Mahmoud K. Elguindi et al.

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1 Mahmoud K. Elguindi et al. Electroneurophysiological Monitoring as an Early Severity Predictor in Acute Anticholinesterase Poisoned Patient and the Effect of Oxime Therapy Manipulation Mahmoud K. Elguindi 1, Heba M. Halawa 2, Iman M. Bayoumy 3 Departments of Poison Control Center 1, Forensic Medicine and Clinical Toxicology 2, Neurology 3, Ain Shams University Hospitals ABSTRACT Introduction: The neuromuscular transmission failure in acute anticholinesterases (e.g. organophosphorus compounds and carbamates) poisoning occurs because of inactivation of the enzyme acetylcholinesterase located in the neuromuscular junction, and is distinguished by single electrical stimulus induced repetitive responses and decrement response upon high rate repetitive nerve stimulation (RNS). Oxime therapy with its action at different sites in the neuromuscular junction would alter the neuroelectrophysiological findings in acute anticholinesterases poisoning. The aim of this study is to evaluate the usefulness of RNS as a prognostic indicator of severity in acute anticholinesterase poisoning and the recovery process and its use as a guide for oxime therapy continuation or discontinuation. Subjects and Methods: The study was conducted on 32 patients with acute organophosphorus poisoning admitted to the poison control center, Ain Shams University Hospitals during the period from January 2007 to June 2007.Patients were subdivided into group I (mild group n=6), group II (moderate group n=20), and group III (severe group n=6). All the cases were clinically evaluated, pseudocholinesterase levels were estimated and RNS was done before and after oxime therapy. Results: The patients were classified according to the decremental response into 3 categories, type 1 response(initial improvement and subsequent lack of improvement),type 2responce(Initial improvement and subsequent normalization of neuromuscular transmission)and type 3 response (lack of improvement with initial dose of toxogonin). In conclusion RNS is a sensitive prognostic test which can be used as an early predictor of acute anticholinesterase poisoning for grading its severity, and assessment of obidoxime (Toxogonin) therapy. As therapeutic benefit of obidoxime is limited by its short duration of action, it is recommended to be administered for a longer period of time under neuroelectrophysiological guidance. (Egypt J. Neurol. Psychiat. Neurosurg., 2008, 45(2): ) INTRODUCTION Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available 1. The total area of agricultural land in Egypt is around 7.6 million feddans. Working in agricultural field is about 34% of the total employment. Several pesticides including, organochloride, organophosphorus, carbamate, and pyrethroid insecticides, fungicides, and herbicides are commonly used in citrus, vegetable and other cropgrowing areas to increase agricultural productivity 2. Anticholinesterases (e.g. organophosphorous (OP) compounds and carbamates) are irreversible inhibitors of the enzyme acetylcholinesterase (AchE), binding of esteratic site of the enzyme. They inhibit both cholinesterase and pseudocholinesterase activity, causing accumulation of acetylcholine (Ach) at synapses with resultant over stimulation of neurotransmission 3. The clinical features are due to excess Ach at the muscarinic and nicotinic receptors with initial stimulation, and then exhaustion of cholinergic synapses. There are three phases in Anticholisnesterase toxicity. Acute cholinergic crises (first 48-72hs), intermediate syndrome (IMS) and delayed polyneuropathy 4. The acute cholinergic phase, is the most serious, usually passes off within 48-72hs but complete clinical recovery may take up to a week. Treatment is supportive with oximes, 443

2 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 atropine and mechanical ventilation in addition to gastric decontamination 5. Obidoxime is the antidote of choice in cases of Anticholinesterases toxicity. It is known to antagonize the effects of Anticholinesterases at the neuromuscular junction 6. In the present study neuroelectrophysiological monitoring of patients with Anticholinesterases poisoning will be evaluated and the decrement response of patients after oxime therapy will be reported. Electrophysiological monitoring using repetitive nerve Stimulation (RNS) is suggested to predict the clinical outcome of cases of Anticholinesterases poisoning. A number of conflicting studies were found about the neuroelectrophysiologic changes during Anticholinesterases toxicity reporting decrement response at low frequency (3hz) suggesting a postsynaptic defect 7. However, Wadia et al. (1987) 8, found no decremental response at low and intermediate frequency (3,10 Hz) but only at high frequency (30Hz). Other studies 9,10 showed decrement response at intermediate frequency. In view of these conflicting studies we designed to study the neuroelectrophysiological changes by using repetitive nerve stimulation (RNS) in patients with anticholinesterases poisoning in an attempt to find out its usefulness as a guide for the treating physician during oxime therapy. The test will be used to predict the severity of poisoning, the duration of therapy, and in addition to assess the development of intermediate syndrome and delayed polyneuropathy. SUBJECTS AND METHODS Subjects: This study was conducted on 32 patients diagnosed as organophosphate poisoning, admitted in the poison control center, Ain Shams University in the period between January 2007 and June Methods: Inclusion Criteria: (i) History of oral ingestion or dermal exposure to an Anticholinesterases. (ii) Characteristic symptoms and signs of muscarinic and nicotinic stimulation. (iii) Reduced level of serum cholinesterase levels (using the calorimetric method). Exclusion Criteria: (i) Patients on mechanical ventilation due to difficult transfer of the patients from the poison control center to the neurology department. (ii) Other factors that decrease serum cholinesterase levels as pregnancy, hepatic disease, malnutrition and metastatic carcinoma 11. Patients were subjected to: 1. Clinical evaluation: a. Complete history taking with special stress on the mode of poisoning and the period between intoxication and hospitalization. b. Thorough clinical examination stressing on symptoms and signs of muscarinic and nicotinic stimulation.the patients were examined for any change in the pupil size, vital signs (heart rate, respiration, blood pressure and temperature), skin manifestations. Special focus was done on the neurological manifestations as muscular weakness, easy fatigue, fasciculations, hypotonia, coma and convulsions, in addition to other muscarinic symptoms as salivation lacrimation, bronchorrhea, gastrointestinal and urinary symptoms. 2. Laboratory investigations: The level of serum cholinesterase was estimated by using calorimetric method according to Waber 12 (normal level u/l). 3. Neuroelectrophysiological studies: The 2 Mk conter point DANTEK amplifier system was used to estimate distal latency, conduction velocity and to perform repetitive nerve stimulation test (RNS) of the median, ulnar, common peroneal and posterior tibial nerves conduction studies. Train of a supramaximal stimuli delivered at 3, 20 and 30 Hz (low, intermediate and high speeds respectively) were used. RNS test was performed before, 30 minutes after toxogonin intravenous 444

3 Mahmoud K. Elguindi et al. administration and then every 24 hours till recovery or failure of response. The median compound muscle action potential (MAP) amplitude (base to negative peek). The presence or absence of repetitive response and the ratios of the amplitude of the fifth response to the first CMAP response during (RNS) at 3, 20 and 30 Hz were noted. This ratio effectively measure the derangement produced by Anticholinesterase toxicity Obidoxime dosage and duration of therapy: Toxogonin was given to the patients in a dose ranging from 1 to 10 intravenous ampoules, according to clinical response (each ampoule contains 250 mg obidoxime). Neuroelectrophysiological studies were performed before, 30 minutes and then daily after obidoxime intravenous injection. Treatment with further doses of obidoxime depends upon the initial response of the patient. If the initial dose is not associated with any improvement in the decrement response no further doses were given. On the other hand, if the initial dose, produced clinical improvement and decrease in the decremental response, the dose was continued (by i.v drip 750 mg/24h). Daily treatment was continued until neuroelectrophysiological tests failed to demonstrate any benefit of administration of obidoxime or return to normal. The treatment comprised the coadministration of atropine and obidoxime in an initial dose of 1amp in all patients. Neuroelectrophysiological studies were performed before and after oxime therapy. The patients were classified according to Ellenhorn et al. 14 into 3 groups: - Group A: Mild poisoning (n=6): The patients had mild cholinergic signs few spontaneous fasciculation and no obvious weakness during the course of illness. - Group B: Moderate poisoning (n=20): The patients had miosis, muscular weakness moderate cholinergic symptoms and fasciculation. - Group C: Severe poisoning (n=6): The patients had severe weakness, flaccid paralysis, pulmonary crepitations, cyanosis, coma grade I, bradycardia and autonomic disturbances. Statistical Analysis: Data collected were tabulated & introduced to PC for statistical analysis. Data analysis were performed using the 11 th version of SPSS (Statistical Package for Social Sciences). Qualitative data is presented in form of frequency tables (number and percent), while quantitative data is presented in the form of mean ± standard deviation. The statistical tests used included independent sample t-test, and Freidman test. RESULTS The studied groups of patients include 14 males and 18 female aged between 6 and 46 years (mean age 20.2 years). All cases were suicidal attempts except one who was accidental poisoning. The patients were subdivided into three groups according to the severity of clinical findings. Group A mild poisoning (n=6): The mean pseudocholinesterase level on admission was 970.5±87.3 then increased to ±361.7 on the 3rd day.the mean delay time was 3.6±2.1 hours and the mean atropinization dose 3.1±1.4 mg. Group B moderate poisoning (n=20): The mean pseudocholinesterase level was 318.3±68.4 on admission and increased to ±217.4 on the 3 rd day. The mean delay time was 6.6±3.2hours and the mean atropinization dose 7.1±2.7 mg. Group C severe poisoning (n=6): The mean pseudocholinesterase level on admission was 188±71.3 and increased to 857.8±95.11 by the 3 rd day. The mean delay time was 7.6±4.2 hours and the mean atropinization dose 18.3±5.9 mg. Clinical Manifestations Hypothermia was found in 53% of the cases especially in the moderate and severe cases. Hypotension was observed in 44% of the cases especially in the severe cases while hypertension was observed only in 6% of the cases. Also bradycardia was more common than tachycardia being observed in 62.5% of the cases. Tachypnea and bronchorrhea were more commonly observed than bradypnea being 44%, 37.5% and 28% of the cases respectively. Miosis was observed in 87.5% of the cases. Skin manifestations as pallor and sweating was observed in 47% and 50% of the cases (Table 1). 445

4 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 Neurological manifestations as easy fatigability, weakness, hypotonia and fasciculations were the commonest to be observed especially in the moderate and severe cases while coma and delayed neuropathy were the least to be observed. All patients had nausea, vomiting and diarrhea. Abdominal colic was very common as it occurred in 94% of the cases. The occurrence of Intermediate syndrome with recurrence of cholinergic manifestations was noticed in 16% of the cases with higher incidence in the severe group (Table 2). Neuroelectrophysiological Studies RNS test was performed for all cases just before, after 30 minutes of toxogonin initial dose then every 24 hours till recovery.in this study median, ulnar, common peroneal and posterior tibial nerves conduction were studied at 3, 20 and 30 Hz. The decremental response of the patients was classified into 3 categories according to their initial improvement and /or in response to cholinesterase reactivation by toxogonin. - Type 1 response: (Initial improvement and subsequent lack of improvement) was observed in 5 patients who had high decremental responses to high rate stimulation (30 Hz). The decrement responses returned to normal following toxogonin therapy. Toxogonin induced neuroelectrophysiologic improvement during the subsequent 2 days with parallel clinical improvement. On the 3 rd day these 5 patients developed recurrence of cholinergic symptoms with increased sweating, salivation and bradycardia (intermediate syndrome). Despite amelioration of the decrement test in 2 cases, toxogonin was given for another 24 hours. On the 4 th day of intoxication both clinical deterioration as well as mild increase in decremental response to (30 Hz) RNS were observed (Fig. 4 a, b, c, and d). Therapy with toxogonin was subsequently discontinued. - Type 2 response: (Initial improvement and subsequent normalization of neuromuscular transmission) was observed in 23 patients. Initial RNS test revealed characteristic abnormalities in the form of decrement responses first at 30 followed by 20 then 3 HZ, improved after toxogonin therapy. Toxogonin in these cases was continued for another hrs and RNS tests continued to improve (Fig. 5 a, b, c, and d). No further doses of toxogonin were given. None of these patients had severe toxicity or required mechanical ventilation. There was good clinical neurophysiologic concordance. In these cases; fasciculations, muscular weakness and other symptoms which were noted upon clinical examination, disappeared after the initial dose of toxogonin. - Type 3 response: (lack of improvement after the first dose) was observed in 4 cases. Initial dose of toxogonin on day 2 and 4 (due to delayed presentation of the patient) failed to produce neurophysiologic amelioration in these cases. The repetitive response persisted and 30 Hz RNS produced mildly worse decrement after therapy. Follow up of these cases revealed delayed polyneuropathy 2-4 weeks later (OPIDN). Assessment of Severity: Decrement response (decrease in amplitude of the fifth response to the first CMAP during RNS) occurred at the period of severest weakness in each case. In severe cases it was marked at 30 Hz stimulation only with decrement more than 50%. In moderate cases the decrement was marked at the height of their weakness at 3 and 30 Hz stimulation, with decrement (30 50 %). In mild cases no or only slight decremental response (10-30%) was evident at 30 Hz and also at 3 HZ stimulation (Table 3). The decremental response of the PMAP in moderate cases evolved a consistent fashion during the course of intoxication i.e. the degree of decrement increased or decreased with the respective worsening and improvement of weakness. All the patients reached the maximum decrement 8 45 hours after intoxication. At this time the CMAP was abolished after a few stimuli with high frequency stimulation (30 Hz) while at low stimulation (3HZ) only a decline in PMAP occurred. Slow recovery had occurred hours later (first low and later high frequencies of stimulation). It was also noted that the posterior tibial and median nerves showed more mean values of percentage of decremental response than the common peroneal and ulnar nerves (Table 3). Statistically significant decrease in the percentage of decrement test was noticed 30 minutes 446

5 Mahmoud K. Elguindi et al. after toxogonin treatment, especially in the posterior tibial, median and common peroneal nerves at 30, 20 and 3 Hz stimulation as shown in table (4). There was also statistically significant decrease in decrement test 2days and 4 days after toxogonin therapy in the posterior tibial, median and common peroneal nerves at 30,20and 3 Hz stimulation as shown in tables (5) and (6). Statistical analysis using "Friedman test" to compare the percentage of decrement at 30 Hz before toxogonin, 30 min, day 2 and day 4 after toxogonin in the mild, moderate and severe groups revealed significant improvement in the percentage of decrement test after toxogonin treatment especially in the posterior tibial followed by the median then the ulnar and lastly the common peroneal nerves in the moderate and sever groups (Table 7). Statistical analysis using "Friedman test" to compare the percentage of decrement at 3 Hz before toxogonin, 30 min, day 2 and day 4 after toxogonin revealed statistically significant improvement in the percentage of decrement test after toxogonin only in the moderate group in (the median, ulnar, common peroneal and posterior tibial nerves). While statistically non significant improvement was observed in the percentage of decrement test after toxogonin in the mild and severe groups at low (3 Hz) stimulation (Table 8). Table 1. Autonomic changes in patients. Mild group Moderate group Severe group Total Clinical (n=6) (n=20) (n=6) (n=32) manifestation No. % No. % No. % No. % Hypothermia Hypotension Hypertension Bradycardia Tachycardia Tachypnea Bradypnea Bronchorrhea Miosis Skin Pallor Sweating Table 2. Neurological and gastrointestinal manifestations among the studied patients. Clinical manifestation Mild group (n=6) Moderate group (n=20) Severe group (n=6) Total (n=32) No. % No. % No. % No. % Neurological manifestation Easy fatigue Weakness Hypotonia Fasciculation Coma Delayed neuropathy GIT Nausea and vomiting Abdominal colic diarrhea Intermediate syndrome

6 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 Table 3. Percentage of decremental response before treatment. Mild group Moderate group Severe group Total Nerve Frequency of n=6 n=20 n=6 n=32 examined stimulation Mean±SD Mean±SD Mean±SD Mean±SD ± ± ± ±16.03 Median ± ± ± ± ± ± ± ± ± ± ± ±1.56 Ulnar 20 15± ± ± ± ± ± ± ± ± ± ± ± Com. per ± ±1.4 59± ± ± ± ± ± ± ± ± ±32.69 Post. tib ± ± ± ± ± ± ± ±34.17 com. per. = common peroneal post. tib. = posterior tibial Table 4. Decrement test before and 30 min. after toxogonin treatment in all cases. Nerve Frequency of Total n=32 examined stimulation Before treatment 30 min. after treatment T value P value ± ± Median ± ± ± ± ±1.56 7± Ulnar ± ± ± ± ± ± Com. per ± ± ± ± ± ± Post. tib ± ± ± ± P< 0.05 =significant, com. per.=common peroneal post. tib.=posterior tibial Table 5. Decrement test before and 2 days after toxogonin treatment in all cases. Nerve Frequency of Total n=32 examined stimulation Before treatment 2 days after treatment T value P value ± ± Median ± ± ± ± ± ± Ulnar ± ± ± ± ± ± Com. per ± ± ± ± ± ± Post. tib ± ± ± ± P< 0.05 =significant, com. per.=common peroneal post. tib.=posterior tibial 448

7 Mahmoud K. Elguindi et al. Table 6. Decrement test before and 4 days after toxogonin treatment in all cases. Nerve examined Median Ulnar Com. per. Post. tib Frequency of stimulation Before treatment Total n=32 4 days after treatment T value P value ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± P< 0.05 =significant, com. per.=common peroneal post. tib.=posterior tibial Table 7. Percentage of decrement at 30 Hz before and after toxogonin therapy. Nerve Median nerve Ulnar nerve Common peroneal nerve Posterior tibial nerve * significant difference at level of P 0.05 Group A Mild n = * * * Group B Moderate n = * * 8.20 * * Group C Severe n = * 8.36 * 8.62 * * Table 8. Percentage of decrement at 3 Hz before and after toxogonin therapy. Nerve Median nerve Ulnar nerve Common peroneal nerve Posterior tibial nerve * significant difference at P 0.05 Group A Mild n = * Group B Moderate n = * * * * Group C Severe n =

8 Decrement % Decremental % Decremental % Decremental response to treatment at 3 Hz Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July Decremental response to Decremental response to treatment at 3 HZ trearment at 20 Hz Befor treatment 30 min. after 2 days after 4 days after Fig. (1): Median, ulnar, common peroneal and posterior tibial nerves respectively Befor treatment 30 min. after 2 days after 4 days after 1 Deremental Decremental response response to treatment at 20 HZ to treatment at 30 Hz Fig. (2): Median, ulnar, common peroneal and posterior tibial nerves respectively Decremental response to treatment at 30 HZ Befor treatment 30 min. after 2 days after 4 days after Fig. (3): Median, ulnar, common peroneal and posterior tibial nerves respectively. 450

9 Mahmoud K. Elguindi et al. Decremental response in the posterior tibial nerve Fig. (4a): Type 1 response in a severe case at high rate (30 Hz) before treatment. Fig. (4b): Type 1 response in a severe case at high rate (30 Hz) 30 min. after treatment. 451

10 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 Fig. (4c): Type 1 response in a severe case at high rate (30Hz) on the 2 nd day. Fig. (4d): Type 1 response in a severe case at high rate (30 Hz) on the 4 th day. 452

11 Mahmoud K. Elguindi et al. Decremental response in the posterior tibial nerve Fig. (5a): Type 1 response in a moderate case at low rate (3 Hz) before treatment. Fig. (5b): Type 2 response in a moderate case at low rate (3 Hz) 30 min. after treatment. 453

12 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 Fig. (5c): Type 2 response in a moderate case at low rate (3Hz) on the 2 nd day. Fig. (5d): Type 2 response in a moderate case at low rate (3 Hz) on the 4 th day. 454

13 Mahmoud K. Elguindi et al. DISCUSSION The symptoms and signs of acute anticholinesterases toxicity are classified on the basis of the 3 anatomic sites of cholinesterase inactivation: autonomic ganglia, neuromuscular junction and central nervous system 15,16. Atropinisation is an optimal antidotal measure to counteract the autonomic muscarinic manifestations. 17 However, the management of Anticholinesterases induced neuromuscular transmission defect is largely symptomatic and supportive 18. Pharmacological agents that could prevent or ameliorate the neuromuscular transmission defects may be vitally useful in reducing the costs of treatment and duration of hospitalization in acute Anticholinesterases poisoning 19. Neuroelectrophysiological studies can be used for the objective assessment of the beneficial or adverse influence of such pharmacotherapeutic agents 20. In this study the potential use of obidoxime (toxogonin) which is an acetyl- cholinesterase reactivator in Anticholinesterases intoxicated patients was evaluated guided by the decremental response of the patients 15,18. Our observations suggest that neuroelectrophysiological studies can predict the benefit of obidoxime therapy in acute anticholinesterases poisoning and this was clear in both Type 1 & 2 responses; and suggest that obidoxime should be continued until normalization of neuromuscular transmission or lack of improvement after obidoxime. The role of oximes in the management of acute anticholinesterases poisoning is controversial. Although Cherian et al. 21, suggest that oximes don t favorably affect the outcome based on several parameters including total atropine requirement and the duration of ventilation and hospitalization.however, Besser et al. 22 and Singh et al. 23, studied the effects of obidoxime administration on neuromuscular transmission and noted dramatic neurophysiologic improvement when the drug was administered within the first 12 hours. When administered after 24 hours of intoxication obidoxime produced mild or no improvement or even worsening. Our results were similar in that improvement was most dramatic with the initial doses of obidoxime. Obidoxime produced improvement in 28 cases out of 32, (88.5%) (5cases type cases type 2 response), however this improvement was noticed only in 23 cases (72%) when it was given on the 3 rd and 4 th days. On the other hand type 3 response confirm the lack of usefulness of oxime therapy in 4 cases (12.5%) (who started therapy after the first day) this could be explained by aging of the enzyme Anticholinesterases complex, a chemical reaction involving the removal of an alkyl group from the complex. This process normally occurs hours after poisoning and renders "the aged complex" inaccessible to reactivation and so obidoxime becomes ineffective. The physiologic activity of AchE will be restored only by re-synthesis of new enzyme. This process occurs in both tissue and plasma at varying rates and full restoration takes up to 6 weeks in untreated patient 24,25. Our study reveals that obidoxime results in short term symptomatic improvement, both in clinical and neurophysiologic parameters. Its beneficial effect is 26, 27 limited by a short half life of 2.5 hours The transient benefit is shown by the transient normalization of neuromuscular transmission after oxime therapy, followed by the reappearance of neuromuscular transmission 24 hs later. Longer durations of treatment may provide favorable outcome rather than the conventional single dose treatment within the first hours. Longer treatment duration may be practically useful under two circumstances. One is poisoning with highly lipophilic compound that gets absorbed into adipocyte pool and is released slowly over a period of days. Second is poisoning with very large doses of anticholinesterases with long organophosphorusacetylcholinesterase complex aging half- life as diethylated organophosphates 28. However there are two drawbacks in longer duration of obidoxime treatment. One is that the variations in the aging half life of the different Organophosphate Choline esterase complexes make it difficult to predict the duration for which reactivation therapy is to be given. The second is that the continued administration of oxime in large doses can produce a paradoxical worsening, due to direct depolarizing effect of oximes 29. In view of its benefits and risks, it is recommended that obidoxime therapy should be carried out under neurolectrophysiologic guidance. 455

14 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July 2008 Anticholinesterases intoxication lead to characteristic end plate dysfunctions that reflect the degree of Ach E inhibition and increase in (Ach) concentration at the neuromuscular junction. The phenomena of decrement in response to repetitive nerve stimulation, is important in staging anticholinesterases intoxication. Decrement response (normally 10%) 30 was the most common and severe in grades II and III patients (moderate and severe cases) being (30 50 %) in moderate and (above 50%) in the severe cases. The increasing amount of decrement and the ability to elicit it at low frequency (3 Hz) evolved rapidly hours after oral intoxication in moderate cases, reflecting the dynamics of anticholinesterases absorption from the intestine and transfer to body tissue. Clinical evaluation showed that the maximum weakness and paralysis occured1-3 days after anticholinesterases poisoning. The time course of decrement severity is the neurophysiologic counterpart of clinical weakness. The slow recovery from the maximum decrement reflects the new synthesis of AchE at the motor end plate. Prior studies 8,13,16 did not show clear correlation between the decrement response and the severity and time course of Anticholinesterases intoxication. Although demonstration of serum cholinesterase levels is the most important laboratory study in the initial diagnosis of anticholinesterases intoxication, neurophysiologic studies represent the best method to estimate the degree of toxicity. Serum cholinesterase is markedly decreased early in the course of intoxication and remained so for variable periods of time (up to 6 weeks) serial levels don't allow staging of neuromuscular junction blockade. Endplate dysfunction in Anticholinesterases toxicity reflects the action of high Ach concentration at the nicotinic receptors at the neuromuscular junction.ach receptors are located pre-and post synaptically and can be sensitized and desensitized by changing Ach concentrations, which caused the abnormalities in our patients 31,32. The intermediate syndrome (recurrence of cholinergic symptoms on the 3 rd day of anticholinesterases poisoning) was observed in 5 patients of this study) could be explained by desensitization block (i.e. changing from depolarization to non depolarizing block). This decrement in slow and medium (3 and 20 Hz) frequencies RNS suggests a post synaptic defect 16. The magnitude of anticholinesterases exposure appears to determine the occurrence and severity of intermediate syndrome (IMS). In our study 5 patients with severe toxicity and very low levels of (Ach E) developed (IMS). Actually IMS is not a discrete entity, but a continuum in severe poisoning and perhaps a centrally mediated phenomena 33. In our study 4 cases developed delayed polyneuropathy 2-4 weeks after anticholinesterases exposure. This appears to follow phosphorylation and subsequent aging of an enzyme in axons called neuropathy target esterase 4. The earliest symptoms were paraesthesia and calf pain. Weakness initially appears in the distal leg muscles causing foot drop, followed by small muscles of the hands. Decrement test showed more affection of (the posterior tibial nerve than the common peroneal nerve) and more affection of (the median nerve than the ulnar nerves). These cases were presented late (after 24 hours) to the Poison Control Center with history of previous occupational exposure to anticholinesterases and did not respond to oxime therapy. In conclusion the neuroelectrophysiological study using RNS is of value in the diagnosis of the severity and complications of anticholinesterases poisoning and also in the follow up after oxime therapy. REEFRENCES 1. Eddleston M, Nick A, Peter E and Andrew H: Management of acute Organophosphate pesticide poisoning. Lancet 2008; 16: Paul B, Ashour B, Moreland C and Romeh A: Health risk assessment of pesticide usage in Menia El Kamh province of sharkia Government in Egypt. Int. J. Mol. Sci. 2002; 3: Booth B. Biosensor for rapid detection of organophosphate insecticides. American Chemical Society: Environmental Science and Technology News [serial online] 2005; Available at /2005/oct/tech/bb_biosensor.html 4. Singh S and Sharma N. Neurological syndromes following OP poisoning. Neurology India 2000; 48 (4):

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16 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 45 (2) July Bowman W.C.,Gibb A.J. and Harvey A.L. Prejunctional actions of cholinoreceptor agonist and antagonist and anticholinesterase drugs.in Kharkevich D.R., ed. New neuromuscular blocking agents: basis and applied aspects. Berlin:Springer-verlag, 1986: Magleby K and Pallota B. A study of desensitization of acetyl choline receptors using nerve released transmitter in frog. J Physiology 1981; 316: Bird SB, Gaspari RJ and Dickson EW. Early death in severe OP poisoning. A centrally mediated process. Acad Emerg 2003; 10: الملخص العربى متابعت الفسيىلىجيا الكهربائيت للجهاز العصبي لالكتشاف المبكر لشدة التسمم الحاد للمادة المضادة للكىلين ايستريس وتأثير العالج بمادة األوكسيم