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The article on Wikipedia says the following:

The effects of nerve agents are long lasting and increase with continued exposure. Survivors of nerve agent poisoning almost invariably suffer chronic neurological damage and related psychiatric effects.

Unfortunately, the original paper seems to be paywalled. Why does this happen? Is it because it takes a long time to replenish the acetylcholinesterase inhibited by the nerve agent?

Here is the link to the original paper.

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  • $\begingroup$ I will have a look at it in the next days. $\endgroup$ – Chris Mar 9 '18 at 20:55
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I would like to add a bit to Chris' answer. While it is true that the underlying mechanism of the long lasting effects of nerve gas has not been established, several hypotheses exist (reworded from Jokanovic et al, 2010):

  1. Long lasting effects could be derived from withdrawal of nerve gas after repeated low-level exposure or acute exposure. This means that the synapses are degraded or even the neurons die because of the constant excitation caused by the nerve gas.
  2. Nerve gas may affect neuropeptide metabolism through the release of endogenous opiates and/or through interactions with yet unidentified receptors
  3. London et al. (2005) reported that exposure to nerve gas may cause serotonin disturbances in the central nervous system, which are implicated in depression and suicide in humans.
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Most of the nerve agents (and quite a number of commercially used pesticides) fall into the class of organophosphates (OP). Their mechanism of action is the inhibition of the acetylcholin esterase which leads to the build-up of acetylcholine in the body and thus a permanent activation of mucarinic and nicotinic acetylcholine receptors. Irreversible inhibitors of AChE may lead to muscular paralysis, convulsions, bronchial constriction, and death by asphyxiation - and organophosphates can act as these. See here for some more information.

According to reference 1, four different toxic effects can be differentiated: The cholinergic syndrome, the intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP) and chronic organophosphate-induced neuropsychiatric disorder (COPIND).

The cholinergic syndrome is happening in the acute phase of the OP poisoning and can be explained by the inhibition of the acetylcholin esterase.

All quotes are from reference 1:

In cases of human poisoning, general acute symptoms of peripheral nicotinic and muscarinic intoxication are clearly apparent. These symptoms include miosis (unreactive to light); sweating, rhinorrhea, lacrimation, and salivation; abdominal cramps and other gastrointestinal symptoms; respiratory difficulties and cough; dyspnea, constriction sensation in the chest, wheezing; twitching of facial muscles and tongue, tremors, and fasciculations; bradycardia and ECG changes, pallor, and cyanosis; anorexia, nausea, vomiting, diarrhea, and involuntary urination and defecation. These signs and symptoms are accompanied by central effects such as dizziness, tremulousness, and confusion; ataxia; headache, fatigability, and paresthesia. Finally, seizures, convulsions, twitching, coma, and respiratory failure may also occur. If the subject survives the first day of poisoning, personality changes, mood swings, aggressive events and psychotic episodes including schizoid reactions, paranoid delusions, and exacerbations of preexisting psychiatric problems may also ensue.

The intermediate syndrome happens after the acute phase, around 7,7% of the patients develop it.

The term Intermediate Syndrome (IMS) was first described by Senanayake and Karalliedde (1987) because it appeared in the interval between the end of the cholinergic crisis and the onset of OPIDP. Following exposure to various OP pesticides, clinical manifestations of IMS typically occur within 24–96 h, and affect patients without fasciculation or other cholinergic signs. The reported incidence of IMS ranges from 7.7% to as high as 84% (Shailesh et al., 1994). Although IMS is well recognized as a disorder of neuromuscular junctions, its exact etiology, incidence, and risk factors are not clearly understood. IMS generally occurs among patients with prolonged and severe inhibition of AChE, although not every patient with severe AChE inhibition develops IMS. Other risk factors of IMS include delayed metabolism of OP pesticides due to toxicokinetic factors or impaired organ function, severity of poisoning, elevated muscle enzymes, plus adequate or late oxime therapy. IMS has been linked with exposure to specific OP pesticides displaying the dimethyl phosphate moiety (e.g. fenthion, dimethoate, monocrotophos, dichlorvos, methylparathion) but has also developed after exposure to parathion (ethyl phosphate) and methamidophos (phosphoramidate; De Bleecker et al., 1993; Yang and Deng, 2007).

The organophosphate-induced delayed polyneuropathy (OPIDP) cones later and has been connected to the phosphorylation and subsequent ageing of the neuropathy target esterase by the OP (see reference 1 and 3).

OPIDP is relatively rare neurodegenerative disorder in humans that is characterized by loss of function and ataxia of distal parts of sensory and motor axons in peripheral nerves and ascending and descending tracts of spinal cord. The early neurological symptoms usually are sharp, cramp-like pains in the calves, tingling in the feet and hands followed by distal numbness and paresthesia. Pain and weakness in muscles spread rapidly and patients become unsteady and unable to keep their balance. Progressive leg weakness occurs, together with depression of tendon reflexes. Symptoms may also appear in the arms and forearms. Sensory loss may be mild. Muscle tonus of the limbs gradually increase and spasticity appears in the lower limbs. Physical examination reveals distal symmetrical and mainly motor polyneuropathy, with wasting and flaccid weakness of distal limb muscles, especially in the lower limbs. In severe OPIDP quadriplegia with foot and wrist drop were observed as well as mild pyramidal signs (Lotti, 1992). There may be some functional recovery in less severe cases with more distal involvement and sparing of spinal cord axons, but pyramidal and other signs of central neurological involvement may become more evident with time. The recovery affects only sensory nerves, while motor neurons may permanently lose function as indicated by Morgan (1982) who described the lack of improvement over 47 years in 11 patients poisoned with TOCP.

The chronic organophosphate-induced neuropsychiatric disorder (COPIND) happens to persons with a chronic exposure to OP and is most likely caused by permanent damages to the central nervous system (CNS), but the real cause is not known yet.

The most common symptoms of COPIND include cognitive deficit (impairment in memory, concentration and learning, problems with attention, information processing, eye-hand coordination and reaction time), mood change (anxiety, depression, psychotic symptoms, emotional lability), chronic fatigue, autonomic dysfunction, peripheral neuropathy and extrapyramidal symptoms such as dystonia, resting tremor, bradikynesia, postural instability and rigidity of face muscles

References

  1. Neurotoxic effects in patients poisoned with organophosphorus pesticides
  2. Long-term health effects of nerve agents and mustard
  3. Neuropathy target esterase (NTE) and organophosphorus-induced delayed polyneuropathy (OPIDP): recent advances
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  • $\begingroup$ While I feel that Thawn's addition provides a better answer for my original question, I really appreciate your answer too. That was an interesting read, thank you! $\endgroup$ – JohnEye Mar 14 '18 at 21:41

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