A.T. Prabhakar, MBBS, MD, DM. Dept. of Neurological sciences, Christian Medical College, Vellore

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1 A.T. Prabhakar, MBBS, MD, DM. Dept. of Neurological sciences, Christian Medical College, Vellore Abstract Status epilepticus is defined as a continuous, generalized, convulsive seizure lasting more than 5 minutes, or two or more seizures during which the patient does not return to baseline consciousness. It is a neurological emergency and early initiation of intravenous anticonvulsants is key to a successful outcome. Lorazepam and diazepam are the drugs of choice for initial administration. Priority must be given to secure the airway and maintain blood pressure. If seizures continue despite the initial therapy, Intensive care unit admission may be required for monitoring and therapy. Corresponding Author: Dr. A.T.Prabhakar atprabhakar@gmail.com Introduction Status epilepticus is a common neurological emergency characterised by continuous seizure activity or recurrent seizures without recovery between attacks. It is associated with high mortality and morbidity and it requires emergent, targeted therapy. Definition Status epilepticus was defined by the International League Against Epilepsy (ILAE) more than 20 years ago as a single epileptic seizure of >30 minutes duration or a series of epileptic seizures during which function is not regained between ictal events in a 30 minute period 1. Since it has been established that generalized tonic-clonic seizures do not last longer than 2 minutes except when it evolves into status epilepticus, and irreversible neuronal injury may start after 20 to 30 minutes of generalized convulsive status epilepticus, it has been suggested that aggressive therapy for status epilepticus be initiated after 5 minutes of generalized tonic-clonic seizures 23. The new proposed operational definition for status epilepticus is defined as a continuous, generalized, convulsive seizure lasting more than 5 minutes, or two or more seizures during which the patient does not return to baseline consciousness 4. The terms impending status Status Epilepticus Status epilepticus is defined as a continuous, generalized, convulsive seizure lasting more than 5 minutes, or two or more seizures during which the patient does not return to baseline consciousness epilepticus and established status epilepticus are useful to guide management and can be defined as follows 5. Impending status epilepticus Impending status epilepticus, is defined as continuous or intermittent seizures lasting more than 5 minutes without full recovery of consciousness between seizures 5. Established status epilepticus Established status epilepticus is defined clinical or electrographic seizures lasting more than 30 minutes without full recovery of consciousness between seizures 5. Etiology The main causes of status epilepticus are low blood concentrations of antiepileptic drugs in patients with chronic epilepsy (34%), metabolic causes (including hypoxia, electrolyte imbalance and alcohol and drug withdrawal ) (30%) remote symptomatic causes (24%), cerebrovascular accidents (22%) 6. Additionally in studies from India central nervous system infections contribute to 28 67% of the aetiologies 7,8. No clear aetiology can be identified in 20% of cases 9. Classification Status epilepticus can be classified based on the presence or absence of convulsions, into CMI 13:2 26 April 2015

2 convulsive SE (CSE) and nonconvulsive SE (NCSE). Nonconvulsive status epilepticus is defined as a mental status changes from baseline of at least 30 to 60 minutes duration associated with continuous or near continuous ictal discharges on EEG 10. Electroclinically status epilepticus can be classified as focal or generalized; and based on the seizure type it can be further classified (Fig.1). Fig. 1: Classification of Status Epilepticus Status Epilepticus Convulsive status Epilepticus Non-convulsive status Epilepticus Generalized convulsive status epilepticus Primary generalized convulsive SE Secondarily generalized convulsive SE (focal onset) Focal motor status epilepticus ( epilepsia partialis continua) Myoclonic Tonic Clonic Typical ("classic") absence status epilepticus Atypical absence status epilepticus Primary generalized NCSE Focal onset with generalized NCSE Complex partial status epilepticus Abbreviations: SE, Status epilepticus; NCSE: non-convulsive status epilepticus Treatment In status epilepticus, time is brain, and early initiation of intravenous anticonvulsants is key to a successful outcome. Experimental data shows that there is time dependent loss of synaptic GABA A receptor followed by movement of N-methyl-Daspartate (NMDA) receptors to the synapse 5,11. Hence, starting therapy early can avoid the time dependent development of pharmacoresistance to benzodiazepines and other anticonvulsants. Early therapy can be initiated at home by the care givers. In the emergency room, along with IV administration of anticonvulsants, priority must be given to secure the airway and maintain blood pressure. If seizures continue despite the initial therapy Intensive care unit admission may be required for further monitoring and therapy. In patients presenting with status epilepticus it is useful to plan therapy in a series of progressive stages (Figure: 2). Out of hospital therapy and emergency room management Benzodiazepines are the drug of choice for out-ofhospital treatment. Since IV access may not be possible in the home setting, other modes of administration such as rectal, buccal and nasal are advised. Rectal diazepam at 0.2 to 0.5 mg per kilogram of body weight has been shown to be effective in home initiated therapy in children 12. Buccal administration of midazolam has been found to be effective and may be more socially acceptable than rectal administration in the out of hospital setting 13. For administration of buccal midazolam, 2 ml (10 mg) is to be drawn into a 2 ml syringe and CMI 13:2 27 April 2015

3 squirted around the buccal mucosa after parting the lips, but without trying to open the jaws 13. Intranasal midazolam sprays are available commercially, and can safely and effectively administered at home 14. Impending status epilepticus Benzodiapepines are the first line therapy in impending status epilepticus. Lorazepam is the drug of choice for intravenous (IV) administration. Diazepam is also effective it has a quicker onset of action but shorter duration of effect. Dosages: Lorazepam- up to 0 1 mg/kg (adults- 4 mg, repeat 2mg after 5-10 mins if necessary). Diazepam - up to mg/kg (5mg, repeat 5mg after 5-10 mins in adults). Midazolam is the drug of choice for intramuscular (IM) administration 15,16. Established Convulsive Status Epilepticus (30 60 Minutes) When benzodiazepines fail to terminate the status epilepticus, IV phenytoin / fosphenytoin, phenobarbitone or sodium valproate is used.,17,16,18,5 Fosphenytoin is preferred to phenytoin because of its water solubility and neutral ph, thereby allowing more rapid administration with less adverse effects such as venous irritation 18. Phenytoin is administered at a dose of 18 to 20 mg/kg intravenously over 20 minutes (with a maximum infusion rate of 50 mg/min). In children when IV access is not possible, intraosseous route can be used. 19 Maintenance dose: 5-7 mg/kg/day. Phenobarbital is often considered when seizures still continue even after loading with hydantoins 20, 21 It can be given as a bolus of 20 mg/kg followed by another 5-10 mg/ kg if needed 20. Intravenous sodium valproate is as effective as phenytoin and can be used as a first line agent when benzodiazepines fail 8,22. Valporate can be loaded intravenously at a dose of 20 to 40 mg/kg infused a rate of 5 mg/kg per minute without adverse effects on blood pressure or heart rate 23,24. Levetiracetam and lacosamide can be used as adjunctive agents in patients with focal or nonconvulsive status epilepticus. Early initiation of intravenous anticonvulsants is key to a successful outcome. I.V. Lorazepam is the drug of choice. Start Phenytoin if seizures continue. Refractory Status Epilepticus (> 60 Minutes) Refractory status epilepticus is defined as the failure of adequate doses of two intravenous drugs to stop seizures 5. Induction of pharmacological coma and adding on AEDs is the strategy that is followed. Intensive care unit admission is advised with endotrachal intubation and mechanical ventilation when required. Midazolam: Midazolam when used as an infusion can be used to treat refractory status epilepticus. It is initiated with a loading dose of 0.2 mg/kg bolus given at a rate of 2 mg/min. Additional boluses should be given every five minutes until seizures stop (up to a maximum of 2 mg/kg), followed by a continuous infusion of 0.1 mg/kg/hour, which can be titrated upwards to as high as 5 mg/kg/hour 25,26. If seizures are not controlled within 45 to 60 minutes of optimal dose of midazolam therapy, alternate strategy for pharmacological coma must be used. Propofol : Propofol is a highly lipophilic phenol derivative and GABA-A agonist with anticonvulsant properties. 27, 26,28. Propofol infusion is initiated with a 1 to 2 mg/kg loading dose, which can be repeated if the seizures do not stop. The infusion rate can be titrated over the next 30 to 60 minutes to maintain a seizure-free state. Continuous EEG monitoring may be used and the dose of the infusion may be titrated to achieve burst suppression pattern. Infusion rates of up to 10 to 12 mg/kg/hour may be required but should not be maintained for more than 48 hours because of the risk of the propofol infusion syndrome 27 [82]. The propofol infusion syndrome consists of rhabdomyolysis, severe metabolic acidosis, and cardiac and renal dysfunction 29. Acidbase imbalance, serum creatine phosphokinase, and serum triglycerides are markers of propofol infusion syndrome and must be monitored while patient is on propofol. Treatment with propofol should be considered unsuccessful if it fails to terminate seizure activity within 45 to 60 minutes of an adequately Continued on page 30 CMI 13:2 28 April 2015

4 Start anti-convulsant therapy IV Lorazepam up to 0 1 mg/kg (4 mg, repeat 2mg after 5-10 mins in adults) or IV Diazepam up to mg/kg (5mg, repeat 5mg after 5-10 mins in adults) Seizures continuing? Intravenous phenytoin mg/kg at 50 mg per min or Intravenous valproic acid mg/kg at 5 mg per kg per min Seizures continuing? Figure 2: Management of Status Epilepticus Flowchart Status Epilepticus 5 minutes of continuous seizures, 2 discrete seizures with incomplete recovery of consciousness between the events Initial Assessment - Secure airway, - Oxygen supplementation - IV access with 2 large bore canulas start anti-convulsant immediately - Monitor respiration, blood pressure, monitor SpO2. - Administer Inj. Thiamine 100 mg IV, followed by 50 ml of 50% dextrose if random blood glucose testing is not available. Additional intravenous Phenytoin 5-10 mg/kg Seizures continuing? Seizures stop Admit in ICU, Will need to be treated as refractory status epilepticus (next box) Endotracheal intubation may be required for securing airway. Seizures stop Take focused history and examination Out of hospital therapy Diazepam Rectal 2-5 years 0.5mg/kg, 6-11 years 0.3mg/kg, 12 years 0.2g/kg (max 20mg) Buccal midazolam : midazolam (0.5mg/kg) upto Max 10 mg squirted around the buccal mucosa after parting the lips, but without trying to open the jaws Intranasal Midazolam (0.2mg/kg) Investigations: Random blood glucose, arterial blood gas, electrolytes, urea, creatinine, liver function test, calcium, magnesium, phosphorous, toxin screening, Neuroimaging (CT/MRI), EEG and CSF if CNS infection is suspected. Refractory status epilepticus Pharmacologic Coma Midazolam loading 0 2 mg/kg followed by mg/kg/h or Propofol loading 2 5 mg/kg, 2 10 mg/kg/h or Pentobarbital loading up to10 mg/ kg followed by mg/kg/h or Thiopental loading with 3 to 5 mg/kg bolus, followed by 3 to 5 mg/kg/hr. Ketamine bolus 1 5 mg/kg followed by mg/kg/h (contraindicated in raised intracranial pressure) Inhalational General Anaesthesia Pharmacologic Coma Management - Titrate infusions to either seizure suppression or burst suppression based on continuous EEG monitoring. - Continue pharmacologic coma for hours. - Add Add-on AEDs (Box 1) before weaning off infusions. Abbreviations: IV, Intravenous; ECG, Electrocardiogram; SpO2, Pulse oximeter oxygen saturation; CSF, Cerebrospinal fluid; CNS, Central nervous system; CT, Computed tomography; MRI, Magnetic resonance imaging; EEG, Electroencephalogram; AED, Anti epileptic drug ; IVIG, Intravenous immunoglobulin. CMI 13:2 29 April 2015

5 ... Continued from page 28 dosed infusion. In this case, switching to barbiturate infusion or adding a benzodiazepine should be considered. Barbiturates (thiopentone, pentobarbital): Thiopentone can be administered as a 3 to 5 mg/kg bolus, followed by additional boluses of 1 to 2 mg/kg every 3 to 5 minutes until seizures are controlled and there is burst suppression pattern on EEG. The infusion should be continued at a rate of 3 to 5 mg/kg/h 30,31. Pentobarbital is administered as a 10 mg/kg bolus, followed by a continuous infusion at a rate of 0.5 to 1.0 mg/kg/h. Prolonged barbiturate infusions are associated with hypotension, cardiac depression and possible immune dysfunction 32. If seizures are terminated with barbiturate infusion, it must be continued for at least hours before being tapered and stopped. Continuous EEG monitoring is useful to detect burst suppression pattern and electrographic control. Before tapering the infusion, adding on additional AEDs and ensuring high therapeutic concentrations of previously loaded AEDs should be considered. Box 1. Add-On AEDs Levetiracetam mg/kg IV Valproate Sodium mg/kg IV. Phenobarbital mg/kg Topiramate 10 mg/kg/d, orally for 2 consecutive days, followed by maintenance doses of 5 mg/kg/d. Lacosamide 200 mg IV Inhalational Anaesthetic Agents: Inhalational anaesthetic agents such as isoflurane and desflurane can be used for refractory status epilepticus. End tidal concentrations of 1.2 5% can be used to achieved seizure control and a burst suppression pattern on EG 33,34,35. Anaesthesia should be stopped once a day, and if seizures recur, resume treatment and continue for another 24 hours. Levetiracetam: Levetiracetam is a newer AED that acts via the synaptic vesicular protein 2A (SV2A). It has less drug interactions and can be safely used in the elderly and patients with multiple medical co-morbidities,37,38,36. In a study comparing the efficacy of phenytoin, valproate and levetiracetam as second-line drugs in status epilepticus, levetiracetam was found to be less effective than valproate to control status epilepticus when used after the administration of benzodiazepine 39 Levetiracetam can be given as an IV loading dose of mg/kg bolus and continued in divided doses as oral or IV 38. Lacosamide: Lacosamide is a new anticonvulsant drug that acts by slow inactivation of the voltagegated sodium channel, and is available as infusion and can be used in refractory status epilepticus 40,41,42. It can be loaded as an IV bolus of 200 mg and continued at mg per day. Topiramate: Topiramate is an AED with multiple mechanisms of action. It blocks voltage-dependent sodium channels, enhances the activity of GABA at a non-benzodiazepine binding site on GABA A receptors, and antagonizes NMDA glutamate receptors. It is also a weak inhibitor carbonic anhydrase. Topiramate can be used as an adjunctive therapy in refractory status epilepticus 43,44. Since IV topiramate is not available the tablets can be crushed and administered through the nasogastric tube. A loading dose of 10 mg /kg over 2 days followed by a maintenance dose of 5 mg per kg can used 44. Ketamine: Ketamine is an NMDA receptor antagonist and has been proved to be effective in proved useful in refractory status epilepticus 45,46. It is neuroprotective and does not produce cardiac depression or hypotension. Ketamine can raise intracranial pressure and hence it is contraindicated in patients with raised intracranial pressure. Despite its adverse effects ketamine is a promising drug to be considered as an agent of last resort 5 Newer Antiepileptic Drugs Newer AEDs have less pharmacokinetic interactions and have a better safety profile. There is growing evidence that they can be used as add- on AEDs after the use of benzodiazepines in status epilepticus. 36,37 Tapering off continuous infusions In patients treated with pharmacological coma, continuous infusions must be continued for 12 to 24 hours after control of seizures and must be gradually CM1 13:2 30 April 2015

6 tapered over the next 24 hours. If seizures recur while tapering, the infusion must be continued for longer and must be tapered more slowly the next time. Prior to re-initiating a taper, adding on another maintenance AED and ensuing high therapeutic levels of other maintenance AEDs must be considered. Maintenance Therapy: Along with emergency treatment, attention must be given to maintenance AED therapy to prevent recurrence of seizures. In patients with known epilepsy, their usual AEDs must be continued and dose adjustments made by monitoring AED levels. In patients presenting with new onset of status epilepticus, the AEDs, phenytoin or valproic acid, which are given as an initial IV loading must be continued as oral maintenance therapy. In refractory status epilepticus controlled with pharmacological coma, it is advisable to add on additional AEDs as maintenance therapy prior to tapering of the infusions 31. Role of Continuous EEG monitoring Electrographic seizures may persist after treatment convulsive status epilepticus and may present clinically as impaired level of consciousness. Hence continuous EEG monitoring (ceeg) is useful in monitoring therapy in patients with convulsive status epilepticus not awake following treatment and also in patients with non-convulsive status epilepticus 47. ceeg monitoring is also useful in the treatment of refractory status epilepticus with pharmacological coma. It is used assess if the target of burst suppression is achieved on induction of pharmacological coma; and to monitor for relapse of seizures during the tapering of infusions. Emerging Therapies Immunomodulation with steroids and IVIG have been tried in cases thought to have an inflammatory or autoimmune etiology. The improved understanding of the role of inflammation in epileptogenesis and the increasing spectrum of autoimmune encephalitis is the rationale for the use of immunomodulation in refractory status epilepticus 48. Non-pharmacological treatments such as resective surgery, ketogenic diet, vagal nerve stimulation, hypothermia and electroconvulsive therapy and transcranial magnetic stimulation have been used in cases of refractory status epilepticus 48,49, 50, 51, 52. Conclusion Early termination of impending status epilepticus by aggressive therapy can prevent refractory status epilepticus. Prehospital treatment is beneficial, and AEDs when used in rapid sequence guided by a defined protocol are useful in termination of status epilepticus. In refractory status epilepticus pharmacological coma induced with midazolam, barbiturates and propofol are useful. There is emerging evidence for the possible role of newer AEDs with a better safety profile in the management of status epilepticus. ********************************************************************************* References 1. Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia 34, (1993). 2. Shinnar, S., Berg, A. T., Moshe, S. L. & Shinnar, R. How long do new-onset seizures in children last? Ann. Neurol. 49, (2001). 3. Theodore, W. H. et al. The secondarily generalized tonicclonic 5. Chen, J. W. Y. & Wasterlain, C. G. Status epilepticus: pathophysiology and management in adults. Lancet Neurol. 5, (2006). 6. DeLorenzo, R. J. et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 46, (1996). 7. Murthy, J. M. K., Jayalaxmi, S. S. & Kanikannan, M. A. seizure: a videotape analysis. Neurology 44, 1403 Convulsive status epilepticus: clinical profile in a 1407 (1994). 4. Lowenstein, D. H., Bleck, T. & Macdonald, R. L. It s time to revise the definition of status epilepticus. Epilepsia 40, (1999). developing country. Epilepsia 48, (2007). 8. Misra, U. K., Kalita, J. & Patel, R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology 67, (2006). CM1 13:2 31 April 2015

7 9. Chin, R. F. M., Neville, B. G. R. & Scott, R. C. A systematic review of the epidemiology of status epilepticus. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 11, (2004). 10. Kaplan, P. W. Nonconvulsive status epilepticus. Semin. Neurol. 16, (1996). 11.Wasterlain, C. G. & Chen, J. W. Y. Mechanistic and pharmacologic aspects of status epilepticus and its treatment with new antiepileptic drugs. Epilepsia 49 Suppl 9, (2008). 12. Dreifuss, F. E. et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N. Engl. J. Med. 338, (1998). 13.Scott, R. C., Besag, F. M. & Neville, B. G. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 353, (1999). 14. Lahat, E., Goldman, M., Barr, J., Bistritzer, T. & Berkovitch, M. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ 321, Silbergleit, R. et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N. Engl. J. Med. 366, (2012). 16. Treiman, D. M. et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N. Engl. J. Med. 339, (1998). 17. Agarwal, P. et al. Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure 16, (2007). 18. Jamerson, B. D. et al. Venous irritation related to intravenous administration of phenytoin versus fosphenytoin. Pharmacotherapy 14, (1994). 19. Khan, T. M. et al. Comparison of plasma levels and pharmacodynamics after intraosseous and intravenous administration of fosphenytoin and phenytoin in piglets. Pediatr. Crit. Care Med. J. Soc. Crit. Care Med. World Fed. Pediatr. Intensive Crit. Care Soc. 1, (2000). 20.Crawford, T. O., Mitchell, W. G., Fishman, L. S. & Snodgrass, S. R. Very-high-dose phenobarbital for refractory status epilepticus in children. Neurology 38, (1988). 21. Wilmshurst, J. M., van der Walt, J.-S., Ackermann, S., Karlsson, M. O. & Blockman, M. Rescue therapy with highdose oral phenobarbitone loading for refractory status epilepticus. J. Paediatr. Child Health 46, (2010). 22.Trinka, E., Höfler, J., Zerbs, A. & Brigo, F. Efficacy and safety of intravenous valproate for status epilepticus: a systematic review. CNS Drugs 28, (2014). 23. Hodges, B. M. & Mazur, J. E. Intravenous valproate in status epilepticus. Ann. Pharmacother. 35, (2001). 24.Limdi, N. A., Shimpi, A. V., Faught, E., Gomez, C. R. & Burneo, J. G. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 64, (2005). 25. Ulvi, H., Yoldas, T., Müngen, B. & Yigiter, R. Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 23, (2002). 26.Prasad, A., Worrall, B. B., Bertram, E. H. & Bleck, T. P. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 42, (2001). 27. Stecker, M. M. et al. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 39, (1998). 28. Rossetti, A. O., Reichhart, M. D., Schaller, M.-D., Despland, P.-A. & Bogousslavsky, J. Propofol treatment of refractory status epilepticus: a study of 31 episodes. Epilepsia 45, (2004). 29. Vasile, B., Rasulo, F., Candiani, A. & Latronico, N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med. 29, (2003). 30. Prabhakar, H., Bindra, A., Singh, G. P. & Kalaivani, M. Propofol versus thiopental sodium for the treatment of refractory status epilepticus. Cochrane Database Syst. Rev. 8, CD (2012). 31. Kälviäinen, R., Eriksson, K. & Parviainen, and I. Refractory generalised convulsive status epilepticus : a guide to treatment. CNS Drugs 19, (2005). 32. Pugin, D. et al. Is pentobarbital safe and efficacious in the treatment of super-refractory status epilepticus: a cohort study? Crit. Care Lond. Engl. 18, R103 (2014). 33. Sakaki, T. et al. Isoflurane in the management of status epilepticus after surgery for lesion around the motor area. Acta Neurochir. (Wien) 116, (1992). 34. Kofke,W.A. etal. Isoflurane for refractory status epilepticus:aclinical series.anesthesiology71, Mirsattari, S. M., Sharpe, M. D. & Young, G. B. Treatment of refractory status epilepticus with inhalational anesthetic agent s isoflurane and desflurane. Arch. Neurol. 61, (2004). 36. Khongkhatithum, C., Thampratankul, L., Wiwattanadittakul, N. & Visudtibhan, A. Intravenous CM1 13:2 32 April 2015

8 levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures. Eur. J. Paediatr. Neurol. EJPN Off. J. Eur. Paediatr. Neurol. Soc. (2015). doi: /j.ejpn Knake, S. et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J. Neurol. Neurosurg. Psychiatry 79, (2008). 38.Gámez-Leyva, G., Aristín, J. L., Fernández, E. & Pascual, J. Experience with intravenous levetiracetam in status epilepticus: a retrospective case series. CNS Drugs 23, (2009). 39. Alvarez, V., Januel, J.-M., Burnand, B. & Rossetti, A. O. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia 52, (2011). 40. Höfler, J. & Trinka, E. Lacosamide as a new treatment option in status epilepticus. Epilepsia 54, (2013). 41. Paquette, V., Culley, C.,Greanya, E. D. & Ensom, M. H. H. Lacosamide as adjunctive therapy in refractory epilepsy in adults: a systematic review. Seizure 25, 1 17 (2015). 42.Sodemann, U., Møller, H. S., Blaabjerg, M. & Beier, C. P. Successful treatment of refractory absence status epilepticuswith lacosamide.j.neurol.261, (2014). 43. Asadi-Pooya, A. A., Jahromi, M. J., Izadi, S. & Emami, Y. Treatment of refractory generalized convulsive status epilepticus with enteral topiramate in resource limited settings. Seizure 24, (2015). 44.Towne, A. R., Garnett, L. K., Waterhouse, E. J., Morton, L. D. & DeLorenzo, R. J. The use of topiramate in refractory status epilepticus. Neurology 60, (2003). 45. Sheth, R. D. & Gidal, B. E. Refractory status epilepticus: response to ketamine. Neurology 51, (1998). 46. Kramer, A. H. Early Ketamine to Treat Refractory Status Epilepticus. Neurocrit. Care 16, (2012). 47. Murthy, J. M. K. & Naryanan, T. J. Continuous EEG monitoring in the evaluation of non-convulsive seizures and status epilepticus. Neurol. India 52, (2004). 48. Prasad, A. N., Stafstrom, C. F. & Holmes, G. L. Alternative epilepsy therapies: the ketogenic diet, immunoglobulins, and steroids. Epilepsia 37 Supple 1, S81 95 (1996). 49.Shorvon, S. & Ferlisi, M. The outcome of therapies in refractory and super-refractory convulsive status epilepticus recommendations for therapy.brain 135, (2012). 50.Englot, D. J., Chang, E. F. & Auguste, K. I. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. J. Neurosurg. 115, (2011). 51.Liu, A., Pang, T., Herman, S., Pascual-Leone, A. & Rotenberg, A. Transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit. Seizure 22, (2013). 52.Zhumadilov, A., Gilman, C. P. & Viderman, D. Management of super-refractory status epilepticus with isoflurane and hypothermia. Front. Neurol. 5, 286 (2014). ******************************************************** Laughter - The Best Medicine What Doctors Say, and What They're Really Thinking Well, well!..., what have we here...? He has no idea and is hoping you'll give him a clue. Let's see how it develops. Maybe in a few days I can pick up something curable. If it doesn't clear up in a week, give me a call. I don't know what it is. Maybe it will go away by itself. Well, we're not feeling so well today, are we...?" I'm stalling for time. I have no idea what you have. There is a lot of that going around." This is the third one this week. I'd better read up about it. I'd like to run some more tests." I can't figure out what's wrong. Maybe the kid in the lab can solve this one. CM1 13:2 33 April 2015