Status Epilepticus—Work-Up and Management in Children

Cristina Barcia Aguilar; Iván Sánchez Fernández; Tobias Loddenkemper

doi:10.1055/s-0040-1719076

Seminars in Neurology, Table of Contents

Semin Neurol 2020; 40(06): 661-674
DOI: 10.1055/s-0040-1719076

Review Article

Status Epilepticus—Work-Up and Management in Children

Authors

Cristina Barcia Aguilar

¹Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts

²Department of Child Neurology, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain
Iván Sánchez Fernández

¹Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts

³Department of Child Neurology, Hospital Sant Joan de Déu, University of Barcelona, Spain
Tobias Loddenkemper

¹Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts

Abstract

Status epilepticus (SE) is one of the most common neurological emergencies in children and has a mortality of 2 to 4%. Admissions for SE are very resource-consuming, especially in refractory and super-refractory SE. An increasing understanding of the pathophysiology of SE leaves room for improving SE treatment protocols, including medication choice and timing. Selecting the most efficacious medications and giving them in a timely manner may improve outcomes. Benzodiazepines are commonly used as first line and they can be used in the prehospital setting, where most SE episodes begin. The diagnostic work-up should start simultaneously to initial treatment, or as soon as possible, to detect potentially treatable causes of SE. Although most etiologies are recognized after the first evaluation, the detection of more unusual causes may become challenging in selected cases. SE is a life-threatening medical emergency in which prompt and efficacious treatment may improve outcomes. We provide a summary of existing evidence to guide clinical decisions regarding the work-up and treatment of SE in pediatric patients.

Keywords

pediatric status epilepticus - diagnosis - treatment

Full Text

References

References
1 Coeytaux A, Jallon P, Galobardes B, Morabia A. Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR). Neurology 2000; 55 (05) 693-697
2 Dham BS, Hunter K, Rincon F. The epidemiology of status epilepticus in the United States. Neurocrit Care 2014; 20 (03) 476-483
3 Raspall-Chaure M, Chin RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol 2006; 5 (09) 769-779
4 Neligan A, Noyce AJ, Gosavi TD, Shorvon SD, Köhler S, Walker MC. Change in mortality of generalized convulsive status epilepticus in high-income countries over time: a systematic review and meta-analysis. JAMA Neurol 2019; 76 (08) 897-905
5 Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC. NLSTEPSS Collaborative Group. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006; 368 (9531): 222-229
6 Schubert-Bast S, Zöllner JP, Ansorge S. et al. Burden and epidemiology of status epilepticus in infants, children, and adolescents: a population-based study on German health insurance data. Epilepsia 2019; 60 (05) 911-920
7 Penberthy LT, Towne A, Garnett LK, Perlin JB, DeLorenzo RJ. Estimating the economic burden of status epilepticus to the health care system. Seizure 2005; 14 (01) 46-51
8 Sánchez Fernández I, Loddenkemper T. Estimating the cost of admissions related to convulsive status epilepticus in the United States of America. Seizure 2018; 61: 186-198
9 Trinka E, Cock H, Hesdorffer D. et al. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia 2015; 56 (10) 1515-1523
10 Goodkin HP, Yeh JL, Kapur J. Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci 2005; 25 (23) 5511-5520
11 Wasterlain CG, Liu H, Naylor DE. et al. Molecular basis of self-sustaining seizures and pharmacoresistance during status epilepticus: the receptor trafficking hypothesis revisited. Epilepsia 2009; 50 (Suppl. 12) 16-18
12 Kittler JT, Delmas P, Jovanovic JN, Brown DA, Smart TG, Moss SJ. Constitutive endocytosis of GABAA receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons. J Neurosci 2000; 20 (21) 7972-7977
13 Jones DM, Esmaeil N, Maren S, Macdonald RL. Characterization of pharmacoresistance to benzodiazepines in the rat Li-pilocarpine model of status epilepticus. Epilepsy Res 2002; 50 (03) 301-312
14 Walton NY, Treiman DM. Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp Neurol 1988; 101 (02) 267-275
15 Kapur J, Macdonald RL. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J Neurosci 1997; 17 (19) 7532-7540
16 Rajasekaran K, Todorovic M, Kapur J. Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. Ann Neurol 2012; 72 (01) 91-102
17 Naylor DE, Liu H, Niquet J, Wasterlain CG. Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis 2013; 54: 225-238
18 Kapur J. Role of NMDA receptors in the pathophysiology and treatment of status epilepticus. Epilepsia Open 2018; 3 (Suppl. 02) 165-168
19 Broomall E, Natale JE, Grimason M. et al. Pediatric super-refractory status epilepticus treated with allopregnanolone. Ann Neurol 2014; 76 (06) 911-915
20 Vaitkevicius H, Husain AM, Rosenthal ES. et al. First-in-man allopregnanolone use in super-refractory status epilepticus. Ann Clin Transl Neurol 2017; 4 (06) 411-414
21 Meldrum BS, Horton RW. Physiology of status epilepticus in primates. Arch Neurol 1973; 28 (01) 1-9
22 Meldrum BS, Brierley JB. Prolonged epileptic seizures in primates. Ischemic cell change and its relation to ictal physiological events. Arch Neurol 1973; 28 (01) 10-17
23 Meldrum BS, Vigouroux RA, Brierley JB. Systemic factors and epileptic brain damage. Prolonged seizures in paralyzed, artificially ventilated baboons. Arch Neurol 1973; 29 (02) 82-87
24 Aminoff MJ, Simon RP. Status epilepticus. Causes, clinical features and consequences in 98 patients. Am J Med 1980; 69 (05) 657-666
25 Corsellis JA, Bruton CJ. Neuropathology of status epilepticus in humans. Adv Neurol 1983; 34: 129-139
26 Norman RM. The neuropathology of status epilepticus. Med Sci Law 1964; 4: 46-51
27 Lawrence R, Inder T. Neonatal status epilepticus. Semin Pediatr Neurol 2010; 17 (03) 163-168
28 Mastrangelo M, Celato A. Diagnostic work-up and therapeutic options in management of pediatric status epilepticus. World J Pediatr 2012; 8 (02) 109-115
29 Riviello Jr JJ, Ashwal S, Hirtz D. American Academy of Neurology Subcommittee, Practice Committee of the Child Neurology Society. et al. Practice parameter: diagnostic assessment of the child with status epilepticus (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2006; 67 (09) 1542-1550
30 Freilich ER, Schreiber JM, Zelleke T, Gaillard WD. Pediatric status epilepticus: identification and evaluation. Curr Opin Pediatr 2014; 26 (06) 655-661
31 Watemberg N, Segal G. A suggested approach to the etiologic evaluation of status epilepticus in children: what to seek after the usual causes have been ruled out. J Child Neurol 2010; 25 (02) 203-211
32 Hirsch LJ, Gaspard N, van Baalen A. et al. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia 2018; 59 (04) 739-744
33 Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure 2019; 68: 72-78
34 Brophy GM, Bell R, Claassen J. Neurocritical Care Society Status Epilepticus Guideline Writing Committee. et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17 (01) 3-23
35 Riviello Jr JJ, Claassen J, LaRoche SM. Neurocritical Care Society Status Epilepticus Guideline Writing Committee. et al. Treatment of status epilepticus: an international survey of experts. Neurocrit Care 2013; 18 (02) 193-200
36 Glauser T, Shinnar S, Gloss D. et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016; 16 (01) 48-61
37 Vasquez A, Gaínza-Lein M, Sánchez Fernández I. Pediatric Status Epilepticus Research Group (pSERG). et al. Hospital emergency treatment of convulsive status epilepticus: comparison of pathways from ten pediatric research centers. Pediatr Neurol 2018; 86: 33-41
38 Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 2005; 25 (34) 7724-7733
39 Eriksson K, Metsäranta P, Huhtala H, Auvinen A, Kuusela AL, Koivikko M. Treatment delay and the risk of prolonged status epilepticus. Neurology 2005; 65 (08) 1316-1318
40 Gaínza-Lein M, Sánchez Fernández I, Jackson M. Pediatric Status Epilepticus Research Group. et al. Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus. JAMA Neurol 2018; 75 (04) 410-418
41 Sánchez Fernández I, Abend NS, Agadi S. Pediatric Status Epilepticus Research Group (pSERG). et al. Time from convulsive status epilepticus onset to anticonvulsant administration in children. Neurology 2015; 84 (23) 2304-2311
42 Cohen NT, Chamberlain JM, Gaillard WD. Timing and selection of first antiseizure medication in patients with pediatric status epilepticus. Epilepsy Res 2019; 149: 21-25
43 Sánchez Fernández I, Gaínza-Lein M, Abend NS. Pediatric Status Epilepticus Research Group (pSERG). et al. Factors associated with treatment delays in pediatric refractory convulsive status epilepticus. Neurology 2018; 90 (19) e1692-e1701
44 Pellock JM, Marmarou A, DeLorenzo R. Time to treatment in prolonged seizure episodes. Epilepsy Behav 2004; 5 (02) 192-196
45 Sánchez Fernández I, Jackson MC, Abend NS. pediatric Status Epilepticus Research Group (pSERG). et al. Refractory status epilepticus in children with and without prior epilepsy or status epilepticus. Neurology 2017; 88 (04) 386-394
46 Hill CE, Parikh AO, Ellis C, Myers JS, Litt B. Timing is everything: where status epilepticus treatment fails. Ann Neurol 2017; 82 (02) 155-165
47 Abend NS, Loddenkemper T. Pediatric status epilepticus management. Curr Opin Pediatr 2014; 26 (06) 668-674
48 Chamberlain JMOP, Okada P, Holsti M. Pediatric Emergency Care Applied Research Network (PECARN). et al. Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. JAMA 2014; 311 (16) 1652-1660
49 Alldredge BK, Gelb AM, Isaacs SM. et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001; 345 (09) 631-637
50 Treiman DM, Meyers PD, Walton NY. Veterans Affairs Status Epilepticus Cooperative Study Group. et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 1998; 339 (12) 792-798
51 Sreenath TG, Gupta P, Sharma KK, Krishnamurthy S. Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: a randomized controlled trial. Eur J Paediatr Neurol 2010; 14 (02) 162-168
52 Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology 2006; 67 (02) 340-342
53 Aiguabella M, Falip M, Villanueva V. et al. Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: a multicentric observational study. Seizure 2011; 20 (01) 60-64
54 Fattouch J, Di Bonaventura C, Casciato S. et al. Intravenous levetiracetam as first-line treatment of status epilepticus in the elderly. Acta Neurol Scand 2010; 121 (06) 418-421
55 Kellinghaus C, Berning S, Immisch I. et al. Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand 2011; 123 (02) 137-141
56 Zhao ZY, Wang HY, Wen B, Yang ZB, Feng K, Fan JC. A comparison of midazolam, lorazepam, and diazepam for the treatment of status epilepticus in children: a network meta-analysis. J Child Neurol 2016; 31 (09) 1093-1107
57 Silbergleit R, Durkalski V, Lowenstein D. NETT Investigators. et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012; 366 (07) 591-600
58 Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Efficacy of nonvenous medications for acute convulsive seizures: a network meta-analysis. Neurology 2015; 85 (21) 1859-1868
59 Sánchez Fernández I, Gaínza-Lein M, Loddenkemper T. Nonintravenous rescue medications for pediatric status epilepticus: a cost-effectiveness analysis. Epilepsia 2017; 58 (08) 1349-1359
60 Nunley S, Glynn P, Rust S, Vidaurre J, Albert DVF, Patel AD. Healthcare utilization characteristics for intranasal midazolam versus rectal diazepam. J Child Neurol 2018; 33 (02) 158-163
61 Nunley S, Glynn P, Rust S, Vidaurre J, Albert DVF, Patel AD. A hospital-based study on caregiver preferences on acute seizure rescue medications in pediatric patients with epilepsy: Intranasal midazolam versus rectal diazepam. Epilepsy Behav 2019; 92: 53-56
62 Cereghino JJ, Mitchell WG, Murphy J, Kriel RL, Rosenfeld WE, Trevathan E. The North American Diastat Study Group. Treating repetitive seizures with a rectal diazepam formulation: a randomized study. Neurology 1998; 51 (05) 1274-1282
63 Dreifuss FE, Rosman NP, Cloyd JC. et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med 1998; 338 (26) 1869-1875
64 Pharmaceuticals. V. Diastat prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020648s014lbl.pdf. Accessed October 27, 2020
65 O'Regan ME, Brown JK, Clarke M. Nasal rather than rectal benzodiazepines in the management of acute childhood seizures?. Dev Med Child Neurol 1996; 38 (11) 1037-1045
66 Detyniecki K, Van Ess PJ, Sequeira DJ, Wheless JW, Meng TC, Pullman WE. Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters-a randomized, double-blind, placebo-controlled trial. Epilepsia 2019; 60 (09) 1797-1808
67 Gaínza-Lein M, Benjamin R, Stredny C, McGurl M, Kapur K, Loddenkemper T. Rescue medications in epilepsy patients: a family perspective. Seizure 2017; 52: 188-194
68 Penovich PE, Buelow J, Steinberg K, Sirven J, Wheless J. Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives. Neurologist 2017; 22 (06) 207-214
69 Chin RF, Neville BG, Peckham C, Wade A, Bedford H, Scott RC. Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7 (08) 696-703
70 Seinfeld S, Shinnar S, Sun S. FEBSTAT study team. et al. Emergency management of febrile status epilepticus: results of the FEBSTAT study. Epilepsia 2014; 55 (03) 388-395
71 Patel AD, Wood EG, Cohen DM. Reduced emergency department utilization by patients with epilepsy using QI methodology. Pediatrics 2017; 139 (02) 139
72 Miró J, Toledo M, Santamarina E. et al. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus: a multicentric prospective study. Seizure 2013; 22 (01) 77-79
73 Poddar K, Sharma R, Ng YT. Intravenous lacosamide in pediatric status epilepticus: an open-label efficacy and safety study. Pediatr Neurol 2016; 61: 83-86
74 Loddenkemper T, Goodkin HP. Treatment of pediatric status epilepticus. Curr Treat Options Neurol 2011; 13 (06) 560-573
75 d'Orsi G, Pascarella MG, Martino T. et al. Intravenous lacosamide in seizure emergencies: observations from a hospitalized in-patient adult population. Seizure 2016; 42: 20-28
76 Dalziel SR, Borland ML, Furyk J. PREDICT research network. et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet 2019; 393 (10186): 2135-2145
77 Lyttle MD, Rainford NEA, Gamble C. Paediatric Emergency Research in the United Kingdom & Ireland (PERUKI) collaborative. et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet 2019; 393 (10186): 2125-2134
78 Tiamkao S, Sawanyawisuth K, Chancharoen A. The efficacy of intravenous sodium valproate and phenytoin as the first-line treatment in status epilepticus: a comparison study. BMC Neurol 2013; 13: 98
79 Mundlamuri RC, Sinha S, Subbakrishna DK. et al. Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam--pilot study. Epilepsy Res 2015; 114: 52-58
80 Gujjar AR, Nandhagopal R, Jacob PC. et al. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: a prospective, randomized study. Seizure 2017; 49: 8-12
81 Chitsaz A, Mehvari J, Salari M, Gholami F, Najafi MR. A comparative assessment the efficacy of intravenous infusion of sodium valproate and phenytion in the treatment of status epilepticus. Int J Prev Med 2013; 4 (Suppl. 02) S216-S221
82 Chakravarthi S, Goyal MK, Modi M, Bhalla A, Singh P. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci 2015; 22 (06) 959-963
83 Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N. Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure 2007; 16 (06) 527-532
84 Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011; 52 (07) 1292-1296
85 Lee YJ, Yum MS, Kim EH, Ko TS. Intravenous levetiracetam versus phenobarbital in children with status epilepticus or acute repetitive seizures. Korean J Pediatr 2016; 59 (01) 35-39
86 Malamiri RA, Ghaempanah M, Khosroshahi N, Nikkhah A, Bavarian B, Ashrafi MR. Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial. Eur J Paediatr Neurol 2012; 16 (05) 536-541
87 Su Y, Liu G, Tian F. et al. Phenobarbital versus valproate for generalized convulsive status epilepticus in adults: a prospective randomized controlled trial in China. CNS Drugs 2016; 30 (12) 1201-1207
88 Kapur J, Elm J, Chamberlain JM. NETT and PECARN Investigators. et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med 2019; 381 (22) 2103-2113
89 Yu KT, Mills S, Thompson N, Cunanan C. Safety and efficacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures. Epilepsia 2003; 44 (05) 724-726
90 Olsen KB, Taubøll E, Gjerstad L. Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults. Acta Neurol Scand Suppl 2007; 187: 51-54
91 Tiamkao S, Sawanyawisuth K. Predictors and prognosis of status epilepticus treated with intravenous sodium valproate. Epileptic Disord 2009; 11 (03) 228-231
92 Eue S, Grumbt M, Müller M, Schulze A. Two years of experience in the treatment of status epilepticus with intravenous levetiracetam. Epilepsy Behav 2009; 15 (04) 467-469
93 Gámez-Leyva G, Aristín JL, Fernández E, Pascual J. Experience with intravenous levetiracetam in status epilepticus: a retrospective case series. CNS Drugs 2009; 23 (11) 983-987
94 Knake S, Gruener J, Hattemer K. et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J Neurol Neurosurg Psychiatry 2008; 79 (05) 588-589
95 Standish JC, Hilmas E, Falchek SJ. Levetiracetam for the treatment of pediatric status epilepticus: a case series. J Pediatr Neurol 2011; 9: 195-201
96 Atmaca MM, Orhan EK, Bebek N, Gurses C. Intravenous levetiracetam treatment in status epilepticus: a prospective study. Epilepsy Res 2015; 114: 13-22
97 Berning S, Boesebeck F, van Baalen A, Kellinghaus C. Intravenous levetiracetam as treatment for status epilepticus. J Neurol 2009; 256 (10) 1634-1642
98 Ortiz de la Rosa JS, Ladino LD, Rodríguez PJ, Rueda MC, Polanía JP, Castañeda AC. Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: a systematic review. Seizure 2018; 56: 34-40
99 Yorns Jr WR, Khurana DS, Carvalho KS, Hardison HH, Legido A, Valencia I. Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy. J Child Neurol 2014; 29 (01) 23-27
100 Misra UK, Dubey D, Kalita J. Comparison of lacosamide versus sodium valproate in status epilepticus: a pilot study. Epilepsy Behav 2017; 76: 110-113
101 Husain AM, Lee JW, Kolls BJ. et al. Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures. Ann Neurol 2018; 83: 1174-1185
102 Wilkes R, Tasker RC. Pediatric intensive care treatment of uncontrolled status epilepticus. Crit Care Clin 2013; 29 (02) 239-257
103 Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies. Seizure 2014; 23 (03) 167-174
104 Sánchez Fernández I, Gaínza-Lein M, Lamb N, Loddenkemper T. Meta-analysis and cost-effectiveness of second-line antiepileptic drugs for status epilepticus. Neurology 2019; 92 (20) e2339-e2348
105 Price KE, Pearce RE, Garg UC. et al. Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study. Clin Pharmacol Ther 2011; 89 (06) 867-874
106 Sánchez Fernández I, Abend NS, Agadi S. Pediatric Status Epilepticus Research Group (pSERG). et al. Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG). Seizure 2014; 23 (02) 87-97
107 Vasquez A, Farias-Moeller R, Tatum W. Pediatric refractory and super-refractory status epilepticus. Seizure 2019; 68: 62-71
108 Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol 2011; 10 (10) 922-930
109 Marchi NA, Novy J, Faouzi M, Stähli C, Burnand B, Rossetti AO. Status epilepticus: impact of therapeutic coma on outcome. Crit Care Med 2015; 43 (05) 1003-1009
110 Hocker SE, Shorvon S. Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study. Neurology 2014; 83 (09) 866
111 Sutter R, De Marchis GM, Semmlack S. et al. Anesthetics and outcome in status epilepticus: a matched two-center cohort study. CNS Drugs 2017; 31 (01) 65-74
112 Alvarez V, Lee JW, Westover MB. et al. Therapeutic coma for status epilepticus: differing practices in a prospective multicenter study. Neurology 2016; 87 (16) 1650-1659
113 Gaínza-Lein M, Sánchez Fernández I, Anderson A. et al. Continuous infusion and outcome in pediatric refractory status epilepticus (the pSERG cohort). Abstract presented at: American Epilepsy Society Annual Meeting 2017. 2017. Washington, DC:
114 Keros S, Buraniqi E, Alex B. et al. Increasing ketamine use for refractory status epilepticus in US pediatric hospitals. J Child Neurol 2017; 32 (07) 638-646
115 Tasker RC, Goodkin HP, Sánchez Fernández I. Pediatric Status Epilepticus Research Group. et al. Refractory status epilepticus in children: intention to treat with continuous infusions of midazolam and pentobarbital. Pediatr Crit Care Med 2016; 17 (10) 968-975
116 Koul R, Chacko A, Javed H, Al Riyami K. Eight-year study of childhood status epilepticus: midazolam infusion in management and outcome. J Child Neurol 2002; 17 (12) 908-910
117 Wilkes R, Tasker RC. Intensive care treatment of uncontrolled status epilepticus in children: systematic literature search of midazolam and anesthetic therapies. Pediatr Crit Care Med 2014; 15 (07) 632-639
118 Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002; 43 (02) 146-153
119 van Gestel JP, Blussé van Oud-Alblas HJ, Malingré M, Ververs FF, Braun KP, van Nieuwenhuizen O. Propofol and thiopental for refractory status epilepticus in children. Neurology 2005; 65 (04) 591-592
120 Gaspard N, Foreman B, Judd LM. et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia 2013; 54 (08) 1498-1503
121 Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011; 134 (Pt 10): 2802-2818
122 Ferlisi M, Shorvon S. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain 2012; 135 (Pt 8): 2314-2328
123 Arya R, Peariso K, Gaínza-Lein M. pediatric Status Epilepticus Research Group (pSERG). et al. Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res 2018; 144: 1-6
124 Appavu B, Vanatta L, Condie J, Kerrigan JF, Jarrar R. Ketogenic diet treatment for pediatric super-refractory status epilepticus. Seizure 2016; 41: 62-65
125 Legriel S, Lemiale V, Schenck M. HYBERNATUS Study Group. et al. Hypothermia for neuroprotection in convulsive status epilepticus. N Engl J Med 2016; 375 (25) 2457-2467
126 Amengual-Gual M, Sánchez Fernández I, Wainwright MS. Novel drugs and early polypharmacotherapy in status epilepticus. Seizure 2019; 68: 79-88
127 Alvarez V, Rossetti AO. Monotherapy or polytherapy for first-line treatment of SE?. J Clin Neurophysiol 2016; 33 (01) 14-17
128 Löscher W. Single versus combinatorial therapies in status epilepticus: novel data from preclinical models. Epilepsy Behav 2015; 49: 20-25
129 Sabharwal V, Ramsay E, Martinez R. et al. Propofol-ketamine combination therapy for effective control of super-refractory status epilepticus. Epilepsy Behav 2015; 52 (Pt A): 264-266
130 Aranda A, Foucart G, Ducassé JL, Grolleau S, McGonigal A, Valton L. Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice. Epilepsia 2010; 51 (10) 2159-2167
131 Navarro V, Dagron C, Elie C. SAMUKeppra investigators. et al. Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial. Lancet Neurol 2016; 15 (01) 47-55
132 Pujar SS, Neville BG, Scott RC, Chin RF. North London Epilepsy Research Network. Death within 8 years after childhood convulsive status epilepticus: a population-based study. Brain 2011; 134 (Pt 10): 2819-2827
133 Pujar SS, Martinos MM, Cortina-Borja M. North London Epilepsy Research Network. et al. Long-term prognosis after childhood convulsive status epilepticus: a prospective cohort study. Lancet Child Adolesc Health 2018; 2 (02) 103-111
134 Maytal J, Shinnar S, Moshé SL, Alvarez LA. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989; 83 (03) 323-331
135 Verity CM, Ross EM, Golding J. Outcome of childhood status epilepticus and lengthy febrile convulsions: findings of national cohort study. BMJ 1993; 307 (6898): 225-228
136 Wu YW, Shek DW, Garcia PA, Zhao S, Johnston SC. Incidence and mortality of generalized convulsive status epilepticus in California. Neurology 2002; 58 (07) 1070-1076
137 DeLorenzo RJ, Hauser WA, Towne AR. et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996; 46 (04) 1029-1035
138 Logroscino G, Hesdorffer DC, Cascino GD, Annegers JF, Bagiella E, Hauser WA. Long-term mortality after a first episode of status epilepticus. Neurology 2002; 58 (04) 537-541
139 Sculier C, Gaínza-Lein M, Sánchez Fernández I, Loddenkemper T. Long-term outcomes of status epilepticus: a critical assessment. Epilepsia 2018; 59 (Suppl 2): 155-169
140 Martinos MM, Pujar S, Gillberg C. et al. Long-term behavioural outcomes after paediatric convulsive status epilepticus: a population-based cohort study. Dev Med Child Neurol 2018; 60 (04) 409-416
141 Wagenman KL, Blake TP, Sanchez SM. et al. Electrographic status epilepticus and long-term outcome in critically ill children. Neurology 2014; 82 (05) 396-404
142 Lewis DV, Shinnar S, Hesdorffer DC. FEBSTAT Study Team. et al. Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study. Ann Neurol 2014; 75 (02) 178-185
143 Yoong M, Martinos MM, Chin RF, Clark CA, Scott RC. Hippocampal volume loss following childhood convulsive status epilepticus is not limited to prolonged febrile seizures. Epilepsia 2013; 54 (12) 2108-2115
144 Arya R, Rotenberg A. Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus. Seizure 2019; 68: 89-96
145 Hirtz D, Ashwal S, Berg A. et al. Practice parameter: evaluating a first nonfebrile seizure in children: report of the quality standards subcommittee of the American Academy of Neurology, The Child Neurology Society, and The American Epilepsy Society. Neurology 2000; 55 (05) 616-623