Acetylcholinesterase Inhibition and the Extrapyramidal Syndrome: A Review of the Neurotoxicity of Organophosphate

NeuroToxicology 22 (2001) 423±427

Review

Acetylcholinesterase Inhibition and the Extrapyramidal Syndrome: A Review of the Neurotoxicity of Organophosphate B.H. Hsieh*, J.F. Deng, J. Ger, W.J. Tsai Division of Clinical Toxicology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC Received 4 December 2000; accepted 15 May 2001

Abstract Organophosphate poisonings are not uncommon, and are the leading cause of death in suicide patients in Taiwan. Acute cholinergic crisis caused by the inhibition of synaptic acetylcholinesterase is the major manifestation of organophosphate poisoning and may cause death within minutes. Delayed neurotoxicities include intermediate syndrome and delayed polyneuropathy have also been described. However, these symptoms may not characterize the complete picture of organophosphate poisoning. Among the 633 patients ever admitted to our hospital with organophosphate poisoning, three patients were found exhibiting impermanent neuromuscular dysfunction, including blepharoclonus, oculogyric crisis, intermittent dystonia, rigidity, and tremor, with two of them developing mask face, dyskinesia and akathisia later, following acute cholinergic crisis. The symptoms appeared within 4 days with the duration ranging from 25 days to 2 months. Other causes of the extrapyramidal syndrome noted on these patients have been excluded, and we consider the extrapyramidal syndrome a possible neurotoxic manifestation of organophosphate poisoning, which is transient, needs no treatment, and may be missed because of the critical condition, in a minority of patients. The mechanism remains to be identi®ed, but may be related to the impediment of the function of acetylcholinesterase to modify nigrostriatal dopaminergic system, which is independent of hydrolyzing acetylcholine. More detailed observation for organophosphate poisoned patients and more studies for the biological functions of acetylcholinesterase including the in¯uence on the nigrostriatal dopaminergic system are needed. # 2001 Elsevier Science Inc. All rights reserved.

Keywords: Insecticide; Organophosphate; Acetylcholinesterase; Extrapyramidal tract; Parkinsonian disorder

INTRODUCTION Organophosphates suppress acetylcholinesterase, and as a result prohibit acetylcholinesterase from breaking down acetylcholine at the synaptic junction. The accumulation of acetylcholine at synaptic junctions then produces acute cholinergic syndrome via continuous neurotransmission. The resulting respiratory muscle weakness, bronchospasm and bronchorrhea may cause death soon. If early intervention by *

Corresponding author. Tel.: ‡886-2-28757525/ext. 207; fax: ‡886-2-28739193. E-mail address: [email protected] (B.H. Hsieh).

administering pralidoxime and atropine with ventilator support is done, most patients will survive the initial cholinergic crisis with few sequelae. For a minority of patients, paralysis of proximal limb muscles, neck ¯exor muscles, respiratory muscles, and various motor cranial nerves may be experienced 1±4 days after poisoning, which has been called intermediate syndrome (Senanayake and Karallidde, 1987). Later, about 2±3 weeks after poisoning, delayed peripheral neuropathy may ensue, which begins with low limb paresthesia and pain and may progress to paresis with an ascending manner (Senanayake and Johnson, 1982). Furthermore, there have been a few case reports describing other atypical neurological manifestations,

0161-813X/01/$ ± see front matter # 2001 Elsevier Science Inc. All rights reserved. PII: S 0 1 6 1 - 8 1 3 X ( 0 1 ) 0 0 0 4 4 - 4

424

B.H. Hsieh et al. / NeuroToxicology 22 (2001) 423±427

including choreo-athetosis, opisthotonos, torticollis, facial grimacing, tongue protrusion, extrapyramidal symptoms and typical parkinsonism (Smith, 1977; Joubert et al., 1984; Joubert and Joubert, 1988; Moody and Terp, 1988; Davis et al., 1978; Senanayake and Sanmuganathan, 1995; Muller-Vahl et al., 1999; Bhatt et al., 1999; Montoya-Cabrera et al., 1999). Among the patients ever admitted to our hospital with organophosphate poisoning, three have developed transient focal dystonia, which was followed by typical parkinsonism in two of them, after acute cholinergic crisis. This unusual presentation of organophosphate poisoning has never been reported before to our knowledge. CASE REPORT Case 1 A 71-year-old female ingested a bottle of yellowishgreen liquid pesticide for committing suicide. Her family soon sent her to a regional hospital where miosis with pupils 1 mm of size, vomiting, confusion, and respiratory failure were noted. She was intubated immediately with ventilator support. Gastric lavage was performed and activated charcoal was given via the NG tube right away. Intravenous atropine and pralidoxime 1 g each were given and then she was transferred to our hospital. On arrival, physical examination revealed confused consciousness, blood pressure 155/82 mmHg, pulse rate 107 min 1, body temperature 368C, pupils 2 mm of size with prompt light re¯ex, and neck stiffness. Breathing sounds were clear and bowel sounds normoactive. There was no obvious sweating. RBC and plasma cholinesterase levels at that time were both 2 UKAT/l (normal ranges of RBC cholinesterase 20±46 UKAT/l, plasma cholinesterase 20±61 UKAT/l). She was transferred to ICU after intravenous infusion of 1 g pralidoxime. Atropine 3 mg per day and pralidoxime 10 g per day continuously were prescribed. After 18 h, she regained her consciousness with clear breathing sounds and normal muscle power, so the endotracheal tube was removed. However, respiratory failure recurred an hour later followed by conscious change. As a result, she was re-intubated. The dose of atropine and pralidoxime were raised to 15 mg per day and 12 g per day, respectively. She developed occasional dystonia of her mouth angles and bilateral upper limbs on the 4th day. And since the next day, intermittent spontaneous dystonia of her face, neck muscle, shoulders and fore limbs was noticed, which could also be induced by

a light knock. Salivation exacerbated and slow hand tremor appeared by degrees. She regained her consciousness again on the 7th day, but rigidity and mask face were noted. Brain CT for ruling out ischemic lesion revealed only slightly enlarged ventricles. She stood the condition without mechanical ventilation since the 22nd day and was transferred out from ICU 2 days later. However, dyskinesia, dysarthria, increased muscle tone with general rigidity, drooling, and mask face persisted, and in the following days cogwheel rigidity, pill-rolling tremor, and postural instability became even more prominent. Spinal tapping was unremarkable. Fortunately, she recovered rapidly with only bradykinesia and shuf¯ing gait left when she was discharged on the 42nd hospital day. We were informed by phone that she totally recovered within a month. Case 2 A 44-year-old male was sent to a regional hospital after ingesting 10 ml monocrotophos for suicide. Nausea, vomiting, and conscious level change with pupils 1 mm of size were noted on arrival. Emergent intubation with ventilator support followed with gastric lavage was performed. Activated charcoal was given via a NG tube. Atropine 2 mg and pralidoxime 500 mg were given soon after. He was then referred to our hospital for further management. At our ER, physical examination revealed clear consciousness, blood pressure 176/81 mmHg, pulse rate 127 min 1, body temperature 35.58C. RBC and plasma cholinesterase levels obtained were 5 and 4 UKAT/l, respectively. He was transferred to ICU immediately. Continuous intravenous atropine and pralidoxime were given with the dose of 10 mg per day and 5 g per day, respectively. About 12 h after intoxication, he developed intermittent focal face dystonia, and soon later neck, shoulder and limbs were involved. General stiffness, tremor, intermittent limb dystonia, tongue protrusion, trismus and facial grimacing were also developed within 3 days. Brain CT scanning revealed no abnormal ®nding. On the 8th day, the endotracheal tube was removed. Unfortunately, acute oculogyric crisis appeared on the 9th day and conscious level change was suspected, so he was intubated again for airway protection. Intermittent general dystonia, especially after a touch, persisted for several days. On the 24th day, he was transferred out from ICU with few sequelae. There was no bradykinesia, gait disturbance, or mask face appearance during the hospitalization. He was discharged with only numbness of ®ngers, but EMG/NCV was

B.H. Hsieh et al. / NeuroToxicology 22 (2001) 423±427

normal. We were told in telephone follow-up that the numbness persisted for only several weeks. Case 3 A 20-year-old girl intentionally ingested a mouthful of organophosphate, methamidophos, and was sent to a regional hospital right away. Gastric lavage followed with activated charcoal was administered. Atropine and pralidoxime were given with the dose of 2 mg and 1 g, respectively, and she was referred to our emergent department. Her consciousness was drowsy on arrival, pupils were of pinpoint sizes, another dose of atropine 1 mg and pralidoxime 500 mg were given after intubation, and she was transferred to ICU for further management. Continuous infusion of atropine 4 mg per day and pralidoxime 8 g per day were administered and the doses were enough to prevent bronchorrhea and muscle fasciculation. RBC and plasma cholinesterase levels were both 2 UKAT/l. She regained her consciousness on the next day, but intermittent dystonia appeared, which seemed to abate after phenytoin therapy. Mask face had been developed since the 6th day, as well as neck rigidity, lead-pipe rigidity of limbs,dysarthria,tremorand bradykinesia,andakathisia. Mechanical ventilation was no more necessary on the same day, and she was transferred to general ¯oor from ICU on the 8th day. Symptoms diminished rapidly. She was able to walk within 2 days but there was still bradykinesia, shuf¯ing gait, and muscle rigidity. She was transferred to another local hospital on the 14th day for subsequent care, when only mild hand tremor and bradykinesia were left. During hospitalization, brain MRI and PET showed normal ®nding, and during OPD follow-up, she had ever complained of numbness of bilateral feet. EMG revealed polyneuropathy. She totally recovered about a month after being discharged. DISCUSSION The organophosphates are a group of toxins that exert their toxicity by inhibiting cholinesterase, including acetylcholinesterase and butyrylcholinesterase. In organophosphate poisoning, the resultant accumulation of acetylcholine within the peripheral synaptic junctions leads to nicotinic and muscarinic symptoms. CNS toxicity, including anxiety, restlessness, ataxia, convulsions, respiratory depression and coma, as well as the atypical neurological manifestations intermediate syndrome and delayed peripheral polyneuropathy, have been observed. Atropine is the physiological antidote of organopho-

425

sphate that can antagonize acetylcholine on muscarinic receptors and in CNS. Oxime is able to regenerate the enzyme acetylcholinesterase within 24±48 h before its aging. Both antidotes seem unable to prevent intermediate syndrome and peripheral neuropathy. Organophosphate pesticides are widely used in Taiwan. According to the collection of the National Taiwan Poison Control Center, there were 2913 telephone consultations for organophosphates poisoning from 1985 to 1999. In all, 633 patients were admitted to our hospital and the agents responsible for the poisonings have been mevinphos in 186 cases, methamidophos in 61, chlorpyrifos in 54, monocrotophos in 14, fenthion in 4, and unknown organophosphates in 102. Most of our patients developed typical cholinergic symptoms only, but the three patients described in this paper drew our attention because of their transient extrapyramidal manifestations and subsequent parkinsonism. All three patients initially developed prominent symptoms of cholinergic crisis including vomiting, diaphoresis, mydriasis, and respiratory failure. The extrapyramidal symptoms appeared within 4 days (4th, 1st and 2nd day, respectively), which were ®rst recognized as facial dystonia, then trunk and limb dystonia, rigidity, coarse tremor, and ®nally, parkinsonism in two of them. The duration of symptoms ranges from 25 days to 2 months. Atropine and pralidoxime were given with suf®cient doses to control respiratory tract secretions and prevent muscle fasciculation. The doses of the antidotes were even raised further for the motor abnormalities, but neither acceptable improvement nor deterioration of the peculiar symptoms was noted. Two patients received re-intubation, one because of early extubation, the other for airway protection. Intermediate syndrome was not observed in any of them, but polyneuropathy developed in the third patient after discharge. No prokinetics were ever prescribed. Only the third patient had ever received two stat doses of neuroleptics haloperidol (5 mg) for controlling agitation when the intermittent dystonia had already appeared. No family history of Parkinson's disease was identi®ed. The causative agents were monocrotophos, methamidophos and an unknown organophosphate. Both RBC cholinesterase and plasma cholinesterase levels were depressed signi®cantly in all of them. All patients received brain CT for ruling out brain lesion and the results revealed no ischemic change. A PET scan for the third patient disclosed a normal result. Searching for the Medline since 1978, we found only a few reports describing extrapyramidal manifestations or parkinsonism complicating organophosphate poisoning (Joubert et al., 1984; Davis et al., 1978; Senanayake

426

B.H. Hsieh et al. / NeuroToxicology 22 (2001) 423±427

and Sanmuganathan, 1995; Muller-Vahl et al., 1999; Bhatt et al., 1999; Montoya-Cabrera et al., 1999; Pullicino and Aquilina, 1989). In these studies, all motor dysfunctions were almost caused by intentional ingestion of large amount of organophosphates except for one case in which the family members were exposed to an organophosphate pesticide fumigated house (Bhatt et al., 1999) and the crop duster developing Parkinson's disease described by Davis et al. (1978). Some developed extrapyramidal symptoms with antecedent cholinergic crisis, but others did not. Bhatt et al. (1999) also described an interesting ®nding that a patient showed recurrent parkinsonism whenever she re-enter the same house fumigated by organophosphate pesticide, even 2 years after the fumigation. No one in these reports had experienced marked extrapyramidal syndrome with prolonged parkinsonism as noted on our patients. Extrapyramidal syndrome or pure parkinsonism have been noticed in some organophosphate poisoned patients. In fact, cholinesterase inhibitors other than organophosphate pesticides, e.g. tacrine, physostigmine, have also been demonstrated to produce dystonia or parkinsonism either in men or in animals (Summers et al., 1986; Davis et al., 1992; Farlow et al., 1992; Eagger et al., 1991; Knapp et al., 1994; Mayorga et al., 1997; Cousins et al., 1999; Rodriguez et al., 1986; Tolosa and Lai, 1979; Clough et al., 1984). It may not have happened that rarely and may have been masked or neglected because of the critical and isolated condition, or regarded as the intermediate syndrome. In organophosphate poisoning, the resultant imbalance between dopamine and acetylcholine in basal ganglia and substantia nigra should cause extrapyramidal syndrome frequently according to the conventional theory. However, the prevalence rate is quite low. Considering the pathogenesis of the motor dysfunction noted on these patients, Muller-Vahl et al. (1999) speculated that striatal cholinergic interneurons stimulate efferent GABA projections to the globus pallidus externus leading via increased glutamatergic excitation in the subthalamic nucleus to a reduced cortical glutamate stimulation, but he failed to explain why it was rarely seen. Senanayake and Sanmuganathan (1995) proposed that certain organophosphate, i.e. fenthion in their reports, might exert the selective access to the basal ganglia and impair the balance between dopamine and acetylcholine. Nevertheless, only part of fenthion poisoned patients developed extrapyramidal syndrome, and other organophosphates could be the causative agents as well. Considering the intrinsic effects of organophosphate, the inhibition of cholinesterase is not absolutely equal

to that of acetylcholine excess in synaptic junctions. It has been demonstrated that acetylcholinesterase possess speci®c functions other than hydrolyzing acetylcholinesterase. Acetylcholinesterase may modify both the electrical activity of dopaminergic nigrostrial neurons and the associated motor behavior, and thereafter cause the circling behavior in rats with the mechanism unrelated to hydrolyzing acetylcholine (Green®eld et al., 1984, 1988, 1989; Hawkins and Green®eld, 1992, 1992). Several other functions, including promotion of neurite regeneration (Srivatsan and Peretz, 1997; Small et al., 1995), acting as a growth enhancing factor for dopaminergic neurons (Jones et al., 1995), and in¯uencing hemopoiesis (Kalmaz and McDonald, 1981; Samuels et al., 1968), have also been noted. Accordingly, organophosphate pesticides probably will cause cholinergic crisis via over-stimulation of acetylcholine and produce extrapyramidal syndrome secondary to the impairment of other function, i.e. modulation the nigrostriatal dopaminergic system. This explains why some cases reported in the past exhibited parkinsonism without antecedent or concomitant cholinergic syndrome. Just like Parkinson's disease, in which the motor dysfunction is not to become clinically evident until the degenerative process has destroyed 60±80% of the nigrostriatal system (Bernheimer et al., 1973; Guttman et al., 1997), we propose that there is a critical level for acetylcholinesterase in basal ganglia to regulate the dopaminergic system. The level is lower than that being necessary for hydrolyzing acetylcholinesterase. If the functional threshold cannot be maintained then extrapyramidal syndrome ensues. We suggest further that some patients' acetylcholinesterases suffer from speci®c functional de®cits, which may be inherited, so the threshold level of the acetylcholinesterase in these patients will rise, and they are vulnerable to develop extrapyramidal syndrome after the organophosphate poisoning. In this way, we are able to explain the prevalence, duration, reversibility, unresponsiveness to atropine and pralidoxime, and also why some patients reported in the literature presented only parkinsonism without experiencing severe cholinergic symptoms. CONCLUSION Organophosphate insecticide poisoning will induce extrapyramidal syndrome or pure parkinsonism, in some patients. The symptoms may be masked by the nicotinic cholinergic effect, and also the critical and isolated conditions of patients with ventilator

B.H. Hsieh et al. / NeuroToxicology 22 (2001) 423±427

dependence in ICU, and may be regarded as the intermediate syndrome. The toxicological mechanism may involve the impairment of neuromodulating function of acetylcholinesterase. More detailed observation for organophosphate poisoned patients and more studies for the biological functions of acetylcholinesterase including the in¯uence on the basal ganglion are needed, so the clinical toxicity of organophosphate insecticide poisoning can be further delineated. REFERENCES Bhatt MH, Elias MA, Mankodi AK. Acute and reversible parkinsonism due to organophosphate pesticide intoxication: five cases. Neurology 1999;52(7):1467±71. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinsonian Huntington: clinical, morphological and neurochemical correlations. J Neurol Sci 1973;20:415±55. Clough CG, Bergmann KJ, Yahr MD. Cholinergic and dopaminergic mechanisms in Parkinson's disease after long-term Ldopa administration. Adv Neurol 1984;40:131±40. Cousins MS, Finn M, Trevitt J, Carriero DL, Conlan A, Salamone JD. The role of ventrolateral striatal acetylcholine in the production of tacrine-induced jaw movements. Pharmacol Biochem Behav 1999;62(3):439±47. Davis KL, Yesavage JA, Berger PA. Single case study: possible organophosphate-induced parkinsonism. J Nerv Ment Dis 1978;166(3):222±5. Davis KL, Thal LJ, Gamzu ER, et al. A double-blind, placebo controlled multicenter trial of tacrine for Alzheimer's disease. N Engl J Med 1992;327:1253±59. Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer's disease. Lancet 1991;337:989±92. Farlow M, Gracon SI, Hershey LA, et al. A controlled trial of tacrine in Alzheimer's disease. JAMA 1992;268:2523±29. Greenfield SA, Chubb IW, Grunewald RA, et al. A noncholinergic function for acetylcholinesterase in the substantia nigra: behavioural evidence. Exp Brain Res 1984;54(3):513±20. Greenfield SA, Jack JJ, Last AT, French M. An electrophysiological action of acetylcholinesterase independent of its catalytic site. Exp Brain Res 1988;70(2):441±4. Greenfield SA, Nedergaard S, Webb C, French M. Pressure ejection of acetylcholinesterase within the guinea-pig substantia nigra has non-classical actions on the pars compacta cells independent of selective receptor and ion channel blockade. Neuroscience 1989;29(1):21±5. Guttman M, Burkholder J, Kish SJ, et al. [11C]RTI-32 PET studies of the dopamine transporter in early dopa-naive Parkinson's disease: implications for the symptomatic threshold. Neurology 1997;48:1578±83. Hawkins CA, Greenfield SA. Non-cholinergic action of exogenous acetylcholinesterase in the rat substantia nigra. Part I. Differential effects on motor behaviour. Behav Brain Res 1992;48(2):153±7. Hawkins CA, Greenfield SA. Non-cholinergic action of exogenous acetylcholinesterase in the rat substantia nigra. Part II. Long-term interactions with dopamine metabolism. Behav Brain Res 1992;48(2):159±63.

427

Jones SA, Holmes C, Budd TC, Greenfield SA. The effect of acetylcholinesterase on outgrowth of dopaminergic neurons in organotypic slice culture of rat mid-brain. Cell Tissue Res 1995;279(2):323±30. Joubert J, Joubert PH. Chorea and psychiatric changes in organophosphate poisoning. S Afr Med J 1988;74:32±4. Joubert J, Joubert PH, van der Spuy M, van Graan E. Acute organophosphate poisoning presenting with choreo-athetosis. J Toxicol Clin Toxicol 1984;22(2):187±91. Kalmaz GD, McDonald TP. Effects of antiplatelet serum and thrombopoietin on the percentage of small acetylcholinesterasepositive cells in bone marrow of mice. Exp Hematol 1981;9(10):1002±10. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA 1994;271:985±91. Mayorga AJ, Carriero DL, Cousins MS, Gianutsos G, Salamone JD. Tremulous jaw movements produced by acute tacrine administration: possible relation to Parkinsonian side effects. Pharmacol Biochem Behav 1997;56(2):273±9. Montoya-Cabrera MA, Escalante-Galindo P, Rivera-Rebolledo JC, Higuera-Romero F, Hernandez-Gutierrez V. Acute methyl parathion poisoning with extrapyramidal manifestations not previously reported. Gac Med Mex 1999;135(1): 79±82. Moody SB, Terp DK. Dystonic reaction possibly induced by cholinesterase inhibitor insecticides. Drug Intell Clin Pharmacol 1988;22:311±2. Muller-Vahl KR, Kolbe H, Dengler R. Transient severe parkinsonism after acute organophosphate poisoning (letter). J Neurol Neurosurg Psych 1999;66(2):253±4. Pullicino P, Aquilina J. Opsoclonus in organophosphate poisoning. Arch Neurol 1989;46(6):704±5. Rodriguez LA, Moss DE, Reyes E, Camarena ML. Perioral behaviors induced by cholinesterase inhibitors: a controversial animal model. Pharmacol Biochem Behav 1986;25(6):1217±21. Samuels AI, Moller L, Fisher JW. Effects of acetylcholinesterase on erythropoiesis in polycythemic and mildly plethoric mice. Ann N Y Acad Sci 1968;149(1):406±8. Senanayake N, Johnson MK. Acute polyneuropathy after poisoning by a new organophosphate insecticide. N Engl J Med 1982;306:155±7. Senanayake N, Karallidde L. Neurotoxic effects of organophosphorus insecticides: an intermediate syndrome. N Engl J Med 1987;316:761±3. Senanayake N, Sanmuganathan PS. Extrapyramidal manifestations complicating organophosphorus insecticide poisoning. Hum Exp Toxicol 1995;14(7):600±4. Small DH, Reed G, Whitefield B, Nurcombe V. Cholinergic regulation of neurite outgrowth from isolated chick sympathetic neurons in culture. J Neurosci 1995;15(1 Pt 1):144±51. Smith DM. Organophosphorus poisoning from emergency use of a hand sprayer. Practitioner 1977;218:877±83. Srivatsan M, Peretz B. Acetylcholinesterase promotes regeneration of neurites in cultured adult neurons of aplysia. Neuroscience 1997;77(3):921±31. Summers WK, Majovski LV, Marsh GM, et al. Oral tetrahydroaminoacridine in long-term treatment of senile dementia: Alzheimer type. N Engl J Med 1986;315:1241±45. Tolosa ES, Lai C. Meige disease: striatal dopaminergic preponderance. Neurology 1979;29(8):1126±30.