structural brain alterations were observed in the amygdala and left anterior cingulate cortex
in those individuals exposed to sarin in the Tokyo subway attack carrying a diagnosis of
post-traumatic stress disorder (PTSD).60,70,71 On brain magnetic resonance imaging (MRI),
there was a significant reduction in the amygdalar volume on both sides of the brain; a
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negative correlation existed between the left amygdalar volume and PTSD and the left
anterior cingulate cortex was also smaller.60 Exposure to an intoxicating dose of sarin as
occurred during the Tokyo subway attack resulted in regional reductions in gray and white
matter; the significant decrease in the white matter volume in the left temporal stem near the
insula correlated with the serum cholinesterase levels and the severity of the somatic
complaints.71 A significant reduction in regional gray matter volume was found in the right
insula, temporal cortices and left hippocampus in comparison with controls.71 Structural
brain changes occurred in veterans exposed to low-dose sarin and cyclosarin. A significant
reduction was found in total gray and white matter volume72,73. Significant reductions in the
CA2 and CA3/dentate gyrus subfields of the hippocampus were reported in individuals
exposed to low-dose chemical warfare agents74 and remodeling of the white matter is
suspected in the temporal stem, corona radiata, superior/inferior cingulum, internal and
external capsule, inferior and superior fronto-occipital fasciculus and nine superficial white
matter areas located between the cortex and deep white matter.75 Taken together, these
results underscore that low-level as well as intoxicating levels of OP nerve agents can result
in structural gray and white matter alterations in the brain long after exposure to OP nerve
agents.
Acknowledgments
Our research has been supported by the CounterACT Program, National Institutes of Health, Office of the Director
and the National Institute of Neurologic Disorders and Stroke [Grant Number 5U01NS058162-07 to MFB].
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Key Point Box
• Organophosphate (OP) nerve agents are deadly poisons that inflict mass
casualties in human populations.
• Irreversible inhibition of acetylcholinesterase activity by OP nerve agents
leads to accumulation of acetylcholine in synapses and hyperstimulation of
muscarinic and nicotinic receptors in the central and peripheral nervous
systems.
• Hyperstimulation of muscarinic receptors in brain results in status epilepticus
• A plethora of clinical manifestations in the central and peripheral nervous
system results from exposure to OP nerve agents; miosis and rhinorrhea are
the most common clinical signs of OP nerve agent exposure.
• Long-term effects occur after low or intoxicating levels of exposure to OP
nerve agents.
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Figure 1. Overview of the mechanism of action and clinical manifestations of the acute exposure
to organophosphate nerve agents
Exposure to organophosphate (OP) nerve agents leads to the irreversible inhibition of
acetylcholinesterase (AChE) resulting in the accumulation of the excitatory neurotransmitter
acetylcholine (ACH) in synapses and hyperstimulation of muscarinic and nicotinic
acetylcholine receptors in the central and peripheral nervous system. The major clinical
manifestation in the central nervous system after exposure to OP nerve agents is
overactivation of muscarinic receptors resulting in status epilepticus. Prolonged status
epilepticus results in hypoxic-ischemic neuronal cell death via an N-methyl-D-aspartate
(NMDA) receptor-mediated mechanism. Clinical manifestations in the peripheral nervous
system depend upon the type of acetylcholine receptors expressed in the particular organ.
Miosis and rhinorrhea are the most common clinical findings of exposure to OP nerve agents
whereas excessive bronchial secretions and respiratory depression lead to death.
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Figueiredo et al. Page 14
Table 1
Preparations and Actions in the field after deployment of an OP nerve agent
Guidelines for
First responders
Field Equipment
and Actions
Exposure
Levels
Clinical symptoms
and signs
Treatment
Personal Protective
Equipment, air supplied
respirators, butyl rubber
gloves and aprons.
HAZMAT teams, experts
in chemical warfare
agents, rapid
decontamination of
individuals exposed to
organophosphate nerve
agents.
Very high Patient is unconscious, in
status epilepticus, having
breathing difficulties,
muscle paralysis, cardiac
dysfunction
Diazepam, 2-PAM and
atropine, oxygen mask,
intravenous access, watch
for deterioration
First responders should
have ATNAA*
autoinjector kits used by
the military as this is the
most efficacious way to
administer life-saving
medical countermeasures
If showers are available,
all patients need to be
divested of their clothes
and washed down rapidly
and extensively to
minimize further
absorption, dermal and
ocular contact of vapors
and liquid
Moderate with caution Patient is recovering from
exposure to
organophosphate nerve
agent. Patient may need to
remain if dermal contact
is suspected or confirmed
in anticipation of delayed
symptoms and signs
2-PAM, atropine and
diazepam should be on
stand-by
Ensure open airway,
breathing and circulation.
Start intravenous fluids
and monitor heart rate,
blood pressure, evidence
of seizures. Have 2-PAM
and atropine close by in
case patient suddenly
deteriorates
Run water over eyes
extensively to reduce eye
injury
Minimal Patient has a few minor
symptoms i.e. miosis,
secretions
No treatment necessary
Report to hospital
approximate number of
seriously affected patients.
Showers for victims,
personal protective
equipment for
Emergency personnel
Extremely High Patient is in prolonged
cardiopulmonary arrest
Assisted ventilation, CPR,
2-PAM, atropine and
diazepam if seizing
*
ATNAA is defined as Antidote treatment-nerve agent autoinjector
Epilepsia. Author manuscript; available in PMC 2019 October 01.
- Summary
Introduction
Background
Acetylcholinesterase
Mechanism of Action
Some characteristics of OP nerve agents
Evaluation after OP nerve agent exposure
Treatment
Long-term effects after exposure to OP nerve agents
Structural brain changes on magnetic resonance imaging after OP nerve agent exposure
References
Figure 1
Table 1