Acta Neurol Scand 2015: 132: 435–439 DOI: 10.1111/ane.12403
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Stiripentol for the treatment of super-refractory status epilepticus Strzelczyk A, Kortland L-M, Knake S, Rosenow F. Stiripentol for the treatment of super-refractory status epilepticus. Acta Neurol Scand 2015: 132: 435–439. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – To determine whether stiripentol (STP) might be a treatment option in super-refractory status epilepticus (SRSE). Methods – Medical records of patients treated due to a status epilepticus in Marburg between January 2013 and June 2014 were reviewed for administration of STP. Primary outcome measures were resolution of SE after initiation of STP. Results – Five adult patients were started with STP due to SRSE. The median age was 78 years (interquartile range [IQR] 11 years), and four patients were female. The median duration of SRSE before initiation of STP was 39 days (IQR 16 days), and the median number of anticonvulsants used before was 6 (IQR 1). SRSE ceased in three patients within 2–4 days after the start of STP. In two patients, SRSE continued after administration of STP and further escalation of anticonvulsant regimen. Both were switched eventually to supportive care only. None serious side effects were observed while on STP. Conclusions – Based on our presented cases and previous experimental animal data, STP may prove useful in treating super-refractory SE. Prospective trials are warranted to examine the efficacy of the STP in adults with refractory SE and to examine whether earlier treatment leads to better control of SE.
Introduction
Super-refractory status epilepticus (SRSE) is characterized by unresponsiveness to initial anesthetic therapy (1). This definition encompasses a status epilepticus (SE) that continues or recurs 24 h or more after the onset of anesthetic therapy and includes those cases in which SE recurs on the reduction or withdrawal of anesthesia (1). SRSE occurs in approximately 12% of all cases of SE (2). SRSE is associated with a high number of fatalities and high morbidity, and treatment is difficult due to the failure of first- and second-line therapy including the application of general anesthesia (3). As no controlled or randomized studies are available regarding SRSE, further therapeutic management is based on clinical reports, expert opinion, and pathophysiological assumptions based on experimental data (1, 3).
A. Strzelczyk1,2, L.-M. Kortland1, S. Knake1, F. Rosenow1,2 1 Department of Neurology and Epilepsy Center Hessen, Philipps-University, Marburg, Germany; 2Department of Neurology and Epilepsy Center Frankfurt Rhine-Main, J.W. Goethe University, Frankfurt am Main, Germany
Key words: status epilepticus; stiripentol; seizure; super-refractory A. Strzelczyk, Department of Neurology and Epilepsy Center Hessen, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany Tel.: +49 6421 5862990 Fax: +49 6421 5865444 e-mail: [email protected] Accepted for publication March 4, 2015
Recently, stiripentol (STP) was reported to be effective in a rodent model of established SE when seizures had already become resistant to treatment with benzodiazepines (4, 5). STP is authorized in the European Union as an orphan drug for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic–clonic seizures in patients with Dravet syndrome. Its efficacy in Dravet syndrome was shown in two small, randomized, placebo-controlled trials (6) and post-marketing studies (7). Given the severity of illness and unfavorable outcome in patients with SRSE (3, 8), there is a critical need for new therapies to stop ongoing seizure activity. Upon publication of the experimental animal data in SE, we considered STP as a potential option for compassionate use in SRSE. The objective of this study was to 435
Strzelczyk et al. determine the utilization, efficacy, and tolerability of STP in patients with SRSE. Methods
Since 2011, treatment of patients with SE is protocolled in detail in our department in a prospective registry approved as such by the local ethics committee. Subjects 24 h 4. VPA 6240 mg/day 5. Thiopental anesthesia >24 h 6. LCM 600 mg 7. TPM 400 mg 8. STP 4000 mg/day
1. LZP 3 mg/day 2. LEV 4000 mg/day 3. LCM 600 mg/day 4. Propofol anesthesia >24 h 5. Midazolam anesthesia >24 h 6. TPM 600 mg/day 7. PHT 1000 mg/day 8. PER 12 mg/day 9. STP 4000 mg/day 10. Steroids
1. LZP 5 mg/day 2. LEV 4000 mg/day 3. VPA 5000 mg/day 4. LCM 800 mg/day 5. Propofol anesthesia 6. Midazolam anesthesia >24 h 7. ZNS 400 mg/day 8. Thiopental anesthesia >24 h 9. TPM 600 mg/day 10. Ketamine anesthesia >24 h 11. PER 12 mg/day 12. Steroids 13. STP 6000 mg/day
Duration of SE before STP Time to EEG resolution after STP
20 days 2.5 days
47 days n.a.
39 days n.a.
29 days 4 days
Concurrent AEDs with STP
LZP, VPA, LEV, TPM, LCM 1039 h (43 days) 46 days 5 Rehabilitation facility 3 months 3 LEV 4000 mg/day LCM 600 mg/day TPM 400 mg/day
1. LZP 4 mg/day 2. LEV 4000 mg/day 3. LCM 400 mg/day 4. LTG 150 mg/day 5. PER 16 mg/day 6. CBZ 600 mg/day 7. TPM 600 mg/day 8. Propofol anesthesia >24 h 9. Midazolam anesthesia >24 h 10. VPA 3000 mg/day 11. Ketamine anesthesia >24 h 12. STP 4000 mg/day 13. Magnesium 14. PHT 750 mg/day 45 days 2 days, recurrence of SE 4 days later, resolution 18 days later LZP, VPA, LTG, LEV, PER, TPM 1292 h (53 days) 85 days 5 Rehabilitation facility 11 months 1 LEV 4000 mg/day STP 3000 mg/day ZNS 300 mg/day
NCSE dyscognitive status 3 LEV 4000 mg/day LCM 600 mg/day TPM 200 mg/day CLB 60 mg/day 1. LZP 3 mg 2. LEV 4000 mg/day 3. LCM 600 mg/day 4. TPM 400 mg/day 5. CLB 80 mg/day 6. Magnesium 7. Ketamine anesthesia >24 h 8. Steroids 9. PB 1000 mg/day 10. ketogenic diet 11. STP 4000 mg/day
LZP, LEV, LCM, ketogenic diet 567 h (23 days) 76 days 6 Death deceased 6 n.a.
LZP, LEV, PHT, PER
LZP, LEV, LCM, TPM, PER 635 h (26 days) 44 days 3–4 Rehabilitation facility 2 months 2 LEV 4000 mg/day LCM 600 mg/day STP 2000 mg/day
SE semiology STESS score AED therapy before admission
Ventilation time Total length of stay mRS score at discharge Disposition Follow-up mRS at last follow-up AEDs at follow-up
638 h (26 days) 61 days 5 Palliative care/nursing home deceased 6 n.a.
CBZ, carbamazepine; CLB, clobazam; CVE, cerebrovascular encephalopathy; GTCSE, generalized tonic–clonic status epilepticus; LCM, lacosamide; LEV, levetiracetam; LZP, lorazepam; LTG, lamotrigine; mRS, modified Rankin Scale; NCSE, non-convulsive status epilepticus; PB, phenobarbital; PER, perampanel; PHT, phenytoin; SE, status epilepticus; STESS, Status Epilepticus Severity Score; STP, stiripentol; TPM, topiramate; VPA, valproate; ZNS, zonisamide.
Discussion
We present five adult patients who were treated with STP for SRSE, and three of them had resolution of SE within 2–4 days after starting administration of STP. Although we describe a small cohort of patients, our study suggests that STP may be a novel therapeutic approach in treating patients with SRSE. Super-refractory status epilepticus is resistant to benzodiazepines, anticonvulsants, and general anesthesia. Pharmacoresistance to benzodiaze-
pines develops rapidly after SE onset and is due to an activity-dependent internalization of benzodiazepine-sensitive synaptic GABAA (c-aminobutyric acid) receptors during SE (11). Stiripentol is a positive allosteric modulator of GABAA receptors that enhances GABAA-mediated inhibition, including the potentiation of miniature inhibitory post-synaptic currents through the slowing of the decay rate (4, 5, 12). Cell recordings from dentate granule cells in hippocampal slices revealed that STP potentiates GABAergic inhibitory post-synaptic currents and 437
Strzelczyk et al. A
B
C
D
Figure 1. Consecutive EEG in patient #5: Before administration of stiripentol with electroencephalographic signs of left hemispheric status epilepticus (A), and at 3 h (B), 2 days (C), and 4 days (D) after initiation of stiripentol (STP) treatment, finally showing cessation of status epilepticus.
tonic currents by acting at a site on the GABAA receptor that is separate from the benzodiazepine binding site (4, 5). This potentiation persisted in established SE, whereas potentiation of GABAergic inhibition by benzodiazepines was lost (4, 5). Therefore, based on the experimental animal data and our presented cases, STP should be considered as a treatment option in SE. Stiripentol was administered in our patients as compassionate use after multiple approved drugs for treatment of SE, anesthetics, and other experimental therapies (1, 13, 14), such as lacosamide, perampanel, topiramate, zonisamide, steroids, magnesium, or ketogenic diet, had already failed. A major limitation of the current study remains its retrospective nature and adjunctive treatment with multiple AEDs, which STP might influence through its inhibitory effect on CYP2C19, CYP3A4, and CYP2D6 enzymes. While we protocolled in detail the specific order and duration of administered AEDs, we did not systematically obtain serum levels. We therefore cannot exclude the possibility that other interventions led to clinical improvement and seizure freedom. Conclusions
Based on our human data and previous experimental animal data, STP may prove useful in treating SRSE. Treatments that suppress refrac438
tory SE, that is, when administered >30 min after SE onset, are critically needed. Further studies should investigate whether earlier treatment with STP leads to better control of SE. STP could be evaluated in a double-blind fashion as add-on treatment to benzodiazepines upon presumed refractoriness of SE. Acknowledgement We are grateful to our colleagues and hospital staff for assistance in conducting the study and the excellent support of Ms Petra M€ uller (study coordinator).
Author contributions Adam Strzelczyk, MD, participated in design, data collection, analysis, and writing and review of the manuscript. Lena-Marie Kortland participated in design, data collection, and writing of the manuscript. Susanne Knake, MD, and Felix Rosenow, MD, participated in design, analysis, and review of the manuscript.
Funding No funding reported.
Conflict of interest Dr. Strzelczyk received honoraria from serving on scientific adivisory boards of Boehringer Ingelheim, Desitin, and Pfizer, received research support from Desitin and UCB
Stiripentol in super-refractory status epilepticus Pharma, and served on the speakers’ bureau of Desitin, Eisai, and UCB Pharma. He received travel support from Bayer HealthCare. He serves as an editorial board member of BMC Neurology. He received funding from University Hospitals Marburg and Giessen, and Deutsche Forschungsgemeinschaft. L.M. Kortland reports no disclosures. Dr. Knake served on the speakers’ bureau of Desitin and UCB. She received funding from Deutsche Forschungsgemeinschaft, the MJF Foundation, the Int. Parkinson Funds, and Behring-R€ ontgen-Stiftung and from University Hospitals Marburg and Giessen. Dr. Rosenow received honoraria as scientific advisor from GlaxoSmithKline, Eisai, UCB Pharma, and Pfizer. He received speaker honoraria from UCB Pharma, GlaxoSmithKline, Eisai, Desitin, Medtronic and educational grants from Nihon-Kohden, UCB Pharma, Medtronics, Cyberonics, and Cerbomed. He received funding from Deutsche Forschungsgemeinschaft and the European Union. Desitin is the distributor of stiripentol (DiacomitÒ, manufactured by Biocodex Laboratoires, France) in middle and eastern Europe.
References 1. SHORVON S, FERLISI M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802– 18. 2. TIAN L, LI Y, XUE X et al. Super-refractory status epilepticus in West China. Acta Neurol Scand 2014;DOI: 10.1111/ane.12336. Online first. 3. FERLISI M, SHORVON S. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain 2012;135: 2314–28.
4. GROSENBAUGH DK, MOTT DD. Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus. Neuropharmacology 2013;67:136–43. 5. GROSENBAUGH DK, MOTT DD. Stiripentol in refractory status epilepticus. Epilepsia 2013;54(Suppl. 6):103–5. 6. CHIRON C, MARCHAND MC, TRAN A et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 2000;356:1638–42. 7. WIRRELL EC, LAUX L, FRANZ DN et al. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. Epilepsia 2013;54:1595–604. 8. HOLTKAMP M, OTHMAN J, BUCHHEIM K, MASUHR F, SCHIELKE E, MEIERKORD H. A “malignant” variant of status epilepticus. Arch Neurol 2005;62:1428–31. 9. ROSENOW F. Status epilepticus im Erwachsenenalter. In: HC Diener et al., eds. Leitlinien f€ ur Diagnostik und Therapie in der Neurologie. Stuttgart: Thieme Verlag, 2012. 10. ROSSETTI AO, LOGROSCINO G, MILLIGAN TA, MICHAELIDES C, RUFFIEUX C, BROMFIELD EB. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol 2008;255:1561–6. 11. CHEN JW, WASTERLAIN CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006;5:246–56. 12. QUILICHINI PP, CHIRON C, BEN-ARI Y, GOZLAN H. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels. Epilepsia 2006;47:704–16. 13. KELLINGHAUS C, BERNING S, STOGBAUER F. Intravenous lacosamide or phenytoin for treatment of refractory status epilepticus. Acta Neurol Scand 2014;129:294–9. 14. STOJANOVA V, ROSSETTI AO. Oral topiramate as an addon treatment for refractory status epilepticus. Acta Neurol Scand 2012;125:e7–11.
439
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Clinical Commentary
Stiripentol for the treatment of super-refractory status epilepticus Strzelczyk A, Kortland L-M, Knake S, Rosenow F. Stiripentol for the treatment of super-refractory status epilepticus. Acta Neurol Scand 2015: 132: 435–439. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – To determine whether stiripentol (STP) might be a treatment option in super-refractory status epilepticus (SRSE). Methods – Medical records of patients treated due to a status epilepticus in Marburg between January 2013 and June 2014 were reviewed for administration of STP. Primary outcome measures were resolution of SE after initiation of STP. Results – Five adult patients were started with STP due to SRSE. The median age was 78 years (interquartile range [IQR] 11 years), and four patients were female. The median duration of SRSE before initiation of STP was 39 days (IQR 16 days), and the median number of anticonvulsants used before was 6 (IQR 1). SRSE ceased in three patients within 2–4 days after the start of STP. In two patients, SRSE continued after administration of STP and further escalation of anticonvulsant regimen. Both were switched eventually to supportive care only. None serious side effects were observed while on STP. Conclusions – Based on our presented cases and previous experimental animal data, STP may prove useful in treating super-refractory SE. Prospective trials are warranted to examine the efficacy of the STP in adults with refractory SE and to examine whether earlier treatment leads to better control of SE.
Introduction
Super-refractory status epilepticus (SRSE) is characterized by unresponsiveness to initial anesthetic therapy (1). This definition encompasses a status epilepticus (SE) that continues or recurs 24 h or more after the onset of anesthetic therapy and includes those cases in which SE recurs on the reduction or withdrawal of anesthesia (1). SRSE occurs in approximately 12% of all cases of SE (2). SRSE is associated with a high number of fatalities and high morbidity, and treatment is difficult due to the failure of first- and second-line therapy including the application of general anesthesia (3). As no controlled or randomized studies are available regarding SRSE, further therapeutic management is based on clinical reports, expert opinion, and pathophysiological assumptions based on experimental data (1, 3).
A. Strzelczyk1,2, L.-M. Kortland1, S. Knake1, F. Rosenow1,2 1 Department of Neurology and Epilepsy Center Hessen, Philipps-University, Marburg, Germany; 2Department of Neurology and Epilepsy Center Frankfurt Rhine-Main, J.W. Goethe University, Frankfurt am Main, Germany
Key words: status epilepticus; stiripentol; seizure; super-refractory A. Strzelczyk, Department of Neurology and Epilepsy Center Hessen, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany Tel.: +49 6421 5862990 Fax: +49 6421 5865444 e-mail: [email protected] Accepted for publication March 4, 2015
Recently, stiripentol (STP) was reported to be effective in a rodent model of established SE when seizures had already become resistant to treatment with benzodiazepines (4, 5). STP is authorized in the European Union as an orphan drug for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic–clonic seizures in patients with Dravet syndrome. Its efficacy in Dravet syndrome was shown in two small, randomized, placebo-controlled trials (6) and post-marketing studies (7). Given the severity of illness and unfavorable outcome in patients with SRSE (3, 8), there is a critical need for new therapies to stop ongoing seizure activity. Upon publication of the experimental animal data in SE, we considered STP as a potential option for compassionate use in SRSE. The objective of this study was to 435
Strzelczyk et al. determine the utilization, efficacy, and tolerability of STP in patients with SRSE. Methods
Since 2011, treatment of patients with SE is protocolled in detail in our department in a prospective registry approved as such by the local ethics committee. Subjects 24 h 4. VPA 6240 mg/day 5. Thiopental anesthesia >24 h 6. LCM 600 mg 7. TPM 400 mg 8. STP 4000 mg/day
1. LZP 3 mg/day 2. LEV 4000 mg/day 3. LCM 600 mg/day 4. Propofol anesthesia >24 h 5. Midazolam anesthesia >24 h 6. TPM 600 mg/day 7. PHT 1000 mg/day 8. PER 12 mg/day 9. STP 4000 mg/day 10. Steroids
1. LZP 5 mg/day 2. LEV 4000 mg/day 3. VPA 5000 mg/day 4. LCM 800 mg/day 5. Propofol anesthesia 6. Midazolam anesthesia >24 h 7. ZNS 400 mg/day 8. Thiopental anesthesia >24 h 9. TPM 600 mg/day 10. Ketamine anesthesia >24 h 11. PER 12 mg/day 12. Steroids 13. STP 6000 mg/day
Duration of SE before STP Time to EEG resolution after STP
20 days 2.5 days
47 days n.a.
39 days n.a.
29 days 4 days
Concurrent AEDs with STP
LZP, VPA, LEV, TPM, LCM 1039 h (43 days) 46 days 5 Rehabilitation facility 3 months 3 LEV 4000 mg/day LCM 600 mg/day TPM 400 mg/day
1. LZP 4 mg/day 2. LEV 4000 mg/day 3. LCM 400 mg/day 4. LTG 150 mg/day 5. PER 16 mg/day 6. CBZ 600 mg/day 7. TPM 600 mg/day 8. Propofol anesthesia >24 h 9. Midazolam anesthesia >24 h 10. VPA 3000 mg/day 11. Ketamine anesthesia >24 h 12. STP 4000 mg/day 13. Magnesium 14. PHT 750 mg/day 45 days 2 days, recurrence of SE 4 days later, resolution 18 days later LZP, VPA, LTG, LEV, PER, TPM 1292 h (53 days) 85 days 5 Rehabilitation facility 11 months 1 LEV 4000 mg/day STP 3000 mg/day ZNS 300 mg/day
NCSE dyscognitive status 3 LEV 4000 mg/day LCM 600 mg/day TPM 200 mg/day CLB 60 mg/day 1. LZP 3 mg 2. LEV 4000 mg/day 3. LCM 600 mg/day 4. TPM 400 mg/day 5. CLB 80 mg/day 6. Magnesium 7. Ketamine anesthesia >24 h 8. Steroids 9. PB 1000 mg/day 10. ketogenic diet 11. STP 4000 mg/day
LZP, LEV, LCM, ketogenic diet 567 h (23 days) 76 days 6 Death deceased 6 n.a.
LZP, LEV, PHT, PER
LZP, LEV, LCM, TPM, PER 635 h (26 days) 44 days 3–4 Rehabilitation facility 2 months 2 LEV 4000 mg/day LCM 600 mg/day STP 2000 mg/day
SE semiology STESS score AED therapy before admission
Ventilation time Total length of stay mRS score at discharge Disposition Follow-up mRS at last follow-up AEDs at follow-up
638 h (26 days) 61 days 5 Palliative care/nursing home deceased 6 n.a.
CBZ, carbamazepine; CLB, clobazam; CVE, cerebrovascular encephalopathy; GTCSE, generalized tonic–clonic status epilepticus; LCM, lacosamide; LEV, levetiracetam; LZP, lorazepam; LTG, lamotrigine; mRS, modified Rankin Scale; NCSE, non-convulsive status epilepticus; PB, phenobarbital; PER, perampanel; PHT, phenytoin; SE, status epilepticus; STESS, Status Epilepticus Severity Score; STP, stiripentol; TPM, topiramate; VPA, valproate; ZNS, zonisamide.
Discussion
We present five adult patients who were treated with STP for SRSE, and three of them had resolution of SE within 2–4 days after starting administration of STP. Although we describe a small cohort of patients, our study suggests that STP may be a novel therapeutic approach in treating patients with SRSE. Super-refractory status epilepticus is resistant to benzodiazepines, anticonvulsants, and general anesthesia. Pharmacoresistance to benzodiaze-
pines develops rapidly after SE onset and is due to an activity-dependent internalization of benzodiazepine-sensitive synaptic GABAA (c-aminobutyric acid) receptors during SE (11). Stiripentol is a positive allosteric modulator of GABAA receptors that enhances GABAA-mediated inhibition, including the potentiation of miniature inhibitory post-synaptic currents through the slowing of the decay rate (4, 5, 12). Cell recordings from dentate granule cells in hippocampal slices revealed that STP potentiates GABAergic inhibitory post-synaptic currents and 437
Strzelczyk et al. A
B
C
D
Figure 1. Consecutive EEG in patient #5: Before administration of stiripentol with electroencephalographic signs of left hemispheric status epilepticus (A), and at 3 h (B), 2 days (C), and 4 days (D) after initiation of stiripentol (STP) treatment, finally showing cessation of status epilepticus.
tonic currents by acting at a site on the GABAA receptor that is separate from the benzodiazepine binding site (4, 5). This potentiation persisted in established SE, whereas potentiation of GABAergic inhibition by benzodiazepines was lost (4, 5). Therefore, based on the experimental animal data and our presented cases, STP should be considered as a treatment option in SE. Stiripentol was administered in our patients as compassionate use after multiple approved drugs for treatment of SE, anesthetics, and other experimental therapies (1, 13, 14), such as lacosamide, perampanel, topiramate, zonisamide, steroids, magnesium, or ketogenic diet, had already failed. A major limitation of the current study remains its retrospective nature and adjunctive treatment with multiple AEDs, which STP might influence through its inhibitory effect on CYP2C19, CYP3A4, and CYP2D6 enzymes. While we protocolled in detail the specific order and duration of administered AEDs, we did not systematically obtain serum levels. We therefore cannot exclude the possibility that other interventions led to clinical improvement and seizure freedom. Conclusions
Based on our human data and previous experimental animal data, STP may prove useful in treating SRSE. Treatments that suppress refrac438
tory SE, that is, when administered >30 min after SE onset, are critically needed. Further studies should investigate whether earlier treatment with STP leads to better control of SE. STP could be evaluated in a double-blind fashion as add-on treatment to benzodiazepines upon presumed refractoriness of SE. Acknowledgement We are grateful to our colleagues and hospital staff for assistance in conducting the study and the excellent support of Ms Petra M€ uller (study coordinator).
Author contributions Adam Strzelczyk, MD, participated in design, data collection, analysis, and writing and review of the manuscript. Lena-Marie Kortland participated in design, data collection, and writing of the manuscript. Susanne Knake, MD, and Felix Rosenow, MD, participated in design, analysis, and review of the manuscript.
Funding No funding reported.
Conflict of interest Dr. Strzelczyk received honoraria from serving on scientific adivisory boards of Boehringer Ingelheim, Desitin, and Pfizer, received research support from Desitin and UCB
Stiripentol in super-refractory status epilepticus Pharma, and served on the speakers’ bureau of Desitin, Eisai, and UCB Pharma. He received travel support from Bayer HealthCare. He serves as an editorial board member of BMC Neurology. He received funding from University Hospitals Marburg and Giessen, and Deutsche Forschungsgemeinschaft. L.M. Kortland reports no disclosures. Dr. Knake served on the speakers’ bureau of Desitin and UCB. She received funding from Deutsche Forschungsgemeinschaft, the MJF Foundation, the Int. Parkinson Funds, and Behring-R€ ontgen-Stiftung and from University Hospitals Marburg and Giessen. Dr. Rosenow received honoraria as scientific advisor from GlaxoSmithKline, Eisai, UCB Pharma, and Pfizer. He received speaker honoraria from UCB Pharma, GlaxoSmithKline, Eisai, Desitin, Medtronic and educational grants from Nihon-Kohden, UCB Pharma, Medtronics, Cyberonics, and Cerbomed. He received funding from Deutsche Forschungsgemeinschaft and the European Union. Desitin is the distributor of stiripentol (DiacomitÒ, manufactured by Biocodex Laboratoires, France) in middle and eastern Europe.
References 1. SHORVON S, FERLISI M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802– 18. 2. TIAN L, LI Y, XUE X et al. Super-refractory status epilepticus in West China. Acta Neurol Scand 2014;DOI: 10.1111/ane.12336. Online first. 3. FERLISI M, SHORVON S. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain 2012;135: 2314–28.
4. GROSENBAUGH DK, MOTT DD. Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus. Neuropharmacology 2013;67:136–43. 5. GROSENBAUGH DK, MOTT DD. Stiripentol in refractory status epilepticus. Epilepsia 2013;54(Suppl. 6):103–5. 6. CHIRON C, MARCHAND MC, TRAN A et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 2000;356:1638–42. 7. WIRRELL EC, LAUX L, FRANZ DN et al. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. Epilepsia 2013;54:1595–604. 8. HOLTKAMP M, OTHMAN J, BUCHHEIM K, MASUHR F, SCHIELKE E, MEIERKORD H. A “malignant” variant of status epilepticus. Arch Neurol 2005;62:1428–31. 9. ROSENOW F. Status epilepticus im Erwachsenenalter. In: HC Diener et al., eds. Leitlinien f€ ur Diagnostik und Therapie in der Neurologie. Stuttgart: Thieme Verlag, 2012. 10. ROSSETTI AO, LOGROSCINO G, MILLIGAN TA, MICHAELIDES C, RUFFIEUX C, BROMFIELD EB. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol 2008;255:1561–6. 11. CHEN JW, WASTERLAIN CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006;5:246–56. 12. QUILICHINI PP, CHIRON C, BEN-ARI Y, GOZLAN H. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels. Epilepsia 2006;47:704–16. 13. KELLINGHAUS C, BERNING S, STOGBAUER F. Intravenous lacosamide or phenytoin for treatment of refractory status epilepticus. Acta Neurol Scand 2014;129:294–9. 14. STOJANOVA V, ROSSETTI AO. Oral topiramate as an addon treatment for refractory status epilepticus. Acta Neurol Scand 2012;125:e7–11.
439
