Abstract
This article presents a systematic review of the recent literature on the scientific support of electromyography (EMG) and nerve conduction velocity (NCV) in diagnosing the exposure and toxicity of organophosphorus pesticides (OP). Specifically, this review focused on changes in EMG, NCV, occurrence of intermediate syndrome (IMS), and OP-induced delayed polyneuropathy (OPIDN) in human. All relevant bibliographic databases were searched for human studies using the key words “OP poisoning”, “electromyography”, “nerve conduction study,” and “muscles disorders”. IMS usually occurs after an acute cholinergic crisis, while OPIDN occurs after both acute and chronic exposures. Collection of these studies supports that IMS is a neuromuscular junction disorder and can be recorded upon the onset of respiratory failure. Due to heterogeneity of reports on outcomes of interest such as motor NCV and EMG amplitude in acute cases and inability to achieve precise estimation of effect in chronic cases meta-analysis was not helpful to this review. The OPIDN after both acute and low-level prolonged exposures develops peripheral neuropathy without preceding cholinergic toxicity and the progress of changes in EMG and NCV is parallel with the development of IMS and OPIDN. Persistent inhibition of acetylcholinesterase (AChE) is responsible for muscle weakness, but this is not the only factor involved in the incidence of this weakness in IMS or OPIDN suggestive of AChE assay not useful as an index of nerve and muscle impairment. Although several mechanisms for induction of this neurodegenerative disorder have been proposed as were reviewed for this article, among them oxidative stress and resulting apoptosis can be emphasized. Nevertheless, there is little synchronized evidence on subclinical electrophysiological findings that limit us to reach a strong conclusion on the diagnostic or prognostic use of EMG and NCV for acute and occupational exposures to OPs.
Keywords
Introduction
Organophosphorus pesticides (OPs) are most widely used insecticides 1,2 because of their low acute mammalian toxicity in comparison with other kinds of pesticides but reports on harmful effects of these chemicals in different organs have increased in recent years. 3 Acute OP poisoning, with high morbidity and mortality, mostly occurs after a suicidal attempt through oral ingestion, whereas chronic exposure usually follows inhalational or dermal exposures. These toxins are mainly an inhibitor of acetylcholinesterase (AChE) in the central and peripheral nervous system. OPs can smoothly pass through the blood–organ barriers and enhance the acetylcholine (ACh) level at the neuromuscular junction. The maximum inhibition of AChE activity is usually obtained 3 h postexposure, lasts for more than 72 h, and then recovers within few days. The neurotoxic effects of acute exposure to OP occur in three successive clinical stages: acute cholinergic crisis, intermediate syndrome (IMS), and OP-induced delayed polyneuropathy (OPIDN). 2,4 The IMS and OPIDN occur 24–96 h and 1–3 weeks postacute poisoning, respectively. The OPIDN can develop within months or years after acute and chronic poisoning without any significant change in the AChE activity. Persistent inhibition of AChE is responsible for muscle weakness, but this is not the only factor involved in the incidence of this weakness in IMS or OPIDN. Therefore, AChE assay cannot provide a sensitive index of functional impairment of nerve and muscle. 5
Respiratory muscle dysfunction in acute OP poisoning is one of the major causes of death. As OP poisoning may lead to the occurrence of muscular paralysis, electromyography (EMG) has been proposed as a diagnostic test in clinic but its value is under debate. There are many studies in this respect that are summarized in Table 1. Electrodiagnostic hallmarks of muscle weakness in IMS include the electrical stimulus-induced repetitive and decremental responses, tetanic fade, and a decrement–increment response at higher frequencies of repetitive nerve stimulation (RNS). 23 Normal nerve conduction velocities (NCVs) and distal latency have also been reported. 24 The nature of failure of neuromuscular transmission (NMT) observed in IMS includes presynaptic feedback that may reduce release of ACh or desensitize postsynaptic ACh receptor (AChR) because of the continual stimulation of nicotinic receptors. 25
Nerve conduction studies after acute, subacute, and chronic exposure to OPs.a
OP: organophosphate; Cont.: control group; exposed: exposed group; ND: not done; MNCV: motor nerve conduction velocity (m/s); SNCV: sensory nerve conduction velocity (m/s); AP: action potential (mv); U: ulnar; S: sural; M: median; P: peroneal; T: tibial; AP: adductor pollicis; ADM: abductor digiti minimi; APB: abductor pollicis brevis; EDB: extensor digitorum brevis.
aValues in parentheses indicate the normal range.
bAcute.
cMild exposure.
dSevere and moderate exposure.
eChronic.
fOccupational exposure.
gSubacute.
Methods
All the bibliographic databases were searched using the key words “organophosphorus or organophosphorous or organophosphate poisoning”, “electromyography”, and “muscles disorders” during 1970–2012. The relevant articles cited in the retrieved publications were also scrutinized in full text and read. The aim of the study was to collect all data published about EMG changes following exposure to OP and conduct a meta-analysis on the diagnostic usefulness of EMG.
Results and discussion
Intermediate syndrome
IMS as a nondepolarization paralysis is observed after recovery from severe cholinergic signs of initial depolarization. The IMS was initially described in 1970 as a syndrome not common to occur after moderate and chronic exposures. 6 The NMT is not common in the first 24 h (the early stages of intoxication) but its chance to occur increases post 48 h. 26 According to the reports, the incidence of IMS ranges from 7.7% 27 to 84%, 28 and it is not evident in every patient with severe signs of AChE inhibition. Although IMS is well recognized as a disorder of neuromuscular junctions, its etiology, incidence, and risk factors are not clearly understood yet.
Reduction in functioning of AChR and failure of ACh release are usually seen in IMS, but there are individual variations in occurrence of NMT defects. Delayed metabolism of OP, organ dysfunction, seriousness of poisoning, and muscle disturbances are other contributive factors. 25 The markers of muscle function such as creatine phosphokinase and lactate dehydrogenase increase in IMS. 29 Interestingly, several studies have shown that applicable therapy with atropine and oxime can reduce the incidence of IMS. 30 –32 Incidence of IMS after exposure to OP with the dimethyl phosphate moiety such as fenthion, dimethoate, monocrotophos, dichlorvos, and methylparathion has been reported high but it is not an absolute rule as IMS has been reported in poisoning with parathion (ethyl phosphate) or methamidophos. 25 In addition, oxidative cellular damage and disorders of glucose metabolism inside the muscle tissues cannot be ignored. 25,33 –37 However, the nature of the NMT failure observed in IMS includes presynaptic feedback and postsynaptic receptor desensitization. 38 The aberrations of NMT occurring in about 75% of OP-poisoned patients make physicians to use mechanical ventilation. In a study, the decremental response and absence of post-tetanic facilitation were shown in 85% of OP-exposed cases, whereas abnormal sensory NCV and simple repetitive responses were observed in 10% and 50% of patients, respectively. Lessening in motor NCV, prolonged distal latency, and repetitive and decrement–increment responses were reported with RNS (30 Hz and 50 Hz). 23,39 Low-frequency RNS, in mild intoxication, did not reveal changes in the amplitudes of the compound muscle action potential (CMAP) but high-frequency RNS (30 Hz and 50 Hz) led to incremental responses in 62%, decremental responses in 17%, or decremental–incremental responses in 21% of total cases. In severe intoxication with overt neuromuscular weakness, without requiring mechanical ventilation, decremental responses were noted in only 9% of patients at low frequency RNS and in 97% of cases with high rates of stimulation. About 60% to 100% of patients who required mechanical ventilation showed decremental responses. 38 A progressive decrement in the amplitudes of CMAP was shown by RNS in 30 Hz, 40 which can be an indicative of impending respiratory failure. 39
The neurophysiological study of the IMS demonstrated that the IMS is a neuromuscular junction disorder that can be characterized by repetitious response after a single stimulus and decrement–increment responses, and severe decrement in response to repetitive stimulation.
OP-induced delayed polyneuropathy
After acute exposure
Several studies on farmers, 41 –45 rescued workers, 46 and individuals identified from hospitals with acute OP-poisoning history 47 –49 have shown that OP poisoning has additional long-term effects. These permanent damages include deficits in cognitive and psychomotor function, reduction in vibration sensitivity, and motor and sensory dysfunction. OPIDN is a unique toxicological phenomenon with a scarce clinical condition that usually appears after 10–20 days or later of a single exposure to OP when AChE inhibition has been recovered, and the patient has been discharged from the hospital. 50 It is characterized by ataxia and a distal paresis in inferior limbs. Fifteen days after dichlorvos poisoning, EMG abnormalities were characterized by an axonal degeneration-type polyneuropathy in inferior limbs and pyramidal tract dysfunction, observed later in upper limbs, proposed involvement of both peripheral and central nervous systems in this polyneuropathy. 50 Neurophysiological findings of OPIDN are positive sharp waves, normal sensory NCV, normal or minimally abnormal motor NCV, prolonged distal latencies, and low amplitude in the motor action potential. 7,19,51 The reduced amplitude of CMAP, delayed terminal motor latencies, and slightly reduced motor NCV were also reported, 52 –54 especially after severe exposure (3 Hz, 10 Hz, and 30 Hz). 7 Fourteen days following acute poisoning with methamidophos, a reduction in amplitude of the ulnar CMAP and sensory NCV was observed. 14 These abnormalities indicate partial denervation of the affected muscles with degeneration of axons, especially in myelin sheaths. 55 The sensory and motor dysfunctions were more significant in the lower limb than that of upper limbs. Data also indicate that in OPIDN, sensory nerves are affected more than motor nerves. 21,56
Postchronic exposure
Although OPIDN occurs most commonly after an acute exposure, it can be seen after chronic exposure as well, which is called chronic OPIDN (COPIDN). 57,58 The occupational exposure of humans usually leads to neurotoxicity in which several other mechanisms, apart from AChE inhibition, play pivotal roles. 6,59,60 Of course, in highly exposed cases, inhibition of AChE takes place. 61 An association between altered peripheral nerve function and previous OP exposure has been found in a cohort epidemiological study that used a vibration sensitivity test. 18 Although any evidence of peripheral neuropathy or muscle weakness have not been found in clinic, there are evidences of subclinical neuropathy and slowed motor NCV. 12,48,62 Electrodiagnostic studies have shown a significant decline in motor and sensory NCV among those studied. The slowed peripheral NCV was not related to AChE inhibition in users of OP and carbamate compounds. 63 A slight reduction in sensory NCV in seven workers and an increased fiber density in four workers were shown, of course, without inhibition of AChE. 11 The relatively low-level dichlorvos exposure caused some alterations in all the investigated EMG parameters. In a subclinical study, reduction in median and peroneal motor NCV and sural sensory NCV was reported. 64 The records from OP workers have shown some degree of repetitive activity, depression of the first potential after voluntary activity, and lower amplitude of CMAP. 6 The reduction in CMAP and motor NCV was found in 10% of subjects. 64 Repetitive activities were shown in 40% of pesticide’s workers, even though reduction in AChE activity was not observed. 60,65 In another study, 61 no significant alteration in neurophysiological parameters immediately after fenthion exposure was observed but 3-week follow-up proved disturbances in the functioning of peroneal motor nerve. About 29% of workers showed repetitive muscle activity, while sensory NCV was normal. 14 Prolonged distal latencies are among the earliest manifestations of a toxic axonopathy. 16 Some researchers concluded that exposure to low-level OP is not always associated with impaired peripheral neurophysiological function. 15,59 In volunteers who ingested mevinphos for 1 month, no effect on NMT was observed and the amount of AChE inhibition was 19%. 10 Supporting this finding, a cross-sectional study in the Washington state revealed that exposure of farmers to low levels of OP during one season was not associated with impaired peripheral neurophysiological function. 66 The motor and sensory NCV and distal latencies of the sural and median nerves were within normal ranges in those exposed to fenthion. 12 Engel et al. have observed that ulnar motor NCV did not significantly become lower than reference values 15 and the amplitudes of the CMAP were normal. 67 No specific abnormalities were observed in peripheral NCV tests in chronically exposed farmers. 17,68 Long-term OP exposures did not cause sensory neuropathy or peripheral abnormalities 17,69 and there were no significant differences between OP applicators and the combined nonexposed group for peroneal, ulnar, and sural NCV. 70
Conclusions
Taken collectively, OPs are very toxic to the peripheral nervous system at both acute and chronic exposures. Although several mechanisms for induction of this neurodegenerative disorder have been proposed as were reviewed for this article, but among them oxidative stress and resulting apoptosis can be emphasized. This kind of neurodegenerative damage is observed mostly upon exposure to high doses of OP through necrosis and cell death inside the brain in acute cases. 58 Peripheral nerves axonal degeneration 71 and the decrease in cytoskeletal proteins are related to this delayed neurotoxicity. 72 The survivors of triorthocresyl phosphate poisoning have shown a good recovery from the peripheral nerve disorder 1–2 years after OP ingestion, but not from the pyramidal tract lesions, because the recovery capability of the central nervous system is too poor. Shifting from initial peripheral lesions to spinal lesions has been raised as a hypothesis regarding the cause of this predominant neuropathy. 73 Some authors have noted that the measurement of blood AChE is not sensitive enough to detect subclinical impairment of NMT and cannot be a good predictor of OP poisoning, specifically, after low-level chronic exposures. 11,56 This can be explained by differences existing between times of recovery of this enzyme in various tissues 8 and inconsistency of blood AChE inhibition. 74
As a matter of fact, a measurable occupational exposure is crucial to the interpretation of any epidemiological studies. 75 In this way, electrodiagnostic studies can help provide some sort of evidence to improve diagnosis of exposure to OP and efficacy of antidotes such as oximes or atropine. 62,67,76,79 EMG data such as prolonged and repetitive end plate potential or a combination of both can account for the weakness and physical disability in acute OP poisoning. The absence of post-tetanic facilitation suggests that a postsynaptic defect can be the cause of paralytic symptoms. The decrement–increment responses at RNS are indicative of a depolarization block due to inactivation of AChE at the motor end plate. The deductions in amplitude of the action potential with normal NCV are suggestive of the anterior horn cell lesion because these cells contain nicotinic AChR. 7 The lesion at anterior horn cells cannot explain the slower NCV in motor nerves related to the cholinergic link between the squid axon and its surrounding Schwann cells. 80 Another possible reason for reduced EMG voltage is an increase in the temporal dispersion of the various components of the CMAP due to a reduction in motor NCV. 8 The upper limbs NCV is higher than inferior limbs because of the greater length of the nerves in inferior limbs that ends up with more damage. 22 Nerve fibers with a smaller diameter are also affected more than large fibers. 81
Among all the studies included in the present review, only in seven studies dichotomous results were reported that were eligible to be included in the meta-analysis (one clinical trial 66 and others were observational studies 6,8,9,18,22,68 ). The effects of OP on motor and sensory nerves in distinct positions have been reported separately for acute and chronic exposures. In acute exposures, outcomes of interest such as motor NCV and EMG amplitude were reported at different positions of motor ulnar 6 and motor upper and lower limbs 82 that caused heterogeneity, which is explainable. Thus, meta-analysis could not be useful for acute poisoning. However, meta-analysis for the outcomes of latency, EMG amplitude, sensory NCV, and motor NCV in prolonged exposure was possible. 18,68,80 Primary evaluation of data in lasting exposure indicated that no more precise estimation of effect is achievable by meta-analysis compared to individual studies. Therefore, the authors decided not to use meta-analysis in chronic cases as well. Taking these studies, it is concluded that there is inadequate evidence on subclinical findings during occupational exposures and specifically since this kind of studies is technically difficult, so some kinds of mistakes are expected such as improper electrode placement, movement of the electrodes during stimulation, change in skin resistance, intramuscular temperature, type of the amplifier, and filter settings. All these mistakes can cause false positive or possibly negative results. It is particularly difficult to use the absolute amplitude for comparison between recordings on different occasions. 11 Among the published studies, exposure assessment was almost always missing. In electrodiagnostic tests, other variables, particularly age, sex, and temperature of limb, should be considered. Future studies should focus to improve the assessment of pesticide’s exposure in individuals and consider the role of genetic susceptibility. The relationship of pesticide’s neurotoxicity with neurodegenerative disease and even other incapacitating chronic ailments is other unresolved issues. 83,84 However, the role of alcohol or any other chemical substances in acceleration or reduction in human toxicity remains unknown and should be further studied.
Footnotes
Acknowledgment
This article is the outcome of an in-house solicited review study. The authors acknowledge the assistance of Iran National Science Foundation (INSF) and Tehran University of Medical Sciences (TUMS).
Conflict of Interest
The authors declared no conflicts of interest.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.