Invited Review Article
A comprehensive review on experimental and clinical findings in intermediate syndrome caused by organophosphate poisoning

https://doi.org/10.1016/j.taap.2011.11.014Get rights and content

Abstract

Acute organophosphate (OP) intoxication is important because of its high morbidity and mortality and occurrence of muscular paralysis associated by inhibition of acetylcholinesterase (AChE) activity at the neuromuscular junction. Cholinergic crisis, intermediate syndrome (IMS), and OP-induced delayed neuropathy (OPIDN) are the evidences that can be observed in OP intoxication. The main cause of morbidity due to OP poisoning is IMS that occurs 24–96 h after poisoning. Mechanisms underlying the IMS are not fully known. Although the electrophysiological aspects of delayed neuropathy are best characterized, the IMS remain very little studied. The aim of this study was to revisit current knowledge related to OP and the IMS. For this purpose, a systematic review without date limitation was performed. A total of 599 relevant articles were found and reviewed. Data were categorized according to experimental and clinical studies. Occurrences of persistent AChE inhibition, electromyography changes, muscle cell injury, and oxidative stress are the most important pieces of evidence for involvement of IMS in OP toxicity.

Delayed AChE inhibition, muscle necrosis, down regulation or desensitization of postsynaptic ACh receptors, failure of postsynaptic ACh release, and oxidative stress-related myopathy are involved in IMS. Toxicokinetic factors, such as a high lipid-solubility, duration of AChE inhibition and metabolite excretion, evolution of alterations on repetitive nerve stimulation (RNS), type and frequency of muscle lesions can estimate the probability of the IMS. Plasma AChE of less than 200 units is a predictor and the 30 Hz RNS decremental response could be a useful marker for the IMS.

Introduction

Organophosphate (OP) poisoning is a major global health problem. This poisoning produces various forms of acute, subacute, or delayed neurotoxicity that causes life-threatening acute neurological complications such as seizures, paralysis, neuromuscular and cardiac conduction disorders. The neurotoxic effects of OP in human range from neurobehavioral and electroencephalographic changes to increase in the variability of action potential (AP) latencies in skeletal muscles. Cholinergic crisis, intermediate syndrome (IMS), and OP-induced delayed neuropathy (OPIDN) can be observed in OP intoxication (Dettbern et al., 2006). OPIDN, a sensory-motor distal axonopathy is believed to be a result of inhibition of neuropathy target esterase (Lotti and Moretto, 2005, Vasconcellos et al., 2002). The IMS following OP poisoning has been described in the mid-1980s by Senanayake and Karalliedde (1987). Approximately 20% of patients following exposure to OP pesticides may experience IMS (Karalliedde et al., 2006). The late onset of respiratory failure associated with IMS is a major contributor to the high morbidity, mortality, and cost of OP poisoning treatment. The IMS is clinically characterized by weakness in the cranial nerves, weakness of respiratory, neck and proximal limb muscles, and depressed deep tendon reflexes. These symptoms appear within 24 to 96 h post OP exposure in two types of paralysis. The type 1 paralysis responds to atropine while type 2 does not. Fasciculation that is seen in type 1 is not part of IMS. Delayed polyneuropathy develops within 1 to 3 weeks but duration of the IMS varies from a few days to several weeks (Van den Neucker et al., 1991).

Clinical and experimental electrophysiological studies in the IMS show that subclinical electrophysiological abnormalities are common and progressive. Studies demonstrate a repetitive firing following a single stimulus, gradual reduction in twitch height or compound muscle action potential (CMAP) followed by an increase with repetitive stimulation (decrement–increment phenomenon), and continued reduction in twitch height or CMAP with repetitive simulation (Jayawardane et al., 2009, Karalliedde et al., 2006).

The aim of this study was to gather all data related to IMS and electromyographic changes that may occur after OP poisoning to clarify understanding the involved mechanisms.

Section snippets

Methods

Bibliographic databases including PubMed and Google Scholar were searched between years 1953 to 2011 for the keywords “organophosphate, organophosphorous, intermediate syndrome, myopathy, neuropathy, and electromyography”. In the first step, 599 articles were found, after elimination of duplicates or irrelevant papers, 58 papers were selected and reviewed. Reference lists of published articles were hand-searched to ensure inclusion of all possible studies (Fig. 1).

IMS description

This syndrome was described in patients who develop proximal muscle weakness and cranial nerve lesions after recovery from a cholinergic crisis. It is apparent that all patients who develop such weakness have progressive neuromuscular junction dysfunction since the time of acute exposure. This phenomenon is thought to be due to primary motor endplate dysfunction resulting from prolonged inhibition of AChE. This involves both presynaptic and postsynaptic failures. Patients who develop weakness

Conclusion

Taking collectively, the mechanisms playing the role in induction and progress of IMS in OP poisoning are summarized and drawn in Fig. 2. We can conclude that mechanisms of IMS include prolonged AChE inhibition, muscle necrosis, down regulation or desensitization of postsynaptic ACh receptors, failure of postsynaptic ACh release, and oxidative stress-related myopathy. Toxicokinetic factors, such as a high lipid-solubility, duration of AChE inhibition and metabolite excretion, evolution of

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgment

This paper is an invited review of Prof. Mohammad Abdollahi and the outcome of an in-house non-financially supported study.

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