2902Journal ofNeurology, Neurosurgery, and Psychiatry 1993;56:290-294 SHORT REPORT J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.3.290 on 1 March 1993. Downloaded from Pathophysiological studies of neuromuscular function in subacute organophosphate poisoning induced by phosmet J L Good, R K Khurana, R F Mayer, W M Cintra, E X Albuquerque Abstract suggested a neuromuscular junction (NMJ) A 51 year old man developed progressive defect of the postsynaptic type, but the exact cranial and proximal muscle weakness, mechanism of the dysfunction was not deter- hyperreflexia and mental change. The mined. 5o disorder progressed over 9 days following We describe the pathophysiological changes the fifth weekly spraying with the organo- in a patient who presented with a subacute phosphate (OP) insecticide, phosmet, progressive neuromuscular syndrome without with limited symptoms of acute toxicity. marked symptoms of acute toxicity after multi- Marked decremental responses of 50-80% ple OP insecticide sprayings. The defect in this on slow and fast rates of stimulation were neuromuscular syndrome occurred at the improved to 15% by edrophonium or endplate-receptor sites, is similar to the inter- neostigmine. Intracellular recordings at mediate syndrome previously reported,10 and the endplate region of intercostal muscle differs from the acute and delayed syndromes. l revealed small miniature endplate poten- These results are important in the diagnosis tials (mepps), reduced mean acetylcho- and management of patients exposed to line sensitivity and normal membrane organophosphates. A preliminary report of potentials. Electronmicroscopy revealed this study has been published in abstract degeneration and regeneration of the form. " endplates. This study demonstrates that OP poisoning due to phosmet can produce a subacute postsynaptic neuromuscular Case report syndrome without marked symptoms of A 51 year old man was admitted to the hospital acute toxicity. 5 days after the onset of diplopia, light headed- ness and a staggering gait. The patient devel- (7 Neurol Neurosurg Psychiatry 1993;56:290-294) oped these symptoms 18 hours after the fifth weekly exposure to a liquid spray insecticide http://jnnp.bmj.com/ University of Organophosphate (OP) insecticide poisoning containing an organophosphate compound, Maryland School of can acute acid Medicine, Baltimore, in humans produce: 1) peripheral phosmet, (phosphorodiothioic S-[(1,3-di- Maryland, USA and central cholinergic block; 2) an inter- hydro-1 ,3-dioxo-2H-isoindol-2-yl) methyl] 0,0- Department of mediate syndrome with weakness, and 3) a dimethylester). He described his face and Neurology delayed distal polyneuropathy. l The acute syn- hands becoming wet from the insecticide and J L Good R K Khurana drome that occurs 12 to 72 hours after he did not bathe until the following morning. R F Mayer exposure to OP involves inhibition of acetyl- Over the next few days, he noted progressive on September 24, 2021 by guest. Protected copyright. Department of cholinesterase (AChE) by the OP24 and direct unsteadiness of gait, dysphagia, change in Pharmacology and actions at the synapse involving a variety of voice tone and excessive diaphoresis. Five days Experimental Therapeutics chemosensitive receptor ion channels.`- Cen- after exposure, he noted jaw weakness and E X Albuquerque tral and peripheral cholinergic signs occur. The droopy eyelids. Laboratory of neuromuscular block to repetitive nerve stim- The patient's general examination was nor- Molecular ulation shows decremental responses that are mal. Profuse oral secretions, bilateral ptosis, Pharmacology II, increased by edrophonium.8 The delayed neu- and marked facial diaphoresis were noted. He Institute of Biophysics "Carlos Chagas ropathic syndrome occurs 1-3 weeks after was alert, mentation was normal, and speech Filho", Federal exposure to the OP and probably results from was dysarthric. Extraocular movements were University of Rio De inhibition of the neurotoxic esterase.9 A distal limited in all directions with the exception of Janeiro, Rio De Janeiro, Brazil axonopathy usually occurs with sensory and downgaze. Pupils were 3 mm and reactive to W M Cintra motor signs. More recently, an intermediate light. There was moderate symmetrical weak- Correspondence to: syndrome has been described in OP poisoning ness of facial, jaw, tongue and neck muscles. Dr Good, Department of that occurs 1-4 after the acute poison- There was mild weakness distal muscles and Neurology, Room N4W46, days of University of Maryland ing.'0 The patients reported developed pro- marked weakness of proximal muscles, es- Hospital, 22 S Greene weakness that was often severe and muscles that The Street, Baltimore, MD gressive pecially antigravity fatigued. 21201, USA involved cranial, respiratory and proximal limb tendon jerks were brisk throughout. Bilateral Received 17 December 1991 muscles which persisted for up to 18 days. Babinski responses were present. Sensory and in revised form Three of the patients had signs suggesting examination was normal. 11 March 1992. Accepted 16 March 1992 CNS dysfunction. Electromyographic studies The patient was admitted with the presumed Endplate studies in OP poisoning 291 diagnosis of acute OP poisoning. Atropine and care was taken to keep the patient warm J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.3.290 on 1 March 1993. Downloaded from (2 mg) and pralidoxime chloride (2-PAM, (rectal temperature of 37°C) during the proce- 1 gm) infusions were started. Within several dure. Recordings were obtained at 9 to 95 days minutes of 2-PAM infusion, the patient had after exposure to phosmet. increased systemic and ventilatory weakness Repetitive stimulation was performed at requiring intubation. After the patient was rates of 2, 5, 10, 20, and 50 Hz for 9 responses stabilised on a ventilator, 3 additional doses of in the median and peroneal nerves. Recordings 2-PAM were given without side effects over the of the median nerve were made before and next 24 hours. Atropine (1 0 mg initially and after 10 mg of intravenous edrophonium at thereafter 0-5 mg) was continued 4 times daily days 11 to 47. Recordings were made 5 to 40 for 6 days. Paralysis was maximum on day 9. minutes after 1-5 mg of intramuscular neo- At this time, he was observed to have visual stigmine on day 12. Measurements of the hallucinations, disorientation, and myoclonic motor amplitudes were peak-to-peak and per- jerks of his extremities. These signs persisted centage change (decrement) was calculated for for approximately 10 days during which time the fourth and ninth responses compared with the EEC showed diffuse slow wave activity. the initial one. The patient remained unchanged for the Concentric needle and single fibre (SF following 18 days, and supportive care con- EMG) electromyography and fibre densities tinued. By day 28, there was improvement in were performed in the extensor digitorum strength of neck flexion, shoulder and anti- communis and first dorsal interosseus muscles gravity muscles. By day 44, he no longer using established techniques. 14 SF EMG required mechanical ventilation or tube feed- recordings were obtained when the patient was ings. Babinski responses were absent. Exam- improving and able to cooperate, 3-4 months ination on day 64 (time of the muscle biopsy) after exposure. showed that he had mild fatiguable proximal A diagnostic intercostal muscle biopsy was and antigravity muscle weakness in the upper obtained 2 months after exposure because of and lower limbs. Facial and oropharyngeal persistent muscle weakness with informed movements were near normal. There was mild consent by the patient. Muscle was removed subjective diplopia on extreme lateral gaze. from the right sixth intercostal space in the Neuromuscular examination was normal by 5 anterior axillary line using standardised aneas- months. thesia and surgical technique. The muscle was Laboratory studies revealed normal routine immediately placed in oxygenated Krebs- blood and urine studies, creatine kinase, EKG Ringer solution and prepared for intracellular and chest radiographs. MRI of the brain was recordings and ultrastructure as previously normal. CSF was normal except for a total described.'5 Conventional microelectrode protein of 75 mg%. On admission red blood techniques were used for recording from cell cholinesterase level was within normal human intercostal muscle. High resistance limits (6110 U/L); and follow up levels on days pipettes (approximately 150 MQ) filled with 16 and 23 were 5420 and 4180 respectively 2 5 M acetylcholine (ACh) were used for and at 10 months (5114 U/L) remained nor- microiontophoretic application of ACh at the mal (normal range 6666-3590). Studies to neuromuscular junctions. Results were com- rule out other causes of neuromuscular disease pared statistically (Student t test) with control were normal. ANA and acetylcholine receptor data that we have obtained from normal adult http://jnnp.bmj.com/ antibody titres were negative. human intercostal muscle biopsied during thoracotomies for cardiopulmonary disease. The muscle fibres were fixed in ice-cold Methods phosphate buffered 2-5% glutaraldehyde for Nerve conduction and repetitive stimulation- thin sectioning and electron microscopic neuromuscular studies were performed in examination of the endplate regions.'5 16 peripheral nerves of upper and lower extrem- on September 24, 2021 by guest. Protected copyright. ities using established techniques.'2 53 Record- ings were performed in the intensive care unit Results Clinical electrophysiology Table 1 Nerve conduction and repetitive stimulation studies in median nerve after Initial recordings were performed 9 days after phosmet exposure exposure at which time the weakness was maximal. Electromyography at this time did % Decrement at 5 Hz not show any spontaneous activity such as Before After Tensilon fasciculations or fibrillation potentials. In Time CMAP DL MCV Days mV MS MIS 4th R 9th R 4th R 9th R median, ulnar and peroneal nerves, distal motor responses were mildly reduced in ampli- 9 90 50 54 48 43 1 1 11-6 55 43 33 19 tude and prolonged in latency. Motor conduc- 12 13-0 58 46 10 7 tion velocities were normal.