Seizure 24 (2015) 114–117
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Treatment of refractory generalized convulsive status epilepticus with enteral topiramate in resource limited settings Ali A. Asadi-Pooya a,b,c,*, Maryam Jalali Jahromi b, Sadegh Izadi b, Yasaman Emami a a
Neurosciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Department of Neurology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran c Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 August 2014 Received in revised form 22 September 2014 Accepted 25 September 2014
Purpose: To explore the feasibility, safety and efficacy of enterally administered topiramate (TPM) as an adjunctive treatment for adult patients with refractory generalized convulsive status epilepticus (RGCSE). Methods: This prospective open-label non-randomized clinical trial was performed at Namazee hospital, Shiraz University of Medical Sciences, Shiraz, Iran from January 2013 through February 2014. Patients 18 years of age and older with RGCSE were enrolled. Topiramate was used, in case of failure of at least two standard anti-epileptic drugs in patients in whom the standard third or fourth line therapies were not available. Topiramate tablets were crushed and administered through the nasogastric tube; 400 mg stat and then 200 mg Bid. Status epilepticus response to TPM was categorized as successful (termination of SE within 24 h following TPM introduction, without modification of concomitant AEDs), possible (SE termination associated with the introduction of TPM, concomitantly with other medications) or unsuccessful. Results: Twenty patients were studied. Topiramate was successful in terminating SE in five (25%) patients; possibly successful in 11 (55%); and not successful in four (20%). No clinically significant adverse effects related to TPM administration were observed. Eleven (55%) patients returned to their baseline clinical condition at the time of discharge from the hospital, but two (10%) patients did not. Conclusion: Treatment with enterally administered topiramate could potentially be efficacious in some patients and appeared to be tolerated well in patients with RGCSE. Low cost and feasibility makes TPM a potentially useful agent in treating patients with RGCSE, especially in resource limited settings. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Adults Status Epilepticus Topiramate Adverse-effects
1. Introduction Status epilepticus (SE) is the most frequent neurological emergency requiring admission to a hospital and often times to an intensive care unit (ICU).1 Untreated, SE can cause serious brain damage and possibly death. Chances of treatment failure of SE rise and prognosis deteriorates with increasing duration of SE, especially if duration exceeds 1 h.2 Refractory generalized convulsive status epilepticus (RGCSE), defined as SE that fails to respond to the acute administration of two antiepileptic drugs (AEDs), occurs in approximately one third of patients with SE, and is associated with increased hospital length of stay, mortality, and
* Corresponding author at: Neurosciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Tel.: +98 9352274990. E-mail addresses: [email protected], [email protected] (A.A. Asadi-Pooya).
functional disability.3 Therefore, rapid treatment of SE is crucial in preventing severe morbidity and mortality; however, this may result in severe iatrogenic complications. Third-line therapies for SE with sedating or anesthetic effects predict poor outcome and death in status epilepticus. Hypotension requiring vasopressor therapy and longer duration of mechanical ventilation induced by these agents may be contributing factors.4 Of course outcome is linked to etiology as well. Good outcome even after prolonged treatment of RGCSE have been reported in some patients.3 Therefore, having more therapeutic options for SE, particularly novel treatment options with more favorable adverse-effect profiles are warranted. Topiramate is a widely used second generation, broadspectrum AED with a favorable pharmacological profile (e.g., absorption is rapid after enteral administration with peak serum concentration 1–4 h after administration). Topiramate blocks voltage-sensitive sodium channels. Topiramate also enhances the activity of GABA at GABA-A receptors by increasing the
http://dx.doi.org/10.1016/j.seizure.2014.09.009 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
A.A. Asadi-Pooya et al. / Seizure 24 (2015) 114–117
frequency at which GABA activates GABA-A receptors. In addition, topiramate inhibits excitatory transmission by antagonizing some types of glutamate receptors. It may also potentiate ATP activated inward rectifying potassium channels. Topiramate is also a weak carbonic anhydrase inhibitor.5 A small number of reports have described the use of topiramate (TPM) in RGCSE in adults and in children.6–8 The aim of the current study was to explore the feasibility, safety profile and efficacy of enterally administered topiramate as an adjunctive treatment for adult patients with RGCSE, especially when the resources are limited.
115
minor adverse effects (e.g., gastro-intestinal upset) of TPM were not studied. This study was conducted in accordance with local ethical regulations with approval by Shiraz University of Medical Sciences Review Board and Ethics Committee (IRCT # 16520 and grant # 90-01-55-2947). All primary care-givers of the patients consented in writing to their participation, after the scope of the study has been explained in a form understandable to them. The collected data was kept confidential through codes. All care-givers of the patients were advised that TPM was not an approved therapy for SE. They were informed of possible adverse drug effects related to TPM.
2. Materials and methods 3. Results This prospective single center open-label non-randomized clinical trial was performed at Namazee hospital, Shiraz University of Medical Sciences, Shiraz, Iran from January 2013 through February 2014. In this study, patients 18 years of age and older with RGCSE were enrolled. Status epilepticus was defined as the clinical occurrence of an ongoing seizure for more than 5 min or repeated seizures without full recovery in between for more than 30 min.9 All patients underwent EEG (at least one 20-min EEG), which was performed the day after hospital admission and later on, due to shortage of personnel in the afternoon and night shifts. All patients underwent brain imaging (CT scan or MRI); laboratory work-up and cerebro-spinal fluid (CSF) analysis was performed as needed. Status epilepticus termination was defined as resolution of clinical ictal signs (i.e., cessation of motor activity and improvement in responsiveness) and confirmed with the disappearance of continuous or repetitive epileptiform discharges on the EEG, assessed at least daily. Topiramate was used as an add-on treatment, in case of failure of two standard AEDs (i.e., intravenous diazepam and phenytoin) and after 30–40 min from the second line (i.e., 10 min after infusion of phenytoin had completed), in patients in whom the standard third line therapy (i.e., intravenous phenobarbital or valproate) was not available or possible (e.g., due to costs, contraindications, etc.), or ICU was not accessible to start the line four of therapy (i.e., intravenous midazolam, propofol, or pentobarbital). Topiramate tablets were crushed and administered through the nasogastric tube. Topiramate dose was 400 mg stat and then 200 mg twice per day, starting 12 h after the bolus dose. Status epilepticus response to TPM was categorized as successful (termination of SE within 24 h following TPM introduction, without modification of concomitant AEDs), possible (SE termination associated with the introduction of TPM, concomitantly with other medications, in case the third line and/or the fourth line of therapy become available after introduction of TPM and within 24 h) or unsuccessful (no response to TPM treatment after 24 h). In patients in whom TPM was successful to stop SE after the 1st (diazepam) and the 2nd (phenytoin) line of treatment failed, we did not prescribe standard third or fourth line of therapy. We prescribed the standard third (i.e., phenobarbital or valproate) or fourth line (i.e., midazolam, propofol, or pentobarbital) therapy at any time, if they became available and the seizures were still ongoing. Successful and possible responses imply that SE does not recur during the same hospitalization. In successful and possible responses, the patient was discharged with TPM 100 mg twice per day for at least 1 month, along with other required therapies (either AEDs or others as needed). Outcome was assessed at the time of discharge from hospital, and categorized as return to the baseline clinical condition, new handicap, or death. The recorded variables included: age, gender, previous epilepsy, other etiology of SE, time to response after TPM administration, TPM success, side effects (e.g., metabolic acidosis, hemodynamic problems, renal stone, etc.), and outcome at discharge. Cognitive side effects and
Twenty patients (14 males and 6 females) were enrolled in the study. The minimum age of the patients was 18 years and the maximum age was 92 (mean = 44.45 and standard deviation = 23.15 years). The clinical characteristics of the patients are shown in Table 1. Four patients were known cases of epilepsy and the remaining had new onset epileptic seizures (presenting as SE). None of the patients with epilepsy were receiving topiramate before. The etiology of SE was as follows: cerebrovascular accidents in four people, neurosurgical conditions in four patients [head injury (in two), brain tumor, subdural empyema], preexisting epilepsy in four cases (in three patients due to stopping their medication and in one due to change in medication by the treating physician), underlying medical conditions in three patients (liver transplantation, myocardial infarction and hepatic encephalopathy), unidentified etiology in three cases, hypoxic brain damage in one and post-operative SE in one patient. Topiramate was successful in terminating RGCSE in five (25%) patients. Status epilepticus stopped after 42 12 min (median: 45 min, range: 30–60 min) from administration of TPM in these five patients. Topiramate was possibly successful in stopping SE in 11 (55%) patients. Status epilepticus stopped after 148 152 min from administration of TPM in these patients (range: 45–480 min). Topiramate was not successful in stopping SE in four (20%) patients. We did not observe any clinically significant adverse effects related to TPM administration in these patients. Thirteen patients (65%) needed intratracheal intubations (due to prolonged convulsions and hemodynamic instability or alternatively drug side effects). None of the patients had cardiac arrhythmia or change in blood pressure during intravenous phenytoin therapy. Later hemodynamic instability in the above-mentioned patients was attributed to the prolonged duration of status epilepticus, side effects of other prescribed drugs (e.g., phenobarbital or midazolam) or the underlying etiology (e.g., cerebrovascular accident or hepatic encephalopathy). Eleven (55%) patients returned to their baseline clinical condition at the time of discharge from hospital. Two (10%) patients did not return to their baseline clinical condition at the time of discharge from hospital and suffered some neurological sequelae. Unfortunately, seven (35%) patients died during their hospital stay. Four patients were nonresponders, who died of refractory seizures. Two patients were among possible responders; one of them died due to renal failure and pneumonia and another patient died because of end-stage pancreatic cancer. One patient, who was a responder, died of pneumonia and respiratory failure. In other words, mortality was 20% (one out of five) among responders and 18% (2 out of 11) among possible responders. Mortality was 100% (four out of four) among non-responders. 4. Discussion Management of refractory SE is often challenging with disappointing results in some patients and significant morbidity (either treatment related or disease related) and even mortality in
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Table 1 The clinical characteristics of the patients studied. Outcome
Success
Intubation
Death
Successful
No
60 30
Postthoracotomy CVA CVA
Successful Successful
No No
1200
30
Epilepsy
Successful
No
10
1600
45
MI
Successful
No
10
10
1200
60
Hypoxia
Hemiplegia Baseline clinical condition Baseline clinical condition Baseline clinical condition Death
Possible
Yes
GCSE
10
10
1400
420
Yes
GCSE
10
10
1200
150
Possible
Yes
Male
60
GCSE
3
10
1200
45
Base line clinical conditiona Baseline clinical condition Death
Possible
60
Previous head trauma High grade glioma Un identified
Possible
Yes
73
Male
70
GCSE
10
10
1400
60
No
18
Male
70
GCSE
10
10
1400
75
Possible
Yes
12
32
Male
60
GCSE
20
20
1200
60
Possible
Yes
13
51
Male
60
GCSE
2
10
1200
75
Possible
Yes
14
24
Male
60
GCSE
10
10
1200
480
Possible
Yes
15
60
Male
70
GCSE
2
10
1400
120
Baseline clinical condition Baseline clinical condition Baseline clinical condition Baseline clinical condition Baseline clinical condition Hemiplegia
Possible
11
Previous head trauma Sub-dural empyema Epilepsy
Possible
Yes
16
18
Male
80
GCSE
10
10
1600
90
17
25
Female
80
GCSE
10
10
1600
2880
18
23
Male
60
GCSE
10
10
1200
180
PBT 30 min after TPM
19
61
Male
60
GCSE
2
10
1200
240
20
23
Female
70
GCSE
3
10
1400
180
PBT 35 min after TPM MDL 40 min after TPM
Dose of PHT (mg) (line 2)
2
10
1200
45
GCSE GCSE
2 5
10 10
1400 1000
60
GCSE
15
10
Male
70
GCSE
15
46
Female
60
GCSE
7
24
Male
70
8
37
Male
9
70
10
Age
Sex
Weight (Kg)
Type of SE
1
40
Male
60
GCSE
2 3
90 92
Female Female
70 50
4
37
Female
5
45
6
Time interval between diagnosis of SE and treatment (min)
Line 3
MDL 30 min after TPM MDL 35 min after TPM PBT 35 min after TPM PBT 30 min after TPM SV 35 min after TPM PBT 35 min after TPM MDL 30 min after TPM PROP 35 min after TPM PBT 35 min after TPM SV 35 min after TPM SV 30 min after TPM SV 30 min after TPM
Line 4
PROP 3 h after MDL MDL 1.5 h after PBT
Liver Tx MDL after MDL after
3h PBT 1h SV
Epilepsy CVA Epilepsy
MDL 1 h after SV + PROP 4 h after MDL MDL 30 min after PBT + PROP 1 h after MDL MDL 1 h after PBT
Possible
No
Un identified
Baseline clinical condition Death
Unsuccessful
Yes
Un identified
Death
Unsuccessful
Yes
CVA
Death
Unsuccessful
Yes
HE
Death
Unsuccessful
Yes
SE, status epilepticus; GCSE, generalized convulsive status epilepticus; DZP, diazepam; PHT, phenytoin; TPM, topiramate; SV, sodium valproate; MDL, midazolam; PROP, propofol; PBT, phenobarbital; Tx, transplantation; CVA, cerebrovascular accident; MI, myocardial infarction; HE, hepatic encephalopathy. a Alive without major neurological problem.
A.A. Asadi-Pooya et al. / Seizure 24 (2015) 114–117
Cause
Duration of SE after TPM was given (min)
Dose of DZP (mg) (line 1)
Patient
A.A. Asadi-Pooya et al. / Seizure 24 (2015) 114–117
others. When resources are limited, the situation is even more challenging. At our center, we do not have access to continuous EEG monitoring for patients with SE. Besides, intravenous lorazepam, intravenous levetiracetam, intravenous lacosamide and sometimes even intravenous valproate are not available. At times, ICU beds are not available and patients should be on a waiting list for a bed at one of the ICUs at the hospital to be available. In the current study, RGCSE could be terminated in 80% of the patients receiving TPM as the third-line therapy. However, in only 25% of the patients the success in terminating SE could possibly be directly related to TPM administration. In the remaining patients (55%), the termination of RGCSE could be related to both topiramate and the natural course of the disease in the presence of several other treatments for SE. Even in those 25%, in a clinical setting when TPM was applied as third line therapy after second line of therapy, it is difficult to ascertain whether TPM alone would have terminated the SE or the combination of different medications was necessary to do the job. Besides, the cerebral peak level is reached slower than the blood level; hence, those patients who reached seizure control in less than 90 min [12 patients (60%)] after topiramate administration may well have responded to the intravenous phenytoin loading rather than the topiramate. But, standard care does not allow waiting for 90 min before a third line therapy is administered if phenytoin proves to be unsuccessful in stopping SE after 10 min of its administration. We did not observe any significant clinical adverse-effects related to TPM. These results were similar to observations in previous studies.6,7 Safety and efficacy of oral TPM seems to be acceptable compared to those with intravenous lacosamide and intravenous levetiracetam for adjunctive treatment of refractory status epilepticus.10–12 Future studies should compare these new medications in treatment of RGCSE. However, cost of TPM is not comparable to these new intravenous formulations of AEDs. Mortality of the patients with RSE was 35% in our study that is similar to some previous studies6 and is much higher than other reports.7 Mortality is not strictly dependent on failure to terminate RGCSE, but also on the underlying etiology of RGCSE. This could explain the observed disparity between various studies. However, we observed that mortality was significantly higher if patients did not respond to topiramate. 5. Conclusion Treatment with enterally administered topiramate could potentially be efficacious in some patients and appeared to be tolerated well in patients with RGCSE. Low cost and feasibility (route of administration and desirable pharmacological profile, including adverse effects) makes TPM a potentially useful agent in treating patients with RGCSE, in resource limited settings, in which
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the standard third line therapy is not accessible, or facilities (e.g., ICU) are not available to start the next lines of standard therapy. 6. Limitations of the study The number of patients studied was small and this was not a double blind randomized clinical trial. We did not have access to continuous EEG monitoring to ascertain the seizure termination electrophysiologically. Conflict of interest statement The authors have no conflict of interest with regard to this study. Acknowledgements This study was the result of the medical thesis by Dr. Maryam Jalali Jahromi (grant # 90-01-55-2947). We would like to thank Shiraz Medical School, Shiraz University of Medical Sciences for their support. References 1. Dham BS, Hunter K, Rincon F. The epidemiology of status epilepticus in the United States. Neurocrit Care 2014 [Epub ahead of print]. 2. Hillman J, Lehtima¨ki K, Peltola J, Liimatainen S. Clinical significance of treatment delay in status epilepticus. Int J Emerg Med 2013;6(1):6. 3. Hocker S, Wijdicks EF, Rabinstein AA. Refractory status epilepticus: new insights in presentation, treatment, and outcome. Neurol Res 2013;35(2): 163–8. 4. Kowalski RG, Ziai WC, Rees RN, Werner Jr JK, Kim G, Goodwin H, et al. Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation. Crit Care Med 2012;40(9): 2677–84. 5. Asadi-Pooya AA, Sperling MR. Antiepileptic Drugs A Clinician’s Manual. Oxford University Press; 2009. ISBN-13: 978-0-19-536821-5; ISBN-10: 0-19-536821-5. 6. Hottinger A, Sutter R, Marsch S, Ru¨egg S. Topiramate as an adjunctive treatment in patients with refractory status epilepticus: an observational cohort study. CNS Drugs 2012;26(9):761–72. 7. Synowiec AS, Yandora KA, Yenugadhati V, Valeriano JP, Schramke CJ, Kelly KM. The efficacy of topiramate in adult refractory status epilepticus: experience of a tertiary care center. Epilepsy Res 2012;98(2–3):232–7. 8. Akyildiz BN, Kumandas¸ S. Treatment of pediatric refractory status epilepticus with topiramate. Childs Nerv Syst 2011;27(9):1425–30. 9. Riviello Jr JJ, Claassen J, Laroche SM, et al. Treatment of status epilepticus: an international survey of experts. Neurocrit Care 2013;18(2):193–200. 10. Sutter R, Marsch S, Ru¨egg S. Safety and efficacy of intravenous lacosamide for adjunctive treatment of refractory status epilepticus: a comparative cohort study. CNS Drugs 2013;27(4):321–9. 11. Miro´ J, Toledo M, Santamarina E, Ricciardi AC, Villanueva V, Pato A, et al. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus: a multicentric prospective study. Seizure 2013;22(1):77–9. 12. Mo¨ddel G, Bunten S, Dobis C, Kovac S, Dogan M, Fischera M, et al. Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus. J Neurol Neurosurg Psychiatry 2009;80(6):689–92.
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Treatment of refractory generalized convulsive status epilepticus with enteral topiramate in resource limited settings Ali A. Asadi-Pooya a,b,c,*, Maryam Jalali Jahromi b, Sadegh Izadi b, Yasaman Emami a a
Neurosciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Department of Neurology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran c Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 August 2014 Received in revised form 22 September 2014 Accepted 25 September 2014
Purpose: To explore the feasibility, safety and efficacy of enterally administered topiramate (TPM) as an adjunctive treatment for adult patients with refractory generalized convulsive status epilepticus (RGCSE). Methods: This prospective open-label non-randomized clinical trial was performed at Namazee hospital, Shiraz University of Medical Sciences, Shiraz, Iran from January 2013 through February 2014. Patients 18 years of age and older with RGCSE were enrolled. Topiramate was used, in case of failure of at least two standard anti-epileptic drugs in patients in whom the standard third or fourth line therapies were not available. Topiramate tablets were crushed and administered through the nasogastric tube; 400 mg stat and then 200 mg Bid. Status epilepticus response to TPM was categorized as successful (termination of SE within 24 h following TPM introduction, without modification of concomitant AEDs), possible (SE termination associated with the introduction of TPM, concomitantly with other medications) or unsuccessful. Results: Twenty patients were studied. Topiramate was successful in terminating SE in five (25%) patients; possibly successful in 11 (55%); and not successful in four (20%). No clinically significant adverse effects related to TPM administration were observed. Eleven (55%) patients returned to their baseline clinical condition at the time of discharge from the hospital, but two (10%) patients did not. Conclusion: Treatment with enterally administered topiramate could potentially be efficacious in some patients and appeared to be tolerated well in patients with RGCSE. Low cost and feasibility makes TPM a potentially useful agent in treating patients with RGCSE, especially in resource limited settings. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Adults Status Epilepticus Topiramate Adverse-effects
1. Introduction Status epilepticus (SE) is the most frequent neurological emergency requiring admission to a hospital and often times to an intensive care unit (ICU).1 Untreated, SE can cause serious brain damage and possibly death. Chances of treatment failure of SE rise and prognosis deteriorates with increasing duration of SE, especially if duration exceeds 1 h.2 Refractory generalized convulsive status epilepticus (RGCSE), defined as SE that fails to respond to the acute administration of two antiepileptic drugs (AEDs), occurs in approximately one third of patients with SE, and is associated with increased hospital length of stay, mortality, and
* Corresponding author at: Neurosciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Tel.: +98 9352274990. E-mail addresses: [email protected], [email protected] (A.A. Asadi-Pooya).
functional disability.3 Therefore, rapid treatment of SE is crucial in preventing severe morbidity and mortality; however, this may result in severe iatrogenic complications. Third-line therapies for SE with sedating or anesthetic effects predict poor outcome and death in status epilepticus. Hypotension requiring vasopressor therapy and longer duration of mechanical ventilation induced by these agents may be contributing factors.4 Of course outcome is linked to etiology as well. Good outcome even after prolonged treatment of RGCSE have been reported in some patients.3 Therefore, having more therapeutic options for SE, particularly novel treatment options with more favorable adverse-effect profiles are warranted. Topiramate is a widely used second generation, broadspectrum AED with a favorable pharmacological profile (e.g., absorption is rapid after enteral administration with peak serum concentration 1–4 h after administration). Topiramate blocks voltage-sensitive sodium channels. Topiramate also enhances the activity of GABA at GABA-A receptors by increasing the
http://dx.doi.org/10.1016/j.seizure.2014.09.009 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
A.A. Asadi-Pooya et al. / Seizure 24 (2015) 114–117
frequency at which GABA activates GABA-A receptors. In addition, topiramate inhibits excitatory transmission by antagonizing some types of glutamate receptors. It may also potentiate ATP activated inward rectifying potassium channels. Topiramate is also a weak carbonic anhydrase inhibitor.5 A small number of reports have described the use of topiramate (TPM) in RGCSE in adults and in children.6–8 The aim of the current study was to explore the feasibility, safety profile and efficacy of enterally administered topiramate as an adjunctive treatment for adult patients with RGCSE, especially when the resources are limited.
115
minor adverse effects (e.g., gastro-intestinal upset) of TPM were not studied. This study was conducted in accordance with local ethical regulations with approval by Shiraz University of Medical Sciences Review Board and Ethics Committee (IRCT # 16520 and grant # 90-01-55-2947). All primary care-givers of the patients consented in writing to their participation, after the scope of the study has been explained in a form understandable to them. The collected data was kept confidential through codes. All care-givers of the patients were advised that TPM was not an approved therapy for SE. They were informed of possible adverse drug effects related to TPM.
2. Materials and methods 3. Results This prospective single center open-label non-randomized clinical trial was performed at Namazee hospital, Shiraz University of Medical Sciences, Shiraz, Iran from January 2013 through February 2014. In this study, patients 18 years of age and older with RGCSE were enrolled. Status epilepticus was defined as the clinical occurrence of an ongoing seizure for more than 5 min or repeated seizures without full recovery in between for more than 30 min.9 All patients underwent EEG (at least one 20-min EEG), which was performed the day after hospital admission and later on, due to shortage of personnel in the afternoon and night shifts. All patients underwent brain imaging (CT scan or MRI); laboratory work-up and cerebro-spinal fluid (CSF) analysis was performed as needed. Status epilepticus termination was defined as resolution of clinical ictal signs (i.e., cessation of motor activity and improvement in responsiveness) and confirmed with the disappearance of continuous or repetitive epileptiform discharges on the EEG, assessed at least daily. Topiramate was used as an add-on treatment, in case of failure of two standard AEDs (i.e., intravenous diazepam and phenytoin) and after 30–40 min from the second line (i.e., 10 min after infusion of phenytoin had completed), in patients in whom the standard third line therapy (i.e., intravenous phenobarbital or valproate) was not available or possible (e.g., due to costs, contraindications, etc.), or ICU was not accessible to start the line four of therapy (i.e., intravenous midazolam, propofol, or pentobarbital). Topiramate tablets were crushed and administered through the nasogastric tube. Topiramate dose was 400 mg stat and then 200 mg twice per day, starting 12 h after the bolus dose. Status epilepticus response to TPM was categorized as successful (termination of SE within 24 h following TPM introduction, without modification of concomitant AEDs), possible (SE termination associated with the introduction of TPM, concomitantly with other medications, in case the third line and/or the fourth line of therapy become available after introduction of TPM and within 24 h) or unsuccessful (no response to TPM treatment after 24 h). In patients in whom TPM was successful to stop SE after the 1st (diazepam) and the 2nd (phenytoin) line of treatment failed, we did not prescribe standard third or fourth line of therapy. We prescribed the standard third (i.e., phenobarbital or valproate) or fourth line (i.e., midazolam, propofol, or pentobarbital) therapy at any time, if they became available and the seizures were still ongoing. Successful and possible responses imply that SE does not recur during the same hospitalization. In successful and possible responses, the patient was discharged with TPM 100 mg twice per day for at least 1 month, along with other required therapies (either AEDs or others as needed). Outcome was assessed at the time of discharge from hospital, and categorized as return to the baseline clinical condition, new handicap, or death. The recorded variables included: age, gender, previous epilepsy, other etiology of SE, time to response after TPM administration, TPM success, side effects (e.g., metabolic acidosis, hemodynamic problems, renal stone, etc.), and outcome at discharge. Cognitive side effects and
Twenty patients (14 males and 6 females) were enrolled in the study. The minimum age of the patients was 18 years and the maximum age was 92 (mean = 44.45 and standard deviation = 23.15 years). The clinical characteristics of the patients are shown in Table 1. Four patients were known cases of epilepsy and the remaining had new onset epileptic seizures (presenting as SE). None of the patients with epilepsy were receiving topiramate before. The etiology of SE was as follows: cerebrovascular accidents in four people, neurosurgical conditions in four patients [head injury (in two), brain tumor, subdural empyema], preexisting epilepsy in four cases (in three patients due to stopping their medication and in one due to change in medication by the treating physician), underlying medical conditions in three patients (liver transplantation, myocardial infarction and hepatic encephalopathy), unidentified etiology in three cases, hypoxic brain damage in one and post-operative SE in one patient. Topiramate was successful in terminating RGCSE in five (25%) patients. Status epilepticus stopped after 42 12 min (median: 45 min, range: 30–60 min) from administration of TPM in these five patients. Topiramate was possibly successful in stopping SE in 11 (55%) patients. Status epilepticus stopped after 148 152 min from administration of TPM in these patients (range: 45–480 min). Topiramate was not successful in stopping SE in four (20%) patients. We did not observe any clinically significant adverse effects related to TPM administration in these patients. Thirteen patients (65%) needed intratracheal intubations (due to prolonged convulsions and hemodynamic instability or alternatively drug side effects). None of the patients had cardiac arrhythmia or change in blood pressure during intravenous phenytoin therapy. Later hemodynamic instability in the above-mentioned patients was attributed to the prolonged duration of status epilepticus, side effects of other prescribed drugs (e.g., phenobarbital or midazolam) or the underlying etiology (e.g., cerebrovascular accident or hepatic encephalopathy). Eleven (55%) patients returned to their baseline clinical condition at the time of discharge from hospital. Two (10%) patients did not return to their baseline clinical condition at the time of discharge from hospital and suffered some neurological sequelae. Unfortunately, seven (35%) patients died during their hospital stay. Four patients were nonresponders, who died of refractory seizures. Two patients were among possible responders; one of them died due to renal failure and pneumonia and another patient died because of end-stage pancreatic cancer. One patient, who was a responder, died of pneumonia and respiratory failure. In other words, mortality was 20% (one out of five) among responders and 18% (2 out of 11) among possible responders. Mortality was 100% (four out of four) among non-responders. 4. Discussion Management of refractory SE is often challenging with disappointing results in some patients and significant morbidity (either treatment related or disease related) and even mortality in
116
Table 1 The clinical characteristics of the patients studied. Outcome
Success
Intubation
Death
Successful
No
60 30
Postthoracotomy CVA CVA
Successful Successful
No No
1200
30
Epilepsy
Successful
No
10
1600
45
MI
Successful
No
10
10
1200
60
Hypoxia
Hemiplegia Baseline clinical condition Baseline clinical condition Baseline clinical condition Death
Possible
Yes
GCSE
10
10
1400
420
Yes
GCSE
10
10
1200
150
Possible
Yes
Male
60
GCSE
3
10
1200
45
Base line clinical conditiona Baseline clinical condition Death
Possible
60
Previous head trauma High grade glioma Un identified
Possible
Yes
73
Male
70
GCSE
10
10
1400
60
No
18
Male
70
GCSE
10
10
1400
75
Possible
Yes
12
32
Male
60
GCSE
20
20
1200
60
Possible
Yes
13
51
Male
60
GCSE
2
10
1200
75
Possible
Yes
14
24
Male
60
GCSE
10
10
1200
480
Possible
Yes
15
60
Male
70
GCSE
2
10
1400
120
Baseline clinical condition Baseline clinical condition Baseline clinical condition Baseline clinical condition Baseline clinical condition Hemiplegia
Possible
11
Previous head trauma Sub-dural empyema Epilepsy
Possible
Yes
16
18
Male
80
GCSE
10
10
1600
90
17
25
Female
80
GCSE
10
10
1600
2880
18
23
Male
60
GCSE
10
10
1200
180
PBT 30 min after TPM
19
61
Male
60
GCSE
2
10
1200
240
20
23
Female
70
GCSE
3
10
1400
180
PBT 35 min after TPM MDL 40 min after TPM
Dose of PHT (mg) (line 2)
2
10
1200
45
GCSE GCSE
2 5
10 10
1400 1000
60
GCSE
15
10
Male
70
GCSE
15
46
Female
60
GCSE
7
24
Male
70
8
37
Male
9
70
10
Age
Sex
Weight (Kg)
Type of SE
1
40
Male
60
GCSE
2 3
90 92
Female Female
70 50
4
37
Female
5
45
6
Time interval between diagnosis of SE and treatment (min)
Line 3
MDL 30 min after TPM MDL 35 min after TPM PBT 35 min after TPM PBT 30 min after TPM SV 35 min after TPM PBT 35 min after TPM MDL 30 min after TPM PROP 35 min after TPM PBT 35 min after TPM SV 35 min after TPM SV 30 min after TPM SV 30 min after TPM
Line 4
PROP 3 h after MDL MDL 1.5 h after PBT
Liver Tx MDL after MDL after
3h PBT 1h SV
Epilepsy CVA Epilepsy
MDL 1 h after SV + PROP 4 h after MDL MDL 30 min after PBT + PROP 1 h after MDL MDL 1 h after PBT
Possible
No
Un identified
Baseline clinical condition Death
Unsuccessful
Yes
Un identified
Death
Unsuccessful
Yes
CVA
Death
Unsuccessful
Yes
HE
Death
Unsuccessful
Yes
SE, status epilepticus; GCSE, generalized convulsive status epilepticus; DZP, diazepam; PHT, phenytoin; TPM, topiramate; SV, sodium valproate; MDL, midazolam; PROP, propofol; PBT, phenobarbital; Tx, transplantation; CVA, cerebrovascular accident; MI, myocardial infarction; HE, hepatic encephalopathy. a Alive without major neurological problem.
A.A. Asadi-Pooya et al. / Seizure 24 (2015) 114–117
Cause
Duration of SE after TPM was given (min)
Dose of DZP (mg) (line 1)
Patient
A.A. Asadi-Pooya et al. / Seizure 24 (2015) 114–117
others. When resources are limited, the situation is even more challenging. At our center, we do not have access to continuous EEG monitoring for patients with SE. Besides, intravenous lorazepam, intravenous levetiracetam, intravenous lacosamide and sometimes even intravenous valproate are not available. At times, ICU beds are not available and patients should be on a waiting list for a bed at one of the ICUs at the hospital to be available. In the current study, RGCSE could be terminated in 80% of the patients receiving TPM as the third-line therapy. However, in only 25% of the patients the success in terminating SE could possibly be directly related to TPM administration. In the remaining patients (55%), the termination of RGCSE could be related to both topiramate and the natural course of the disease in the presence of several other treatments for SE. Even in those 25%, in a clinical setting when TPM was applied as third line therapy after second line of therapy, it is difficult to ascertain whether TPM alone would have terminated the SE or the combination of different medications was necessary to do the job. Besides, the cerebral peak level is reached slower than the blood level; hence, those patients who reached seizure control in less than 90 min [12 patients (60%)] after topiramate administration may well have responded to the intravenous phenytoin loading rather than the topiramate. But, standard care does not allow waiting for 90 min before a third line therapy is administered if phenytoin proves to be unsuccessful in stopping SE after 10 min of its administration. We did not observe any significant clinical adverse-effects related to TPM. These results were similar to observations in previous studies.6,7 Safety and efficacy of oral TPM seems to be acceptable compared to those with intravenous lacosamide and intravenous levetiracetam for adjunctive treatment of refractory status epilepticus.10–12 Future studies should compare these new medications in treatment of RGCSE. However, cost of TPM is not comparable to these new intravenous formulations of AEDs. Mortality of the patients with RSE was 35% in our study that is similar to some previous studies6 and is much higher than other reports.7 Mortality is not strictly dependent on failure to terminate RGCSE, but also on the underlying etiology of RGCSE. This could explain the observed disparity between various studies. However, we observed that mortality was significantly higher if patients did not respond to topiramate. 5. Conclusion Treatment with enterally administered topiramate could potentially be efficacious in some patients and appeared to be tolerated well in patients with RGCSE. Low cost and feasibility (route of administration and desirable pharmacological profile, including adverse effects) makes TPM a potentially useful agent in treating patients with RGCSE, in resource limited settings, in which
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the standard third line therapy is not accessible, or facilities (e.g., ICU) are not available to start the next lines of standard therapy. 6. Limitations of the study The number of patients studied was small and this was not a double blind randomized clinical trial. We did not have access to continuous EEG monitoring to ascertain the seizure termination electrophysiologically. Conflict of interest statement The authors have no conflict of interest with regard to this study. Acknowledgements This study was the result of the medical thesis by Dr. Maryam Jalali Jahromi (grant # 90-01-55-2947). We would like to thank Shiraz Medical School, Shiraz University of Medical Sciences for their support. References 1. Dham BS, Hunter K, Rincon F. The epidemiology of status epilepticus in the United States. Neurocrit Care 2014 [Epub ahead of print]. 2. Hillman J, Lehtima¨ki K, Peltola J, Liimatainen S. Clinical significance of treatment delay in status epilepticus. Int J Emerg Med 2013;6(1):6. 3. Hocker S, Wijdicks EF, Rabinstein AA. Refractory status epilepticus: new insights in presentation, treatment, and outcome. Neurol Res 2013;35(2): 163–8. 4. Kowalski RG, Ziai WC, Rees RN, Werner Jr JK, Kim G, Goodwin H, et al. Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation. Crit Care Med 2012;40(9): 2677–84. 5. Asadi-Pooya AA, Sperling MR. Antiepileptic Drugs A Clinician’s Manual. Oxford University Press; 2009. ISBN-13: 978-0-19-536821-5; ISBN-10: 0-19-536821-5. 6. Hottinger A, Sutter R, Marsch S, Ru¨egg S. Topiramate as an adjunctive treatment in patients with refractory status epilepticus: an observational cohort study. CNS Drugs 2012;26(9):761–72. 7. Synowiec AS, Yandora KA, Yenugadhati V, Valeriano JP, Schramke CJ, Kelly KM. The efficacy of topiramate in adult refractory status epilepticus: experience of a tertiary care center. Epilepsy Res 2012;98(2–3):232–7. 8. Akyildiz BN, Kumandas¸ S. Treatment of pediatric refractory status epilepticus with topiramate. Childs Nerv Syst 2011;27(9):1425–30. 9. Riviello Jr JJ, Claassen J, Laroche SM, et al. Treatment of status epilepticus: an international survey of experts. Neurocrit Care 2013;18(2):193–200. 10. Sutter R, Marsch S, Ru¨egg S. Safety and efficacy of intravenous lacosamide for adjunctive treatment of refractory status epilepticus: a comparative cohort study. CNS Drugs 2013;27(4):321–9. 11. Miro´ J, Toledo M, Santamarina E, Ricciardi AC, Villanueva V, Pato A, et al. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus: a multicentric prospective study. Seizure 2013;22(1):77–9. 12. Mo¨ddel G, Bunten S, Dobis C, Kovac S, Dogan M, Fischera M, et al. Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus. J Neurol Neurosurg Psychiatry 2009;80(6):689–92.
