Journal of Clinical Medicine and Research Vol. 3(4) pp. 57-59, April 2011 Available online http://www.academicjournals.org/JCMR ISSN 2141-2235 ©2011 Academic Journals
Short Communication
Management of refractory status epilepticus in acute endosulphan poisoning by levetiracetam: A case report Jain P. K.1, Sharma Awadhesh Kumar1*, Agarwal Navnit1, Kankane Arvind2, Sengar N. S.3, Siddiqui Mohd Zaki1 and Pawal Praveen1 1
Department of Medicine, MLB Medical College, Jhansi (U.P.) – 284128 India. 2 Neurology Unit, MLB Medical College, Jhansi, (U.P.) – 284128, India. 3 Department of Nephrology, MLB Medical College, Jhansi (U.P.) – 284128 India. Accepted 16 April, 2011
A 27 years old female was brought to emergency department of Maharani Laxmi Bai Medical College, Jhansi, India with suicidal consumption of endosulphan, presented with status epilepticus not responded to phenabarbitone, and phenytoin iv loading doses was later managed by iv levetiracetam. After acute ingestion of endosulphan refractory status epilepticus (RSE) is a common problem in intensive care units and emergency departments. Refractory status epilepticus (RSE) once develop requires more aggressive treatment as it is associated with higher mortality and morbidity. To date, no randomized controlled trials have been done for the management of RSE after acute ingestion of endosulphan by iv levacitaram. The most experience exists with pharmacologic agents like pentobarbital, midazolam and propofol. New evidence suggests for the possible role of iv levetiracetam. Key words: Endosulphan poisioning, refractory status epilipticus, levetiracetam, organochloride insecticides, pentobarbital, midazolam, propofol, emergency. INTRODUCTION Organochloride insecticides are chlorinated cyclic hydrocarbons that have molecular weights in the range of 300 to 550 dalton (Andrea and Edward, 2005). They have a long half-life in the human body and cause moderate toxicity. One of such insecticides is endosulfan (6,7,8,9,10-10hexachloro1,5,5a,6,9,9a-hexahydro-6methano-2,4,3-xadithioxanthiepin 3-oxide), which has been widely used in agriculture since 1960. The uncontrolled use of these compounds in developing countries has resulted in the deaths of animals and humans. There are isolated case reports of accidental and suicidal poisoning with endosulfan in the literature (Jeong and Byeong, 2009). Our present case report
*Corresponding author. E-mail:
[email protected]. Abbreviations: RSE, Refractory status epilepticus; IV, intra venous; EEG, electro encephalo graphy; MRI, magnetic rasonance imaging; GABA, gamma-amino butyric acid; CNS, central nervous system; AST, aspartate amino transferase; ALT, alkaline amino transferase; CPK, creatine phospo kinase; NMDA, N-methyl-D aspartate; LEV, levetiracetam.
discusses the role of iv levetiracetam in refractory status of epilepticus which is a common emergency problem after acute ingestion of endosulphan. CASE REPORT A 27 years old female Mrs Hema Devi, Housewife, was brought by her relatives in the emergency department of Maharani Laxmi Bai Medical College, Jhansi, India in unconscious state with complaints of generalized tonic clonic movements with uprolling of eye balls and frothing from mouth for 30 min typically suggestive of status epilepticus. On enquiring the history from her relatives it was revealed that she consumed approximately 130 ml of thiadone (endosulphan) insecticidal 3 h before admission in the hospital after quarrelling with her husband on some family issue. Her general condition was poor. At the time of admission pulse rate was 120/min, blood pressure was 130/80 mm of Hg. Pupils were normal in size and reactive to light. On chest auscultation, bilateral crepitations were present most likely because of aspiration, cardiac auscultation revealed sinus tachycardia with
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normal heart sounds, other systemic examination was within normal limits. Along with general management of acute poisoning in the form of gastric lavage with distill water, management of status epilepticus was instituted with loading of intravenous phenytoin (20 mg/kg at the rate of 50 mg/min) after initial securing of proper air way with Guedels airway. Inspite of phenytoin loading in full dose, patient’s seizures did not subside. Then according to the protocol, loading with iv valproate and iv phenabarbitone was done in adequate doses. But we were not able to control patient’s seizure. Then iv levetiracetam in loading dose of 1000 mg in 100 ml normal saline, was infused over 30 min, followed by a mean maintenance dose of 2000 mg/day in four equally divided doses. After this patient’s seizures abolished and her condition gradually improved within 2 to 3 days. Investigations on the 2nd day revealed total leukocyte count-14500/mm3, serum creatinine-1.14 mg/dl, SGOT150 IU/ml, SGPT-195 IU/ml, serum CPK-300 IU/ml,S. Na-136 meq /ml, S.K+ - 4.2 meq/ml, rest investigation revealed no abnormality. EEG and MRI brain was normal at the time of discharge. She was discharged on 5th day of her hospital admission. DISCUSSION Endosulfan is a polychlorinated hydrocarbon pesticide used in agriculture. Endosulfan is a widely used insecticide that is associated with a high fatality rate in humans when ingested accidentally or with the aim of suicide. Amount ingested being greater than 35 g of endosulfan was the most independent variable that predicted patient mortality. In present case, patients consumed approximately 130 ml that is 48 g which is much greater then toxic dose. Patients with this risk factor must be treated aggressively during the early stage of endosulfan poisoning. Acute toxicity may result in permanent neurological impairment. The predominant toxicological effect is over-stimulation of the central nervous system (CNS), by inhibiting Ca- and Mg-ATPase and antagonising chloride ion transport in gammaaminobutyric acid (GABA) receptors with little or no peripheral component. Characteristic clinical signs after acute exposure are indicative of CNS disturbances or overstimulation. These signs include seizures, nausea, vomiting, abdominal discomfort, hyperaesthesia of the mouth and face, tongue and extremities, headaches, agitation, hyperactivity, incoordination, confusion, dizziness and myoclonus. Our patient was presented in a state of status epilepticus with agitation, hyperactivity and vomiting which is because of CNS stimulation as primary manifestation in acute poisoning. Endosulfan poisoning may be suspected in the presence of primary central nervous system manifestations including seizures, with or without clinical or laboratory evidence of other organ dysfunction, such as liver failure (Karatas et al., 2006;
Sood et al., 1994). Convulsions are a common and severe manifestation. Endosulfan is also toxic to the liver, kidney and lung and can cause rhabdomyolysis in higher doses. Liver function tests are abnormal in the form of deranged AST or ALT. In the present case too, acute hepatic impairment was reported as patient’s liver enzymes were found to be elevated 4 to 5 times of the normal serum level. But no signs and symptoms of fulminant hepatic failure were present. CPK level was 300 IU in our case which is attributed to mild rhabdomyolysis or due to persistent seizure activity but no myoglobinuria was seen. Renal functions assessed by serum levels of S. Creatinine and blood urea were within normal limit. No electrolyte abnormality was seen in our case. Severe poisoning may result in death due to status epilepticus that can lead to asphyxia. Status epilepticus refers to a condition in which there is a failure of the "normal" factors that serve to terminate a typical seizure. γ-Aminobutyric acid (GABA) receptor-mediated inhibition may be responsible for the normal termination of a seizure. In addition, the activation of the N-methyl-D aspartate (NMDA) receptor by the excitatory neurotransmitter glutamate may be required for the propagation of seizure activity. Status epilepticus that is refractory to treatment may be the result of several processes and has been attributed to a mechanistic shift from inadequate GABAergic inhibitory receptor-mediated transmission to excessive NMDA excitatory receptormediated transmission. The toxic effects generally seem to be completely reversible; hence, it is necessary to identify the poison and spare no effort to resuscitate the patient. Seizures should be controlled with benzodiazepine, followed by phenobarbital if seizures persist (Murthy, 2006). Phenytoin is probably less effective in these cases, given the effect of endosulfan on GABA receptors. To date, no randomized controlled trials have been done for status epilepticus in these cases refractory to first- and second-line therapy. The most experience exists with continuous infusion (cIV) of pentobarbital, midazolam and propofol. Levetiracetam (LEV) is a new antiepileptic drug available for treatment of refractory epilepsy after endosulphan poisoning. The mean levetiracetam loading dose was 944 mg, usually given over 30 min followed by a mean maintenance dose of 2,166 mg/day. There were no serious adverse effects. Efficacy was impressive, with clinical seizure activity stopping in all patients and rarely recurring. Levetiracetam seems to desynchronize neuronal networks without affecting normal neuronal transmission, thereby preventing burst firing. The most interesting discovery has been that levetiracetam binds to synaptic vesicle protein 2A, a regulator of vesicular traffic and therefore, of neurotransmitter release and the potency of binding seems to correlate with antiseizure efficacy. It may be preferable to utilize IV administration during acute seizure circumstances. Nonetheless, IV levetiracetam has many attractive features that will ensure
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its common use in the inpatient setting, including: mostly renal clearance, virtually no interactions, rare allergic reactions, minimal respiratory and cardiovascular effects with IV loading, broad-spectrum efficacy and ease of use. No other IV medication for seizures shares these features. In our case too we found that seizure activity did not respond to first and second line therapy and patients seizure get abolished by the infusion of levetiracetam. This is in accordance with a study, which illustrate the efficacy of iv levetiracetam in secondary genralised status epilepticus in 4 patients with control of seizures. According to this study iv LEV may be an alternative for the treatment of status epilepticus in the future, even in patients that did not respond to benzodiazepines (Knake et al., 2008). In another study the safety and efficacy of levetiracetam in patients with uncontrolled focal epilepsy, in a common practice-based setting was established. It is concluded that levetiracetam is both efficacious and safe as an add-on therapy in patients with refractory epilepsy treated by clinicians in their daily practice (Genton et al., 2006). So the use of levetiracetam in this case promises its future use in management of refractory seizures after acute ingestion of endosulphan not responding to usual drugs. Levetiracetam may represent a useful alternative in the treatment of RSE, particularly if a parenteral form of administration becomes available; to better define its role in this setting, prospective studies are needed (Andrea and Edward, 2005). Though data is not conclusive for its routine use in these cases and needs further randomized controlled trials. CONCLUSIONS Endosulfan is a highly toxic organochlorine insecticide that produces well-known neurological symptoms of tonic-clonic convulsions, headache, dizziness and ataxia but also can cause gastrointestinal symptoms and metabolic disturbances. Life-threatening cerebral edema and hemodynamic instability may occur. Treatment is symptomatic and supportive. Early termination of convulsive status epilepticus by aggressive treatment is
the best way to prevent mortality. Refractory seizures once develop, requires more aggressive treatment as it is associated with higher mortality and morbidity. To date, no randomized controlled trials have been done for refractory seizures. The most experience exists with coma inducing agents like pentobarbital, midazolam and propofol. Newer evidence suggests for the possible role of new anti epileptic drug levetiracetam in cases of refractory status epilepticus. ACKNOWLEDGEMENTS The authors are highly thankful to the residents of Postgraduate Department of Medicine, MLB Medical College, Jhansi, UP-India for their ever tiring hard work for working on this study. We thank Mr Praveen Srivastava, computer assistant for keeping the autonomic database. REFERENCES Andrea OR, Edward BB (2005). Levetiracetam in the Treatment of Status epilepticus in Adults: A Study of 13 Episodes. Eur. Neurol., 54: 34-38. Genton P, Sadzot B, Fejerman N, Peltola J, Despland PA, Steinhoff B, Rektor I, Wroe S, Maubrey MC, Vandervelden C, van Hammée G, Schlit AF, van Paesschen W (2006). Levetiracetam in a broad population of patients with refractory epilepsy: interim results of the international SKATE trial. Acta Neurol Scand., 113(6): 387-394. Jeong MM, Byeong JC (2009). Acute endosulfan poisoning: a retrospective study. Hum. Exp. Toxicol., 28(5): 309-316. Karatas AD, Aygun D, Baydin A (2006). Characteristics of endosulfan poisoning: a study of 23 cases: Singapore Med. J., 47(12): 30. Knake S, Gruener J, Hattemer K, Klein KM, Bauer S, Oertel WH, Hamer HM, Rosenow F (2008). Intravenous Levetiracetam in the Treatment of Benzodiazepine Refractory Status Epilepticus. J. Neurol. Neurosurg. Psychiatr., 79(5): 588-589. Murthy J (2006). Refractory status epilepticus. Neurol India, 54: 354358. Sood AK, Yadav SP, Sood S (1994). Endosulfan poisoning presenting as status epilepticus. Indian J. Med. Sci., 48: 68-69.
