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Official Journal of the European Paediatric Neurology Society
Original Article
Etiology, clinical course and response to the treatment of status epilepticus in children: A 16-year single-center experience based on 602 episodes of status epilepticus Ruzica Kravljanac a,b,*, Milena Djuric a,b, Borisav Jankovic a,b, Tatjana Pekmezovic a,c a
Faculty of Medicine, University of Belgrade, Serbia Institute for Mother and Child Healthcare of Serbia, Serbia c Institute for Epidemiology, Serbia b
article info
abstract
Article history:
Objective: evaluation of etiology, clinical course and response to the treatment of status
Received 3 February 2014
epilepticus (SE) in children, with particular investigation of superrefractory SE.
Received in revised form
Materials and methods: The retrospective study included children with convulsive SE aged
21 April 2015
0.2e18 years, treated from 1995 to 2011. Status epilepticus is defined as a continuous
Accepted 25 May 2015
seizure or intermittent seizures without full recovery of consciousness between seizures for at least 30 min. Refractory SE is diagnosed if SE lasts for more than 60 min, while
Keywords:
superrefractory SE if SE continues or recurs 24 h or more after the onset of an anesthesia
Status epilepticus
therapy, including those cases that recur after reduction or withdrawal of an anesthesia.
Superrefractory
The etiology was summarized in five categories: idiopathic/cryptogenic, remote symp-
Etiology
tomatic, febrile SE, acute symptomatic and progressive encephalopathy. The patients were
Treatment
treated according to the same hospital protocol. Midazolam iv and diazepam rectally were given as the first line drugs, phenobarbital/phenytoin iv as the second line drugs. If they failed, third line drugs, midazolam and thiopental were given in continuous intravenous infusion. The medication was defined as effective if seizure clinically stopped within 20 min, without recurrence within the next 6 h. Midazolam was assessed as effective even if it failed as the first line, but was effective in intravenous infusion as the third line drug. Results: The study consisted of 602 SE in 395 children. There were 305 (50.7%) refractory SE episodes, and 43 (7.1%) of superrefractory SE. Idiopathic/cryptogenic and febrile SE was the most common etiology in the first SE, while progressive encephalopathy and remote symptomatic was in recurrent and superrefractory SE. The most effective drugs were: midazolam (306/339) given in mean dose of 0.4 mg/kg (range 0.1e1.2 mg/kg), thiopental (47/ 57) in mean dose of 4 mg/kg (range 3e5 mg/kg), phenobarbital (91/135) in dose of 20 mg/kg. Midazolam successfully stopped 306/339 SE episodes (90.3%), 67 SE (21.9%) by equal or lower dose than 0.2 mg/kg as the first line drug, while all other 239 episodes (78.9%) were
* Corresponding author. Institute for Mother and Child Healthcare of Serbia, 6 Radoje Dakic St., 11070 Belgrade, Serbia. Tel.: þ381 642612210. E-mail address: [email protected] (R. Kravljanac). http://dx.doi.org/10.1016/j.ejpn.2015.05.007 1090-3798/© 2015 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
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stopped by intravenous infusion in range 0.2e1.2 mg/kg/h (mean 0.4 mg/kg/h) as the third line drug. Adverse effects were frequent in superrefractory SE (60.5%). In 15 patients, corticosteroids contributed to the reduction of seizure recurrence after anesthetic withdrawal and cessation of epilepsia partialis continua. Case fatality rate was 5.1% in all patients, while 21.3% in patients with superrefractory SE. Conclusion: Status epilepticus in children was characterized by heterogeneous etiology, prolonged duration and commonly good response to midazolam only given in high doses. Superrefractory SE was not so rare in children, especially among the patients with progressive encephalopathy. © 2015 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
1.
Introduction
Status epilepticus (SE) is one of the most urgent conditions in paediatrics and requires fast and appropriate treatment. It is defined as an acute epileptic condition characterized by continuous seizures (partial or generalized, convulsive or nonconvulsive) for at least 30 min, or by 30 min of intermittent seizures without full recovery of consciousness between seizures.1 Refractory SE (RefSE) is diagnosed if SE lasts for more than 60 min. Superrefractory status epilepticus (SuperRefSE) is defined as status epilepticus that continues or recurs 24 h or more after the onset of anesthesia therapy, including those cases that recur after reduction or withdrawal of anesthesia.2 Convulsive SE in childhood is more common, it includes a different range of causes and a lower risk of death compared with adults.3 Mortality rate in children with SE has decreased from 6% to 3%, probably due to earlier treatment and better intensive care facilities.4 Shorvon highlighted that the main aim in SE treatment is prevention of brain damage caused by direct effect of epileptic activity, so it is important to interrupt both clinical and electrical manifestation of the seizures.5 Тreiman et al. compared four ways of SE treatment in a large multicentric double-blind randomized study with 518 patients included.6 In initial SE treatment, lorazepam was effective in 52,2%, phenobarbital in 49,2%, combination of phenytoin and diazepam in 43.1% and phenytoin in 36.8%. The management of SE might be challengeable because SE is not a single entity and comprises different electro-clinical syndromes with various etiologies. Thus, the treatment of all SE by the same algorithm could have certain disadvantages. Particularly, the management of refractory SE could be associated with many difficulties. Costello and Cole recommended aggressive management of SE and highlighted that giving an appropriate dose of the first- and second-line anticonvulsive medication is very important.7 The excessive dose of initial medications is far less associated with SE morbidity compared to prolonged seizure activity and treatment in ICU. It is suggested that neurologists with EEG knowledge should be consulted during the early stage of SE treatment.7 This manuscript presents a single center experience concerning etiology, clinical course and response to the treatment of a large number of convulsive SE episodes, with particular emphasis on the most complicated group of patients with superrefractory SE.
2.
Materials and methods
The retrospective study included first and recurrent convulsive SE episodes in children aged 0.2e18 years treated in Institute for Mother and Child Healthcare of Serbia in the period from January 1995 to January 2011. Recurrent SE was defined as repeated SE at least 48 h after cessation of the previous SE, either during the same or new hospitalization. The patients were treated in intensive care unit (ICU) and neurological department. The criteria for ICU admission were: seizing on admission with no response to initial treatment in emergency room by diazepam rectally (0.5 mg/kg) or midazolam intravenously (0.1e0.2 mg/kg), prolonged duration of seizures, severity of underlying disorder, disturbances of consciousness and vital functions. The patients with only electrographic features of SE, without any clinical manifestations such as electrical status during slow-wave sleep and other SE with no motor manifestation as absence seizures were excluded. Patients with the loss of consciousness due to underling disorder, and with including motor manifestation of seizures such as epilepsia partialis continua, were included in the study. Etiology of SE was summarized in five categories8: idiopathic/cryptogenic, remote symptomatic, febrile SE, acute symptomatic and progressive encephalopathy. Cryptogenic/idiopathic SE included SE in patients with generalized or focal idiopathic epilepsies and/or epilepsies of unknown etiology. Remote symptomatic SE was defined as SE caused by previous hypoxic ischemic encephalopathy, intracranial hemorrhage, cerebral palsy, CNS abnormalities, including malformations and vascular abnormalities and previous head injury or surgery. Febrile seizure which lasted for more than 30 min was defined as febrile SE. Acute symptomatic SE was caused by acute brain disease or injuries including CNS infections, cerebrovascular insults, acute systemic disease, hypertension, drugs and acute metabolic disorders. Progressive encephalopathy included different disorders with progressive course: neurodegenerative, metabolic, neurogenetic, malignant and neurocutaneous disease. Etiology distribution was analyzed in the group of first, recurrent and superrefractory SE episodes. SE duration was divided in six groups: 30e60 min, 60e90 min, 90e180 min, 180e360 min, 360 min-24 h and more than 24 h. All patients with seizures were treated in the Institute according to the same protocol and neurologist was consulted in early or
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established phase of SE. The hospital protocol for seizure treatment was shown in Fig. 1. It was suggested to apply the maximal dose of medication and wait for 20 min before giving the next drug. All children under two years of age with idiopathic/cryptogenic SE were given 100 mg pyridoxine for initial SE treatment. Midazolam was given as the first line drug in intravenous injection 0.1e0.2 mg/kg, but also as the third line drug in intravenous infusion in range 0.1e1.2 mg/kg/h if second line drugs (phenobarbital/phenytoin) failed. Midazolam was assessed as effective even if it failed as the first line, but was effective in intravenous infusion as the third line drug. The drug efficacy assessment included all drugs applied from the onset of seizure treatment, irrespective of whether the drug was applied within first 30 min of seizure duration or after this period. The drug efficacy was presented as a percentage of stopped SE episodes compared to total number of SE episodes treated by a certain drug. Prolonged coma was defined if coma lasted for more than 12 h after discontinuation of injection or infusion. Intensive therapy was necessary due to: 1) SE resistant to antiepileptic drugs and administration of high dosage of anesthetic agents; 2) respiratory complication of SE; 3) respiratory depression as adverse effect of drugs; 4) respiratory and circulatory impairment due to underlying disorders or comorbidity; 5) prolonged coma after SE (Fig. 2).
Fig. 1 e The hospital protocol forseizure/status epilepticus treatment in children in condition with and without intravenous access. The treatment according protocol start as soon as the seizure is diagnosed.
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In the data analysis, descriptive statistics (absolute and relative numbers or percentages) were used. The study was approved by the Institutional Ethics Board.
3.
Results
The retrospective study included 602 convulsive SE episodes in 395 patients aged from 0.2 to 18 years (mean age 4.3, SD 4 years), with similar gender distribution (male 219, female 176). The etiology of first, recurrent and superrefractory SE was shown in Table 1. The most frequent etiology in the first SE was idiopathic or cryptogenic SE, including 10 children with focal benign early occipital epilepsy in childhood or Panayiotopoulos syndrome9. Idiopathic/cryptogenic and febrile SE was the most common etiology of the first SE, while none of SuperRefSE was caused by those two etiologies. The patients with remote symptomatic SE and progressive encephalopathy were in high risk for SE recurrence and SuperRefSE. The patients with hypoxic-ischemic encephalopathy within the group of remote symptomatic SE had the highest risk for SE recurrence. The patients with neurodegenerative disease (neuronal ceroid lipofuscinosis, Lafora disease, Gaucher type II, gangliozidosis, Krabbe disease and other progressive myoclonus epilepsies) and mitochondrial disease within the group of patients with progressive encephalopathy had the highest risk for SE recurrence and superrefractory SE. The duration of SE was commonly prolonged and 305 (50.7%) lasted > 60 min presenting RefSE. SuperRefSE was diagnosed in 43 episodes and made 7.14% of all SE (Table 1). The most common SE type was generalized convulsive 252 (41.9%), secondary generalized convulsive 181 (31.4%), while complex and simple focal were rare. In the group of superRefSE, ten episodes had features of epilepsia partialis continua with/without secondary generalization. The drugs used in SE treatment and their efficacy were presented in Table 2. The mean dose, range and the way of drugs administration were presented in Table 3. Seven SE episodes stopped spontaneously, eleven SE were refractory to any antiepileptic drugs, while in six patients with RefSE they continued until death. The etiology in these cases was: nonketotic hyperglycinemia (3), mitochondrial disorders (2) and unknown progressive neurodegenerative disease (1). The most available benzodiazepine for parenteral use in hospital was midazolam for initial SE treatment, but also as a third line drug if phenobarbital or phenytoin failed. The dose of midazolam was significantly higher in intravenous infusion, and we assessed that drug as effective even if it failed as intravenous injection but was effective in infusion. The drug successfully stopped 306 of 339 SE episodes (90.3%). In only 67 SE (21.9%) of successfully stopped SE, the dose of midazolam given as the first line drug was equal or lower than 0.2 mg/kg. In all other 239 episodes (78.9%), the effective dose was higher in range from 0.2 to 1.2 mg/kg/h (mean 0.4 mg/kg/h) and was given as the third line drug in intravenous infusion. In the group of SuperRefSE, MDZ was given in intravenous infusion as a third line drug and was significantly less effective, only in 17/30 episodes (56.6%). The commonly used anesthetic drugs were midazolam (MDZ) and thiopental in continuous intravenous infusion,
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Thiopental
47 57
Diazepam+ Pbenobarbital
10
35
Phenobarbital
91
Diazepam
Number of pa ents in whom drug was effec ve
135
92
Number of pa ents received drug
271
Midazolam
306 0
100
200
339
300
400
Fig. 2 e Distribution of patients according to efficacy of the most frequently used drugs.
both in high doses and with median duration about 48 h (range 1e720 h). The increasing rate for MDZ was 0.1 mg/kg/h up to seizure cessation (maximum 1.2 mg/kg/h) and for thiopental 1 mg/kg/h every 1e2 h (maximum 5 mg/kg/h), The long duration of MDZ infusion was due to very slow drug titration. The decrease of the mentioned drugs dosage started 24 h after the clinical seizure cessation. One of the main therapeutic problems in SE management by MDZ in continuous infusion was recurrence of the seizures after infusion withdrawal. In those cases, loading dose of benzodiazepines was given orally:
clobazam 0.5e1.5 mg/kg or clonazepam 0.1e0.3 mg/kg. In two cases, MDZ iv administration was associated with the worsening of seizures: in one case with Lennox Gastaut syndrome, MDZ infusion provoked tonic seizures and in one case with cryptogenic SE after MDZ administration, the frequency of seizures increased. In the group of SuperRefSE, all antiepileptic drugs were less effective. Midazolam was given in intravenous infusion in range 0.2e1.2 mg/kg/h with efficacy in 17 of 30 episodes (56.6%). Thiopental was given in intravenous infusion with
Table 1 e Etiology of the first, recurrent and super-refractory status epilepticus. Etiology
First SE
Recurrent SE
Total SE
SuperRefSE
N
%
N
%
N
%
N
%
108 56 18 4 24 6 2 2
27.3 14.2 e e e e e e
5 70 35 5 15 10 4 1
2.4 33.8 e e e e e e
113 126 53 9 39 16 6 3
18.8 20.9 e e e e e e
2 7 7 0 0 0 0 0
4.6 16.3
Febrile SE
92
23.3
1
0.5
93
15.4
0
0
Acute symptomatic CNS infections Acute systemic disease Cerebrovascular insult Drugs PRES Acute metabolic disorder
67 49 7 3 2 1 2
16.7 e e e e e e
34 33 0 0 0 0 1
16.4 e e e e e e
101 82 7 3 2 1 3
16.8 e e e e e e
7 7 0 0 0 0 0
16.3 e e e e e e
72 20 23 4 7 7 11 395
18.2 e e e e e e 100
97 41 17 10 1 4 24 207
46.8 e e e e e e 100
169 61 40 14 8 11 35 602
28.1 100
26 7 6 0 2 0 11 43
60.5 e e e e e e 100
Idiopathic/cryptogenic Remote symptomatic HIE ICH Cerebral palsy CNS malformations Vascular abnormalities Head injury
Progressive encephalopathy Neurodegenerative Neurogenetic/metabolic Neuroinflammatorya Malignant Neurocutaneous disease Mitochondriopathy Total
-
SE e status epilepticus, SuperRefSE e super-refractory status epilepticus, HIC e hypoxic ischemic encephalopathy, ICH - intracranial hemorrhage, PRES e posterior reversible encephalopathy syndrome. a Neuroinflammatory progressive disease included Rasmussen encephalitis and subacute sclerosing panencephalitis.
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Table 2 e Efficacy of the drugs used in the treatment of status epilepticus. Drug Midazolam Diazepam Phenobarbital Diazepam þ phenobarbital Thiopental Phenytoina Chloral-hydratea Lidocaina Lorazepama Clobazama Clonazepama Levetiracetama Propofola Ketaminea Valproatea
N
Effective
Effective %
339 271 135 35 57 4 6 2 3 5 2 11 2 2 2
306 92 91 10 47 2 3 0 2 4 2 7 0 0 1
90.3 33.9 67.4 28.6 82.4 e e e e e e e e e e
a
Since the drugs were given in limited number of stratus epilepticus episodes, the efficacy was not presented in percentage.
mean dose of 4.5 mg/kg/h with efficacy of 4/9 (44.4%). The mean duration of intravenous infusion of anesthetics was 156.6 h. The new antiepileptic drugs were given only in a few cases in our study when all previous drugs failed: propofol in two, lidocain in two and ketamine in two cases, and none stopped SE. Levetiracetam stopped three SuperrefSE episodes. In one girl with juvenile phenotype of CLN1, levetiracetam caused severe bradicardia with heart rate about 30/min. Eleven SuperRefSE were resistant to all drugs and six patients continued seizing until death. Intravenous infusions of corticosteroids were given in 15 RefSE episodes caused by inflammatory or immune-mediated diseases, in episodes of epilepsia partialis continua, in a patient with resistant focal convulsive SE caused by cortical dysplasia and two cases with mitochondrial disorders. Methylprednisolone was given in the dose of 500 mg/m2 in intravenous infusion lasting for 4 h for five consecutive days. In two patients, 20 mg/m2 dexamethason was given intravenously, divided in four doses for four days. We found that
Table 3 e Mean dose, range and drug administration routes in the SE treatment. Drug Diazepam Phenobarbital Midazolam Thiopental Lidocain Lorazepam Levetiracetam Propofol Ketamine 10% Chloral hydrate Valproate
Mean dose (mg/kg)
Range of dose (mg/kg)
Administration route
0.35 18.9 0.4 4.0 1 0.1 43 2 1.5 0.5 ml/kg
0.25e0.5 10e20 0.1e1.2 3e5 1 0.1 30e60 2e4 1.5 0.5 ml/kg
iv/rectally iv iv/infusion/im iv/infusion iv/infusion iv iv, orally, gt iv infusion orally, gt Rectally
30
30
iv
iv e intravenously, im e intramuscular, gt e gastric tube.
5
corticosteroids were beneficial and contributed to the reduction of the recurrence of seizures after MDZ/thiopental infusion withdrawal, and cessation of resistant epilepsia partialis continua. None of the patients in our study were treated by ketogenic diet or surgery, including vagus nerve stimulation as acute SE treatment. Intensive therapy was required in 244 (40.5%) SE episodes: oxygen therapy in 61, mechanical ventilation in 183 and circulatory stimulation in 68 SE. In the group of SuperRefSE, mechanical ventilation with/without circulatory stimulation was required in 33/43 (76.7%) episodes. Adverse effects of the drugs were noticed in 128 (21.3%) episodes, especially in SE treated by prolonged and high dosage of continuous infusion of midazolam (58.1%) and thiopental (55.5%). Tachiphylaxia was noticed only in episodes treated by continuous midazolam infusion. Depression of consciousness and severe respiratory impairment (ARDS) mostly happened in episodes treated by long lasting and high dosage continuous infusion of midazolam and thiopental. Six cases with RefSE caused by progressive encephalopathies treated by continuous high dosage infusion of midazolam, were suffering acute respiratory distress syndrome (ARDS). They required withdrawal of midazolam, introducing corticosteroids and appropriate mechanical ventilation conditions. Respiratory impairment was commonly caused by aspiration pneumonia, ARDS or airway hypersecretion. In the group of SuperRefSE, the side effects were more common, in 60.5%, mostly requiring mechanical ventilation (25) and circulatory stimulation (8).Table 4 shows the most severe adverse effects of antiepileptic drugs used in SE treatment. Patients with progressive encephalopathy such as Krabbe disease, neuronal ceroid lipofuscinosis, progressive myoclonus epilepsies and mitochondrial disorders were very sensitive to benzodiazepines and barbiturate. They experienced respiratory depression after common dose of benzodiazepines or barbiturates with prolonged coma. Having recognized this phenomenon, we have become cautious about the application of high dose and long-lasting infusions of MDZ and barbiturate. We found good response to levetiracetam in a limited number of patients (three cases) with progressive encephalopathy in loading doses from 30 to 60 mg/kg. Case-fatality rate was 5.1% in all analyzed SE, while in the group of SuperRefSE, it was 21.3%.
4.
Discussion
The retrospective study included large number of convulsive SE episodes in children. The etiology of SE was heterogenous with different distribution in the groups of the first, recurrent or superrefractory SE. We found that febrile disease and idiopathic/cryptogenic etiology were the most common causes of first SE with no risk of SE recurrence. The patients with progressive encephalopathy (progressive, myoclonic epilepsies, progressive neuroinflammatory, mitochondrial, neurocutaneous disease) and remote symptomatic etiology (especially hypoxic-ischemic encephalopathy) had a high risk of SE recurrence. Therefore, it is very important to educate the parents or caregivers of those children to give appropriate rescue drugs for prehospital seizure treatment.
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Table 4 e Most severe adverse effects of the drugs used in SE treatment. Adverse effects
N
%
Tachiphylaxia Depression of consciousness Respiratory depression Respiratory impairment Cardiovascular impairment
38 93 10 20 58
16a 15.4 1.7 3.3 9.6
a
Only episodes treated by continuous midazolam infusion was included.
Comparing our results to study of Claassen et al.,10 we found that our patients were given higher MDZ average dosage (0.4 mg/kg/h comparing to 0.19 mg/kg/h), including maximal dosage (1.2 mg/kg/h comparing to 0.22 mg/kg/h) with longer duration of infusion. That could be the explanation of better efficacy of midazolam in our study. Recurrence rate after stopping the infusion was observed in both studies and could be a serious therapeutic problem.10 Our results support recently published recommendation of Italian League Against Epilepsy about faster increase of MDZ in intravenous infusion and higher dosage in initial treatment.11 Our hospital has accepted this recommendation and will implement it in the new protocol for SE treatment. Recent open-label, uncontrolled study provides Class IV evidence that intravenous ketamine might be effective and safe in treating children with RefSE.12 In our study, ketamine was ineffective given through gastric tube in two cases without co-medication with intravenous midazolam. Recently published data suggested that some non-medication treatment such as ketogenic diet13 or urgent surgical treatment14 could be helpful in terminating RefSE in children, but none of our cases were treated by them. Adverse effects were frequent in our patients, especially regarding SuperRefSE. The factors which could contribute to more common adverse effects were: underlying disorders, preexisting neurological abnormalities and coexisting infection. Prolonged MDZ and thiopental half-life after long-lasting continuous infusion could be explained by accumulation of the drugs in periferal tissues, especially in lipid tissue.15e17 It potentially contributed to prolonged coma in some of our patients. We found that SuperRefSE is a particular type of SE, characterized by progressive encephalopathy as the most common etiology, common adverse effects, high mortality, poor response to anticonvulsive drugs, frequently requiring intensive therapy. Recently published protocol for SuperRefSE treatment2 could be very helpful in clinical practice and further studies. Despite the improvement in the treatment in the last decades, SE is still associated with high morbidity and mortality.18,19 The mortality in pediatric group of patients ranged from 3 to 11%, and it is obvious that prognosis is better in children than in older patients.3,7,20e22 The outcome in children treated in intensive care unit is favorable in most of the cases, but mortality and morbidity rates are still very high: neurological consequences occurred in 12.9% patients, casefatality rate was 9.3% and recurrence rate was 21%.23 The
results of our study showed that the group of SuperRefSE had significantly higher case-fatality rate compared to all SE episodes. Etiology and prior neurological abnormalities were the main predictors of mortality, while the main predictor of morbidity was underlying etiology.23 Hocker et al. analyzed the outcome of RefSE including superRefSE (90%), and concluded that mortality is high and independent of the choice of anesthetic agent, type of SE, and preexisting epilepsy.24 Some authors highlighted the difference between features of SE in children and adults.25,26 Alldredge et al. pointed out the impact of prehospital SE treatment to the course and duration of SE.27 Status epilepticus treatment according to the established protocol was recommended despite certain disadvantages. It is important to modify algorithm depending on drug availability in certain hospitals or regions and also to educate the parents or caregivers how to stop the seizures in prehospital conditions. We would also like to emphasize the importance of different approaches to SE treatment in children compared to adults, especially to the most vulnerable group of children with preexisting neurological deficit and progressive encephalopathy. Our data suggested that the patients with progressive encephalopathy have a higher risk for SuperRefSE making them strong candidates to the prescription of rescue drugs even before the experience of the first episode of SE. There are some limitations of the study. We compared the efficacy of drugs from different lines, e.g, the efficacy of the first line with the second or the third line drugs. The new antiepileptic drugs for SE treatment were given only in few cases. Also, we were unable to avoid cummulative effect in assessment of the drug given after previously ineffective drugs. Current treatment protocols for convulsive SE in children and adults are based on limited controlled trials performed predominantly in adults.28 Recently published protocol for SuperRefSE treatment2 showed how challengeable is the treatment of this particular SE type. Since the most beneficial treatment algorithm for both children and adults is not known,28 the data from this manuscript might be helpful in making better SE treatment approach in similar circumstances as in our hospital. In conclusion, status epilepticus in children was characterized by heterogeneous etiology, prolonged duration and commonly good response to midazolam only given in high doses. Superrefractory SE was not so rare in children, especially among the patients with progressive encephalopathy.
Conflict of interest None of the authors has any conflict of interest to disclose.
Ethical approval All authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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Acknowledgment 12.
Tatjana Pekmezovic was supported by grant from the Ministry of Science and Education of the Republic of Serbia (grant no. 175087).
13.
14.
references 15. 1. Wasterlain CG, Chen JW. Definition and classification of status epilepticus. In: Wasterlain CG, Treiman DM, editors. Status epilepticus: mechanisms and management. Massachusetts. London: The MIT Press Cambridge; 2006. p. 11e6. 2. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802e18. 3. Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC, NLSTEPSS Collaborative Group. Incidence, cause and shortterm outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:222e31. 4. Arzimanoglou A. Outcome of status epilepticus in children. Epilepsia 2007;48(Suppl. 8):91e3. 5. Shorvon SD. Emergency treatment of acute seizures, serial seizures, seizure cluster and status epilepticus. In: Shorvon SD, editor. Handbook of epilepsy treatment. Oxford: Blackwell Science; 2000. p. 173e94. 6. Treiman D, Meyers P, Walton N, Collins J, Colling C, Rowan A, Handforth A, Faught E, Calabrese V, Ulthman B, Ramsay R, Mamdani M. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Group. N Eng J Med 1998;339:792e8. 7. Costello DJ, Cole AJ. Treatment of acute seizures and status epilepticus. J Intensive Care Med 2007;22:319e47. 8. Shinnar S. Epidemiology of childhood status epilepticus. In: Wasterlain CG, Treiman DM, editors. Status epilepticus: mechanisms and management. Massachusetts. London: The MIT Press Cambridge; 2006. p. 39e51. 9. Panayiotopoulos CP, Michael M, Sanders S, Valeta T, Koutroumanidis M. Benign childhood focal epilepsies: assessment of established and newly recognized syndromes. Brain 2008;131:2264e86. 10. Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: a survey of neurologists. J Neurol Sci 2003;211:37e44. 11. Capovilla G, Beccaria F, Beghi E, Minicucci F, Sartori S, Vecchi M. Treatment of convulsive status epilepticus in
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childhood: recommendations of the Italian League against Epilepsy. Epilepsia 2013;54(Suppl. 7):23e34. Rosati A, L'Erario M, Ilvento L, Cecchi C, Pisano T, Mirabile L, Guerrini R. Efficacy and safety of ketamine in refractory status epilepticus in children. Neurology 2012;79(24):2355e8. Sort R, Born A, Pedersen K, Fonsmark L, Uldall P. Ketogenic diet in 3 cases of childhood refractory status epilepticus. EJPN 2013;17(6):531e6. Schrader D, Steinbok P, Connolly M. Urgent, respective surgery for medically refractory, convulsive status epilepticus. EJPN 2009;13(1):10e7. Albert HH. Therapie und prognose des status epilepticus. Lebensversicherungmedizin 1983;35(4):83e4. Lowenstein DH, Aminoff MJ, Simon RP. Barbiturate anesthesia in the treatment of status epilepticus: clinical experience with 14 patients. Neurology 1998;38:395e400. Nartoku DK, Sinha S. Prolongation of midazolam half-life after sustained infusion for status epilepticus. Neurology 2000;54:1366e8. Cascino GD, Hesdorff er D, Logroscino G, Hauser WA. Morbidity of nonfebrile status epilepticus in Rochester, Minnesota, 1965e1984. Epilepsia 1998;39:829e32. Logroscino G, Hesdorff er D, Cascino G, Annegers JF, Bagiella E, Hauser AW. Long-term mortality after the first episode of status epilepticus. Neurology 2002;58:537e41. Aicardi JE, Chevrie JJ. Convulsive status epilepticus in infants and children: a study of 239 cases. Epilepsia 1970:187e97. Maytal J, Shinnar S, Moshe S. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323e31. DeLorezo RJ, Hauser WA, Towne AR. A prospective population-based epidemiology study of status epilepticus in Richmond. Virginia. Neurology 1996;46:1029e35. Kravljanac R, Djuric M, Jovic N, Jankovic B, Pekmezovic T. Outcome in children treated in intensive care unit: a study of 302 cases. Epilepsia 2011;52(2):358e63. Riikonen R. Childhood convulsive status epilepticus (comment). Lancet 2006;368:184e5. Hocker S, Britton J, Mandrekar J, Wijdicks E, Rabinstein A. Predictors of outcome in refractory status epilepticus. JAMA Neurol 2013;70(1):72e7. Chin RF, Verhulst L, Neville BGR, Peters MJ, Scott RC. Inappropriate emergency management of status epilepticus in children contributes to need for intensive care. JNNP 2004;75:1584e8. Alldredge BK, Wall DB, Ferriero DM. Effect of prehospital treatment on the outcome of status epilepticus in children. Pediatr Neurol 1995;12:213e6. Loddenkemper T, Goodkin H. Treatment of pediatric status epilepticus. Curr Treat Options Neurol 2011;13:560e73.
Official Journal of the European Paediatric Neurology Society
Original Article
Etiology, clinical course and response to the treatment of status epilepticus in children: A 16-year single-center experience based on 602 episodes of status epilepticus Ruzica Kravljanac a,b,*, Milena Djuric a,b, Borisav Jankovic a,b, Tatjana Pekmezovic a,c a
Faculty of Medicine, University of Belgrade, Serbia Institute for Mother and Child Healthcare of Serbia, Serbia c Institute for Epidemiology, Serbia b
article info
abstract
Article history:
Objective: evaluation of etiology, clinical course and response to the treatment of status
Received 3 February 2014
epilepticus (SE) in children, with particular investigation of superrefractory SE.
Received in revised form
Materials and methods: The retrospective study included children with convulsive SE aged
21 April 2015
0.2e18 years, treated from 1995 to 2011. Status epilepticus is defined as a continuous
Accepted 25 May 2015
seizure or intermittent seizures without full recovery of consciousness between seizures for at least 30 min. Refractory SE is diagnosed if SE lasts for more than 60 min, while
Keywords:
superrefractory SE if SE continues or recurs 24 h or more after the onset of an anesthesia
Status epilepticus
therapy, including those cases that recur after reduction or withdrawal of an anesthesia.
Superrefractory
The etiology was summarized in five categories: idiopathic/cryptogenic, remote symp-
Etiology
tomatic, febrile SE, acute symptomatic and progressive encephalopathy. The patients were
Treatment
treated according to the same hospital protocol. Midazolam iv and diazepam rectally were given as the first line drugs, phenobarbital/phenytoin iv as the second line drugs. If they failed, third line drugs, midazolam and thiopental were given in continuous intravenous infusion. The medication was defined as effective if seizure clinically stopped within 20 min, without recurrence within the next 6 h. Midazolam was assessed as effective even if it failed as the first line, but was effective in intravenous infusion as the third line drug. Results: The study consisted of 602 SE in 395 children. There were 305 (50.7%) refractory SE episodes, and 43 (7.1%) of superrefractory SE. Idiopathic/cryptogenic and febrile SE was the most common etiology in the first SE, while progressive encephalopathy and remote symptomatic was in recurrent and superrefractory SE. The most effective drugs were: midazolam (306/339) given in mean dose of 0.4 mg/kg (range 0.1e1.2 mg/kg), thiopental (47/ 57) in mean dose of 4 mg/kg (range 3e5 mg/kg), phenobarbital (91/135) in dose of 20 mg/kg. Midazolam successfully stopped 306/339 SE episodes (90.3%), 67 SE (21.9%) by equal or lower dose than 0.2 mg/kg as the first line drug, while all other 239 episodes (78.9%) were
* Corresponding author. Institute for Mother and Child Healthcare of Serbia, 6 Radoje Dakic St., 11070 Belgrade, Serbia. Tel.: þ381 642612210. E-mail address: [email protected] (R. Kravljanac). http://dx.doi.org/10.1016/j.ejpn.2015.05.007 1090-3798/© 2015 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
2
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stopped by intravenous infusion in range 0.2e1.2 mg/kg/h (mean 0.4 mg/kg/h) as the third line drug. Adverse effects were frequent in superrefractory SE (60.5%). In 15 patients, corticosteroids contributed to the reduction of seizure recurrence after anesthetic withdrawal and cessation of epilepsia partialis continua. Case fatality rate was 5.1% in all patients, while 21.3% in patients with superrefractory SE. Conclusion: Status epilepticus in children was characterized by heterogeneous etiology, prolonged duration and commonly good response to midazolam only given in high doses. Superrefractory SE was not so rare in children, especially among the patients with progressive encephalopathy. © 2015 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
1.
Introduction
Status epilepticus (SE) is one of the most urgent conditions in paediatrics and requires fast and appropriate treatment. It is defined as an acute epileptic condition characterized by continuous seizures (partial or generalized, convulsive or nonconvulsive) for at least 30 min, or by 30 min of intermittent seizures without full recovery of consciousness between seizures.1 Refractory SE (RefSE) is diagnosed if SE lasts for more than 60 min. Superrefractory status epilepticus (SuperRefSE) is defined as status epilepticus that continues or recurs 24 h or more after the onset of anesthesia therapy, including those cases that recur after reduction or withdrawal of anesthesia.2 Convulsive SE in childhood is more common, it includes a different range of causes and a lower risk of death compared with adults.3 Mortality rate in children with SE has decreased from 6% to 3%, probably due to earlier treatment and better intensive care facilities.4 Shorvon highlighted that the main aim in SE treatment is prevention of brain damage caused by direct effect of epileptic activity, so it is important to interrupt both clinical and electrical manifestation of the seizures.5 Тreiman et al. compared four ways of SE treatment in a large multicentric double-blind randomized study with 518 patients included.6 In initial SE treatment, lorazepam was effective in 52,2%, phenobarbital in 49,2%, combination of phenytoin and diazepam in 43.1% and phenytoin in 36.8%. The management of SE might be challengeable because SE is not a single entity and comprises different electro-clinical syndromes with various etiologies. Thus, the treatment of all SE by the same algorithm could have certain disadvantages. Particularly, the management of refractory SE could be associated with many difficulties. Costello and Cole recommended aggressive management of SE and highlighted that giving an appropriate dose of the first- and second-line anticonvulsive medication is very important.7 The excessive dose of initial medications is far less associated with SE morbidity compared to prolonged seizure activity and treatment in ICU. It is suggested that neurologists with EEG knowledge should be consulted during the early stage of SE treatment.7 This manuscript presents a single center experience concerning etiology, clinical course and response to the treatment of a large number of convulsive SE episodes, with particular emphasis on the most complicated group of patients with superrefractory SE.
2.
Materials and methods
The retrospective study included first and recurrent convulsive SE episodes in children aged 0.2e18 years treated in Institute for Mother and Child Healthcare of Serbia in the period from January 1995 to January 2011. Recurrent SE was defined as repeated SE at least 48 h after cessation of the previous SE, either during the same or new hospitalization. The patients were treated in intensive care unit (ICU) and neurological department. The criteria for ICU admission were: seizing on admission with no response to initial treatment in emergency room by diazepam rectally (0.5 mg/kg) or midazolam intravenously (0.1e0.2 mg/kg), prolonged duration of seizures, severity of underlying disorder, disturbances of consciousness and vital functions. The patients with only electrographic features of SE, without any clinical manifestations such as electrical status during slow-wave sleep and other SE with no motor manifestation as absence seizures were excluded. Patients with the loss of consciousness due to underling disorder, and with including motor manifestation of seizures such as epilepsia partialis continua, were included in the study. Etiology of SE was summarized in five categories8: idiopathic/cryptogenic, remote symptomatic, febrile SE, acute symptomatic and progressive encephalopathy. Cryptogenic/idiopathic SE included SE in patients with generalized or focal idiopathic epilepsies and/or epilepsies of unknown etiology. Remote symptomatic SE was defined as SE caused by previous hypoxic ischemic encephalopathy, intracranial hemorrhage, cerebral palsy, CNS abnormalities, including malformations and vascular abnormalities and previous head injury or surgery. Febrile seizure which lasted for more than 30 min was defined as febrile SE. Acute symptomatic SE was caused by acute brain disease or injuries including CNS infections, cerebrovascular insults, acute systemic disease, hypertension, drugs and acute metabolic disorders. Progressive encephalopathy included different disorders with progressive course: neurodegenerative, metabolic, neurogenetic, malignant and neurocutaneous disease. Etiology distribution was analyzed in the group of first, recurrent and superrefractory SE episodes. SE duration was divided in six groups: 30e60 min, 60e90 min, 90e180 min, 180e360 min, 360 min-24 h and more than 24 h. All patients with seizures were treated in the Institute according to the same protocol and neurologist was consulted in early or
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established phase of SE. The hospital protocol for seizure treatment was shown in Fig. 1. It was suggested to apply the maximal dose of medication and wait for 20 min before giving the next drug. All children under two years of age with idiopathic/cryptogenic SE were given 100 mg pyridoxine for initial SE treatment. Midazolam was given as the first line drug in intravenous injection 0.1e0.2 mg/kg, but also as the third line drug in intravenous infusion in range 0.1e1.2 mg/kg/h if second line drugs (phenobarbital/phenytoin) failed. Midazolam was assessed as effective even if it failed as the first line, but was effective in intravenous infusion as the third line drug. The drug efficacy assessment included all drugs applied from the onset of seizure treatment, irrespective of whether the drug was applied within first 30 min of seizure duration or after this period. The drug efficacy was presented as a percentage of stopped SE episodes compared to total number of SE episodes treated by a certain drug. Prolonged coma was defined if coma lasted for more than 12 h after discontinuation of injection or infusion. Intensive therapy was necessary due to: 1) SE resistant to antiepileptic drugs and administration of high dosage of anesthetic agents; 2) respiratory complication of SE; 3) respiratory depression as adverse effect of drugs; 4) respiratory and circulatory impairment due to underlying disorders or comorbidity; 5) prolonged coma after SE (Fig. 2).
Fig. 1 e The hospital protocol forseizure/status epilepticus treatment in children in condition with and without intravenous access. The treatment according protocol start as soon as the seizure is diagnosed.
3
In the data analysis, descriptive statistics (absolute and relative numbers or percentages) were used. The study was approved by the Institutional Ethics Board.
3.
Results
The retrospective study included 602 convulsive SE episodes in 395 patients aged from 0.2 to 18 years (mean age 4.3, SD 4 years), with similar gender distribution (male 219, female 176). The etiology of first, recurrent and superrefractory SE was shown in Table 1. The most frequent etiology in the first SE was idiopathic or cryptogenic SE, including 10 children with focal benign early occipital epilepsy in childhood or Panayiotopoulos syndrome9. Idiopathic/cryptogenic and febrile SE was the most common etiology of the first SE, while none of SuperRefSE was caused by those two etiologies. The patients with remote symptomatic SE and progressive encephalopathy were in high risk for SE recurrence and SuperRefSE. The patients with hypoxic-ischemic encephalopathy within the group of remote symptomatic SE had the highest risk for SE recurrence. The patients with neurodegenerative disease (neuronal ceroid lipofuscinosis, Lafora disease, Gaucher type II, gangliozidosis, Krabbe disease and other progressive myoclonus epilepsies) and mitochondrial disease within the group of patients with progressive encephalopathy had the highest risk for SE recurrence and superrefractory SE. The duration of SE was commonly prolonged and 305 (50.7%) lasted > 60 min presenting RefSE. SuperRefSE was diagnosed in 43 episodes and made 7.14% of all SE (Table 1). The most common SE type was generalized convulsive 252 (41.9%), secondary generalized convulsive 181 (31.4%), while complex and simple focal were rare. In the group of superRefSE, ten episodes had features of epilepsia partialis continua with/without secondary generalization. The drugs used in SE treatment and their efficacy were presented in Table 2. The mean dose, range and the way of drugs administration were presented in Table 3. Seven SE episodes stopped spontaneously, eleven SE were refractory to any antiepileptic drugs, while in six patients with RefSE they continued until death. The etiology in these cases was: nonketotic hyperglycinemia (3), mitochondrial disorders (2) and unknown progressive neurodegenerative disease (1). The most available benzodiazepine for parenteral use in hospital was midazolam for initial SE treatment, but also as a third line drug if phenobarbital or phenytoin failed. The dose of midazolam was significantly higher in intravenous infusion, and we assessed that drug as effective even if it failed as intravenous injection but was effective in infusion. The drug successfully stopped 306 of 339 SE episodes (90.3%). In only 67 SE (21.9%) of successfully stopped SE, the dose of midazolam given as the first line drug was equal or lower than 0.2 mg/kg. In all other 239 episodes (78.9%), the effective dose was higher in range from 0.2 to 1.2 mg/kg/h (mean 0.4 mg/kg/h) and was given as the third line drug in intravenous infusion. In the group of SuperRefSE, MDZ was given in intravenous infusion as a third line drug and was significantly less effective, only in 17/30 episodes (56.6%). The commonly used anesthetic drugs were midazolam (MDZ) and thiopental in continuous intravenous infusion,
4
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Thiopental
47 57
Diazepam+ Pbenobarbital
10
35
Phenobarbital
91
Diazepam
Number of pa ents in whom drug was effec ve
135
92
Number of pa ents received drug
271
Midazolam
306 0
100
200
339
300
400
Fig. 2 e Distribution of patients according to efficacy of the most frequently used drugs.
both in high doses and with median duration about 48 h (range 1e720 h). The increasing rate for MDZ was 0.1 mg/kg/h up to seizure cessation (maximum 1.2 mg/kg/h) and for thiopental 1 mg/kg/h every 1e2 h (maximum 5 mg/kg/h), The long duration of MDZ infusion was due to very slow drug titration. The decrease of the mentioned drugs dosage started 24 h after the clinical seizure cessation. One of the main therapeutic problems in SE management by MDZ in continuous infusion was recurrence of the seizures after infusion withdrawal. In those cases, loading dose of benzodiazepines was given orally:
clobazam 0.5e1.5 mg/kg or clonazepam 0.1e0.3 mg/kg. In two cases, MDZ iv administration was associated with the worsening of seizures: in one case with Lennox Gastaut syndrome, MDZ infusion provoked tonic seizures and in one case with cryptogenic SE after MDZ administration, the frequency of seizures increased. In the group of SuperRefSE, all antiepileptic drugs were less effective. Midazolam was given in intravenous infusion in range 0.2e1.2 mg/kg/h with efficacy in 17 of 30 episodes (56.6%). Thiopental was given in intravenous infusion with
Table 1 e Etiology of the first, recurrent and super-refractory status epilepticus. Etiology
First SE
Recurrent SE
Total SE
SuperRefSE
N
%
N
%
N
%
N
%
108 56 18 4 24 6 2 2
27.3 14.2 e e e e e e
5 70 35 5 15 10 4 1
2.4 33.8 e e e e e e
113 126 53 9 39 16 6 3
18.8 20.9 e e e e e e
2 7 7 0 0 0 0 0
4.6 16.3
Febrile SE
92
23.3
1
0.5
93
15.4
0
0
Acute symptomatic CNS infections Acute systemic disease Cerebrovascular insult Drugs PRES Acute metabolic disorder
67 49 7 3 2 1 2
16.7 e e e e e e
34 33 0 0 0 0 1
16.4 e e e e e e
101 82 7 3 2 1 3
16.8 e e e e e e
7 7 0 0 0 0 0
16.3 e e e e e e
72 20 23 4 7 7 11 395
18.2 e e e e e e 100
97 41 17 10 1 4 24 207
46.8 e e e e e e 100
169 61 40 14 8 11 35 602
28.1 100
26 7 6 0 2 0 11 43
60.5 e e e e e e 100
Idiopathic/cryptogenic Remote symptomatic HIE ICH Cerebral palsy CNS malformations Vascular abnormalities Head injury
Progressive encephalopathy Neurodegenerative Neurogenetic/metabolic Neuroinflammatorya Malignant Neurocutaneous disease Mitochondriopathy Total
-
SE e status epilepticus, SuperRefSE e super-refractory status epilepticus, HIC e hypoxic ischemic encephalopathy, ICH - intracranial hemorrhage, PRES e posterior reversible encephalopathy syndrome. a Neuroinflammatory progressive disease included Rasmussen encephalitis and subacute sclerosing panencephalitis.
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Table 2 e Efficacy of the drugs used in the treatment of status epilepticus. Drug Midazolam Diazepam Phenobarbital Diazepam þ phenobarbital Thiopental Phenytoina Chloral-hydratea Lidocaina Lorazepama Clobazama Clonazepama Levetiracetama Propofola Ketaminea Valproatea
N
Effective
Effective %
339 271 135 35 57 4 6 2 3 5 2 11 2 2 2
306 92 91 10 47 2 3 0 2 4 2 7 0 0 1
90.3 33.9 67.4 28.6 82.4 e e e e e e e e e e
a
Since the drugs were given in limited number of stratus epilepticus episodes, the efficacy was not presented in percentage.
mean dose of 4.5 mg/kg/h with efficacy of 4/9 (44.4%). The mean duration of intravenous infusion of anesthetics was 156.6 h. The new antiepileptic drugs were given only in a few cases in our study when all previous drugs failed: propofol in two, lidocain in two and ketamine in two cases, and none stopped SE. Levetiracetam stopped three SuperrefSE episodes. In one girl with juvenile phenotype of CLN1, levetiracetam caused severe bradicardia with heart rate about 30/min. Eleven SuperRefSE were resistant to all drugs and six patients continued seizing until death. Intravenous infusions of corticosteroids were given in 15 RefSE episodes caused by inflammatory or immune-mediated diseases, in episodes of epilepsia partialis continua, in a patient with resistant focal convulsive SE caused by cortical dysplasia and two cases with mitochondrial disorders. Methylprednisolone was given in the dose of 500 mg/m2 in intravenous infusion lasting for 4 h for five consecutive days. In two patients, 20 mg/m2 dexamethason was given intravenously, divided in four doses for four days. We found that
Table 3 e Mean dose, range and drug administration routes in the SE treatment. Drug Diazepam Phenobarbital Midazolam Thiopental Lidocain Lorazepam Levetiracetam Propofol Ketamine 10% Chloral hydrate Valproate
Mean dose (mg/kg)
Range of dose (mg/kg)
Administration route
0.35 18.9 0.4 4.0 1 0.1 43 2 1.5 0.5 ml/kg
0.25e0.5 10e20 0.1e1.2 3e5 1 0.1 30e60 2e4 1.5 0.5 ml/kg
iv/rectally iv iv/infusion/im iv/infusion iv/infusion iv iv, orally, gt iv infusion orally, gt Rectally
30
30
iv
iv e intravenously, im e intramuscular, gt e gastric tube.
5
corticosteroids were beneficial and contributed to the reduction of the recurrence of seizures after MDZ/thiopental infusion withdrawal, and cessation of resistant epilepsia partialis continua. None of the patients in our study were treated by ketogenic diet or surgery, including vagus nerve stimulation as acute SE treatment. Intensive therapy was required in 244 (40.5%) SE episodes: oxygen therapy in 61, mechanical ventilation in 183 and circulatory stimulation in 68 SE. In the group of SuperRefSE, mechanical ventilation with/without circulatory stimulation was required in 33/43 (76.7%) episodes. Adverse effects of the drugs were noticed in 128 (21.3%) episodes, especially in SE treated by prolonged and high dosage of continuous infusion of midazolam (58.1%) and thiopental (55.5%). Tachiphylaxia was noticed only in episodes treated by continuous midazolam infusion. Depression of consciousness and severe respiratory impairment (ARDS) mostly happened in episodes treated by long lasting and high dosage continuous infusion of midazolam and thiopental. Six cases with RefSE caused by progressive encephalopathies treated by continuous high dosage infusion of midazolam, were suffering acute respiratory distress syndrome (ARDS). They required withdrawal of midazolam, introducing corticosteroids and appropriate mechanical ventilation conditions. Respiratory impairment was commonly caused by aspiration pneumonia, ARDS or airway hypersecretion. In the group of SuperRefSE, the side effects were more common, in 60.5%, mostly requiring mechanical ventilation (25) and circulatory stimulation (8).Table 4 shows the most severe adverse effects of antiepileptic drugs used in SE treatment. Patients with progressive encephalopathy such as Krabbe disease, neuronal ceroid lipofuscinosis, progressive myoclonus epilepsies and mitochondrial disorders were very sensitive to benzodiazepines and barbiturate. They experienced respiratory depression after common dose of benzodiazepines or barbiturates with prolonged coma. Having recognized this phenomenon, we have become cautious about the application of high dose and long-lasting infusions of MDZ and barbiturate. We found good response to levetiracetam in a limited number of patients (three cases) with progressive encephalopathy in loading doses from 30 to 60 mg/kg. Case-fatality rate was 5.1% in all analyzed SE, while in the group of SuperRefSE, it was 21.3%.
4.
Discussion
The retrospective study included large number of convulsive SE episodes in children. The etiology of SE was heterogenous with different distribution in the groups of the first, recurrent or superrefractory SE. We found that febrile disease and idiopathic/cryptogenic etiology were the most common causes of first SE with no risk of SE recurrence. The patients with progressive encephalopathy (progressive, myoclonic epilepsies, progressive neuroinflammatory, mitochondrial, neurocutaneous disease) and remote symptomatic etiology (especially hypoxic-ischemic encephalopathy) had a high risk of SE recurrence. Therefore, it is very important to educate the parents or caregivers of those children to give appropriate rescue drugs for prehospital seizure treatment.
6
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Table 4 e Most severe adverse effects of the drugs used in SE treatment. Adverse effects
N
%
Tachiphylaxia Depression of consciousness Respiratory depression Respiratory impairment Cardiovascular impairment
38 93 10 20 58
16a 15.4 1.7 3.3 9.6
a
Only episodes treated by continuous midazolam infusion was included.
Comparing our results to study of Claassen et al.,10 we found that our patients were given higher MDZ average dosage (0.4 mg/kg/h comparing to 0.19 mg/kg/h), including maximal dosage (1.2 mg/kg/h comparing to 0.22 mg/kg/h) with longer duration of infusion. That could be the explanation of better efficacy of midazolam in our study. Recurrence rate after stopping the infusion was observed in both studies and could be a serious therapeutic problem.10 Our results support recently published recommendation of Italian League Against Epilepsy about faster increase of MDZ in intravenous infusion and higher dosage in initial treatment.11 Our hospital has accepted this recommendation and will implement it in the new protocol for SE treatment. Recent open-label, uncontrolled study provides Class IV evidence that intravenous ketamine might be effective and safe in treating children with RefSE.12 In our study, ketamine was ineffective given through gastric tube in two cases without co-medication with intravenous midazolam. Recently published data suggested that some non-medication treatment such as ketogenic diet13 or urgent surgical treatment14 could be helpful in terminating RefSE in children, but none of our cases were treated by them. Adverse effects were frequent in our patients, especially regarding SuperRefSE. The factors which could contribute to more common adverse effects were: underlying disorders, preexisting neurological abnormalities and coexisting infection. Prolonged MDZ and thiopental half-life after long-lasting continuous infusion could be explained by accumulation of the drugs in periferal tissues, especially in lipid tissue.15e17 It potentially contributed to prolonged coma in some of our patients. We found that SuperRefSE is a particular type of SE, characterized by progressive encephalopathy as the most common etiology, common adverse effects, high mortality, poor response to anticonvulsive drugs, frequently requiring intensive therapy. Recently published protocol for SuperRefSE treatment2 could be very helpful in clinical practice and further studies. Despite the improvement in the treatment in the last decades, SE is still associated with high morbidity and mortality.18,19 The mortality in pediatric group of patients ranged from 3 to 11%, and it is obvious that prognosis is better in children than in older patients.3,7,20e22 The outcome in children treated in intensive care unit is favorable in most of the cases, but mortality and morbidity rates are still very high: neurological consequences occurred in 12.9% patients, casefatality rate was 9.3% and recurrence rate was 21%.23 The
results of our study showed that the group of SuperRefSE had significantly higher case-fatality rate compared to all SE episodes. Etiology and prior neurological abnormalities were the main predictors of mortality, while the main predictor of morbidity was underlying etiology.23 Hocker et al. analyzed the outcome of RefSE including superRefSE (90%), and concluded that mortality is high and independent of the choice of anesthetic agent, type of SE, and preexisting epilepsy.24 Some authors highlighted the difference between features of SE in children and adults.25,26 Alldredge et al. pointed out the impact of prehospital SE treatment to the course and duration of SE.27 Status epilepticus treatment according to the established protocol was recommended despite certain disadvantages. It is important to modify algorithm depending on drug availability in certain hospitals or regions and also to educate the parents or caregivers how to stop the seizures in prehospital conditions. We would also like to emphasize the importance of different approaches to SE treatment in children compared to adults, especially to the most vulnerable group of children with preexisting neurological deficit and progressive encephalopathy. Our data suggested that the patients with progressive encephalopathy have a higher risk for SuperRefSE making them strong candidates to the prescription of rescue drugs even before the experience of the first episode of SE. There are some limitations of the study. We compared the efficacy of drugs from different lines, e.g, the efficacy of the first line with the second or the third line drugs. The new antiepileptic drugs for SE treatment were given only in few cases. Also, we were unable to avoid cummulative effect in assessment of the drug given after previously ineffective drugs. Current treatment protocols for convulsive SE in children and adults are based on limited controlled trials performed predominantly in adults.28 Recently published protocol for SuperRefSE treatment2 showed how challengeable is the treatment of this particular SE type. Since the most beneficial treatment algorithm for both children and adults is not known,28 the data from this manuscript might be helpful in making better SE treatment approach in similar circumstances as in our hospital. In conclusion, status epilepticus in children was characterized by heterogeneous etiology, prolonged duration and commonly good response to midazolam only given in high doses. Superrefractory SE was not so rare in children, especially among the patients with progressive encephalopathy.
Conflict of interest None of the authors has any conflict of interest to disclose.
Ethical approval All authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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Acknowledgment 12.
Tatjana Pekmezovic was supported by grant from the Ministry of Science and Education of the Republic of Serbia (grant no. 175087).
13.
14.
references 15. 1. Wasterlain CG, Chen JW. Definition and classification of status epilepticus. In: Wasterlain CG, Treiman DM, editors. Status epilepticus: mechanisms and management. Massachusetts. London: The MIT Press Cambridge; 2006. p. 11e6. 2. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802e18. 3. Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC, NLSTEPSS Collaborative Group. Incidence, cause and shortterm outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:222e31. 4. Arzimanoglou A. Outcome of status epilepticus in children. Epilepsia 2007;48(Suppl. 8):91e3. 5. Shorvon SD. Emergency treatment of acute seizures, serial seizures, seizure cluster and status epilepticus. In: Shorvon SD, editor. Handbook of epilepsy treatment. Oxford: Blackwell Science; 2000. p. 173e94. 6. Treiman D, Meyers P, Walton N, Collins J, Colling C, Rowan A, Handforth A, Faught E, Calabrese V, Ulthman B, Ramsay R, Mamdani M. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Group. N Eng J Med 1998;339:792e8. 7. Costello DJ, Cole AJ. Treatment of acute seizures and status epilepticus. J Intensive Care Med 2007;22:319e47. 8. Shinnar S. Epidemiology of childhood status epilepticus. In: Wasterlain CG, Treiman DM, editors. Status epilepticus: mechanisms and management. Massachusetts. London: The MIT Press Cambridge; 2006. p. 39e51. 9. Panayiotopoulos CP, Michael M, Sanders S, Valeta T, Koutroumanidis M. Benign childhood focal epilepsies: assessment of established and newly recognized syndromes. Brain 2008;131:2264e86. 10. Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: a survey of neurologists. J Neurol Sci 2003;211:37e44. 11. Capovilla G, Beccaria F, Beghi E, Minicucci F, Sartori S, Vecchi M. Treatment of convulsive status epilepticus in
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