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Combination drug therapy for the treatment of status epilepticus Expert Rev. Neurother. 15(6), 639–654 (2015)
Xuefeng Wang*, Jing Jin‡ and Rong Chen‡ Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China *Author for correspondence: Tel.: +86 136 2835 9876 Fax: +86 023 8901 2878 [email protected]
Status epilepticus (SE) is a common neurological emergent disease with high mortality and disability rates. Rapidly and effectively controlling seizures is key to saving the lives of patients and improving their prognoses. Traditional antiepileptic drugs for SE are ineffective in 30–40% of cases. In light of the diverse etiology and complex pathogenesis of SE, combination drug therapy for SE might be more conducive for the treatment of all patients because the combined use of drugs can produce synergistic effects via different mechanisms. This review summarizes combination drug therapies used for SE in animal experiments and clinical practice, the potential advantages of combination drug therapy and specific combination drug therapies using different antiepileptic drugs. The aim is to help researchers seek better treatments for early termination of SE. KEYWORDS: AEDs . animal experiment . clinical practice . combination drug therapy . monotherapy . SE . seizure
‡
Joint first authors
Status epilepticus (SE) is a common neurological emergency and severe disease. Controlling seizures early is key to saving lives and improving prognoses [1,2]. Currently, the traditional antiepileptic drugs (AEDs) for SE are widely used in the clinical setting. Although they are effective in 60–70% of cases of SE, the remaining 30–40% of patients do not benefit from the currently available treatment [3]. Combination drug therapy for SE may be more conducive for the treatment of all patients because the combined use of drugs can produce synergistic effects via different mechanisms, which might ensure the effective application of AEDs to terminate SE early. Because experimental and clinical evidence of the effectiveness of combination drug therapy over monotherapy for improving the prognosis of patients with SE is absent, exploring combination drug therapies for SE may be of value [4,5]. Combination therapy was defined as any one of the following: . .
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two or more types of AEDs are used simultaneously (including add-on treatments); progressive sequential therapy: the intentional use of a first drug, and then the administration of a second drug when the pharmacological effects of the prior drug still exist (the intention is for the two drugs to produce a combined effect);
10.1586/14737175.2015.1045881
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combination of an AED with non-pharmacological strategies, neuromodulation drugs or immunomodulating therapy. The add-on treatment can also be considered as combination therapy for SE as the long half-lives of most of the compounds used before the add-on treatment will interact with the addon drugs during sequential treatment.
Materials & methods
We performed a review of the recent literature on the treatment of SE and refractory status epilepticus (RSE), summarized the current combination therapy for commonly utilized AEDs and provided an argument for early combination therapy in SE/RSE. A PubMed and Medline literature search was performed for relevant articles published prior to 2015 using the following search terms: ‘status epilepticus plus drug therapy’, ‘status epilepticus plus add-on treatment’, ‘status epilepticus plus combination’. Clinical trials, animal experiments, review articles and practice guidelines were all included. Combination drug therapy for SE in animal experiments
Mazarati et al. [6] used an experimental model of self-sustaining SE (SSSE) in rats that was induced by electrical stimulation of the
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Wang, Jin & Chen
perforant path [7,8]. Once this model was induced, the rats were resistant to traditional AEDs, such as diazepam and phenytoin. Ten minutes after the perforant path stimulation, the following drugs were separately administered by intraperitoneal injection: levetiracetam (LEV) (50, 200, 500 and 1000 mg/kg), diazepam (1, 5 mg/kg), a combination of diazepam (5 mg/kg) and LEV (1, 3, 10 and 200 mg/kg) and a combination of diazepam (1 mg/kg) and LEV (25, 50 and 200 mg/kg). The study found that 200 mg/kg LEV shortened the seizure duration and spike frequency by 50%. The combination of LEV (200 mg/kg) and an individually ineffective dose of diazepam (1 mg/kg) shortened the seizure duration by 99% and the spike frequency by 97%. An analysis of the average termination time for SSSE in each experimental group indicated that the length of time for the different doses of the combination of LEV and diazepam was significantly shorter than the time for monotherapy. Even when the doses of both drugs were far below the therapeutic doses, these combinations still had a significant curative effect, and there were fewer side effects. However, higher doses are usually required for rodents compared to humans per unit weight. As there is a lack of studies about the tolerability of high doses of LEV in humans, it is difficult to precisely compare toxicity in rodents versus humans. Some animal experiments [7,9,10] have found that combinations of LEV and other AEDs can produce a synergetic effect and that LEV can enhance the anticonvulsant action of other AEDs. Kaminski et al. [11] found that LEV can significantly enhance the inhibitory effect of other AEDs in seizures in the amygdala in a rat model. LEV can also enhance the seizure suppression of other AEDs in audiogenic susceptible mice [9]. A combination of a noncompetitive N-methyl-D-aspartic (NMDA) receptor antagonist with diazepam was found to be superior to diazepam monotherapy in many animal experiments. One study found that a combination of a single dose of MK 801 (4 mg/kg) with diazepam (10 mg/kg) administered 60 min after SE onset stopped SE more easily than diazepam alone [12]. Wasterlain et al. [5] used a model of severe SE induced by cholinergic agents, which might apply to battlefield or terrorism situations as these agents are components in some bioweapons. The following drugs were separately administered by intraperitoneal injection: monotherapy with ketamine (10 mg/kg), valproate (30 mg/kg), brivaracetam (10 mg/kg) or diazepam (1, 5 or 10 mg/kg); combination therapy with diazepam (1 mg/kg), ketamine (10 mg/kg) + valproate (30 mg/kg) and combination therapy with diazepam (1 mg/kg), ketamine (10 mg/kg) + brivaracetam (10 mg/kg). Some data from this study have not been published, but ‘toxicity score’ data and the number of post-treatment seizures have been presented in the literature. ‘Toxicity score’ (analysis of ataxia, righting reflex, response to tail pinch and corneal reflex) was used to measure drug toxicity during the first hour. The number of posttreatment seizures was used to measure SE outcome. Monotherapy with ketamine, valproate, brivaracetam, diazepam and other AEDs failed to stop SE. The available data indicated that the combina-tions were significantly more effective and less toxic 640
than monotherapy in this model. In the kainic acid-induced post-SE model, another widely used and well-characterized animal model for temporal lobe epilepsy, Vermoesen et al. [13] treated the rats with the following drugs by intraperitoneal injection after the SE had continued for 90 min: diazepam (10, 20 mg/kg), ketamine (50 mg/kg), the combination of ketamine (50 mg/kg) and diazepam (10 mg/kg) or the combination of ketamine (50 mg/kg) and diazepam (20 mg/kg). A 10 mg/kg dose of diazepam terminated 28% of SE, 20 mg/kg diazepam terminated 50% of SE, the combination of ketamine (50 mg/kg) and diazepam (10 mg/kg) terminated 33% of SE and ketamine (50 mg/kg) did not terminate SE and increased the spike frequency. The combina-tion of ketamine (50 mg/kg) and diazepam (20 mg/kg) terminated SE at both the behavioral level and the electrographic level in all rats. Francois et al. [14] used a model of lithium–pilocarpineinduced SE, leading to spontaneous recurrent seizures (SRS). The following drugs were administered by intraperitoneal injection: combination therapy with topiramate (10, 30 or 60 mg/kg) at the onset of SE and 10 h later and diazepam (2.5 and 1.25 mg/kg) at 2 and 10 h after SE, followed by topiramate twice daily for 6 days. For other rats, two injections of diazepam were administered on the day of SE. The cell count data, the occurrence and frequency of SRS and the MRI T2-weighted signal in the hippocampus and ventral cortices were precisely collected and analyzed. The results showed that the combination therapy of topiramate and diazepam could partly protect the hippocampus and ventral entorhinal cortex, both of which are crucial to epileptogenesis. However, diazepam–topiramate treatment had no impact on the latency and frequency of SRS, which indicates that the antiepileptogenic effects of the diazepam–topiramate combination were not sufficient. However, animal experiments have their limitations. Animal experiments are flawed as animal models do not completely simulate human function. It is also very difficult to distinguish between cause and effect as the lesions or stimuli inducing seizures may produce neuronal damage. Whether the outcomes of animal experiments can be used in humans is always unclear. More clinical trials are still needed to support the results of animal experiments. Clinical practice with combination drug therapy for SE
Synowiec et al. [15] retrospectively analyzed 11 benzodiazepineresistant SE patients in 2003–2011, using ketamine as an add-on drug. Seven patients had systemic or central nervous system infections. One patient had metabolic disease. In three patients, SE was thought to be caused by an insufficient initial dose of AEDs. RSE was defined as terminated if the clinical signs and/or the electroencephalo-graph (EEG) seizures disappeared after ketamine withdrawal for 24 h. All patients with SE resistant to AEDs received ketamine iv., in combination with other drugs, such as lorazepam or phenytoin. In all patients (11/11), RSE was completely controlled with no obvious side effects. Uges et al. [16] designed a prospective, single center, no-control, non-blinded study to evaluate the efficacy and safety of LEV added to a standard therapy scheme of SE. The study included 11 adults Expert Rev. Neurother. 15(6), (2015)
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Combination drug therapy for the treatment of SE
(median age: 60 years) with SE, five of whom had generalized convulsive SE (GCSE), five had partial seizures and one had non-convulsive SE. SE etiology was identified in all subjects, including stroke, meningoencephalitis, malignant glioma and acute subdural hematoma. All of the patients were treated with LEV combined with other AEDs. One patient died for reasons unrelated to LEV; in the rest of the patients, SE was fully controlled within 24 h with no obvious side effects. Gallentine et al. [17] retrospectively analyzed LEV as an add-on treatment in children with RSE. The study included 11 children (median age: 2.5 months) in 2000–2007. RSE etiology was identified in all subjects, including perinatal hypoxic ischemic encephalopathy, transfer of neural tube cells, brain tumor and congenital malformation. LEV as an add-on therapy was effective in 45% of patients (5/11), and the effect was uncertain in 27% (3/11). The average time between LEV use and the cessation of RSE was 1.5 (1–8) days without obvious side effects. Su et al. [18] analyzed 15 children who were diagnosed with electrical SE of sleep (ESES) syndrome. Compared with clonazepam (CZP) or LEV monotherapy, LEV combined with CZP more effectively controlled the clinical seizures and sleep epileptiform discharges. The combination therapy also led to fewer adverse reactions. Rossetti et al. [19] retrospectively analyzed 31 instances of RSE in 27 adult patients from 1997 to 2002. All of the patients were treated with iv. propofol. To maintain the lowest effective dose of propofol, other AEDs (mainly CZP or phenytoin) were continuously used, and six patients later used thiopental as an addon drug. The average speed of propofol infusion was 4.8 (2.1– 13) mg/kg/d. The duration of treatment was 3 (1–9) days, and the ICU stay was 7 (2–42) days. CZP or phenytoin combined with propofol terminated 21 (67%) episodes, and the thiopental follow-up effectively terminated three (10%) episodes. No serious side effects occurred.
Review
was prolonged, the activity of GABA receptors on the postsynaptic membrane decreased, and the number and activity of NMDA receptors increased. This repeated and prolonged exposure induces an increasing incidence of RSE [37]. The combined application of drugs that act on different neurotransmitters may have more advantages. Particularly, the use of some new AEDs as additive drugs may improve the prognosis of patients [3,4,16,36,38,45] Combination therapy may improve brain damage
Sustained seizures cause substantial damage to the brain [4,25,35,37,46], including neuronal loss and cerebral edema. For example, Vespa et al. [47,48] studied patients with posttraumatic non-convulsive electrographic seizures. These in-depth studies found that severe traumatic brain injury might cause frequent non-convulsive seizures, which seemed to be related to long-term hippocampal atrophy. In addition, non-convulsive electrographic post-traumatic seizures might cause an increase in both intracranial pressure and the microdialysis lactate/ pyruvate ratio, which indicates a poor prognosis for patients with traumatic brain injury. Combination therapy may shorten SE duration
The delayed treatment of SE is a risk to patients, and the early use of AEDs that affect multiple mechanisms is conducive to terminating SE early to improve the prognosis [1,39,44,49–54]. In a review [55], the author assembled data on outcome factors in SE. One of the most studied risk factors for death in SE was SE duration after SE onset. The studies of SE outcome showed that a critical determining factor for mortality was an SE duration of more than 1 h, and increases in mortality and hospital stay were apparent when the number of hours of seizure activity increased. Combination drug therapy with different AEDs
The potential advantages of combination therapy for SE
Both the animal experiments and clinical studies above support the rationale of combination therapy for SE. Cook et al. [20] also found that the clinical practice of combination therapy for SE and RSE is much more prevalent than reported in the literature, and wider attention is currently paid to it. The following reasons support the use of combination therapy for SE. Combination therapy may have multiple mechanisms of action
SE is a multifactorial and heterogeneous disease. SE not only has many causes, but it also has a very complicated mechanism [21–30]. The combined application of AEDs with various mechanisms of action may be preferred in clinical practice over benzodiazepine monotherapy with a single mechanism of action [4,5,7,31].
At present, combination drug therapy mainly involves drugs such as LEV, ketamine, midazolam, phenytoin, barbiturates, stiripentol, immunomodulatory drugs, lacosamide, topiramate, non-pharmacological strategies and neuromodulation drugs (TABLE 1). Levetiracetam
LEV is a broad-spectrum antiepileptic drug that is involved in the regulation of calcium channels, NMDA receptors and GABA transportation [16,17,42,56–58]. The characteristics of LEV include rapid action, linear pharmacokinetics, nerve protection, little impact on cognition and few drug interactions [16,17,56,59]. Mazarati et al. [59] found, in animal experiments, that combination therapy with diazepam and LEV for the treatment of SE had strong synergistic effects. In clinical practice, combination therapy with LEV for SE has gradually increased in frequency [16–18,60].
Combination therapy may act on different neurotransmitters
The combination therapy with LEV
SE is a continuous disease process, and the pathogenesis might not be identical at different time points [32–35]. Wasterlain et al. [36] found that as the seizures repeated and the duration of SE
First, LEV and benzodiazepines are used simultaneously. Second, LEV is used as an add-on treatment when the first-line or second-line drugs fail [16–18,60].
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641
642
45
11
1
5
35
27
2013
2013
2013
2013
2012
2012
60 years (44–75 years) F (4); M (7)
3.8 years (2.5 months–11 years) F (10); M (17)
60.5 years (19–84 years) F (16); M (19)
27 years (22–34 years) F (2); M (3)
17 years M (1)
52 years (22–82 years) F (4); M (7)
64.7 years (49.5–80 years) F (25); M (20)
8 years (8.5–13.5 years) F (6); M (9)
Age/sex
Retrospective study
Unknown
Prospective study
Retrospective study
Yes (11) No (24)
Yes (6) No (5)
Case series
Retrospective study
Yes (6); No (5)
No (5)
Retrospective study
Yes (15); No (30)
Case report
Retrospective study
Yes (15)
No (1)
Study type
History of epilepsy
Metabolic problems (3); cerebrovascular accidents (4); meningoencephalitis (1); glioblastoma (2); pyramidal tetraparesis (1)
Meningitis or encephalitis (11); febrile SE (7); cerebral cortical dysgenesis (5); hypoxic ischemic encephalopathy (3); Trauma (1)
Cerebrovascular accidents (12); brain tumors (8); hypoxic brain damage (5);CNS infections (4); metabolic problems (4); Dandy–Walker syndrome (1); malcompliance 1(1)
Unknown
Anti-N-Methyl-D-Aspartate receptor encephalitis
CNS infection (2); Metabolic disturbance (1); Low AED levels (3); Sepsis (2); Systemic infection (3)
Acute symptomatic seizures (25); remote symptomatic unprovoked seizures (17); unprovoked seizures of unknown etiology (3)
Unknown (13); febrile history (1); family history of epilepsy (1)
Etiology of RSE
LEV, DZP
MDZ, DZP
Within hours Initial SE (8); established SE (10); RSE (9)
36 min (15–90 min)
TPM
2 days (2–23 days) NCSE (17); GCSE (4); SPSE (14)
NCSE (1); GCSE (5); FCSE (5)
Immunomodulating therapy
Immunomodulating therapy 12 days (1); Unknown (4)
32 days
KET
NORSE syndrome
GTCSE (1)
5 days (1–11 days)
LCM
Unknown
Simple partial/ complex/ absence (17); GCSE (1); NCSE (27) GTCSE (6); NCSE (5)
LEV, CBZ
The main drug of combination therapy
Unknown
SE duration prior to combination therapy
ESES syndrome
SE type
[16]
[76]
[98]
[90]
[86]
[15]
[91]
[18]
Ref.
CBZ: Carbamazepine; CNS: Central nervous system; DZP: Diazepam; F: Female; FCSE: Focal convulsive status epilepticus; GCSE: Generalized convulsive status epilepticus; GTCSE: Generalized tonic–clonic status epilepticus; h: Hours; KET: Ketamine; LCM: Lacosamide; LEV: levetiracetam; M: Male; MDZ: Midazolam; NCSE: Non-convulsive status epilepticus; NORSE: New-onset refractory status epilepticus; PHT: Phenytoin; RSE: Refractory status epilepticus; SE: Status epilepticus; SPSE: Simple partial(motor/versive/aura) status epilepticus; TPM: Topiramate.
11
15
2014
2009
Patients (n)
Year
Table 1. Demographics and clinical data of combination drug therapy in SE/RSE.
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Expert Rev. Neurother. 15(6), (2015)
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CBZ: Carbamazepine; CNS: Central nervous system; DZP: Diazepam; F: Female; FCSE: Focal convulsive status epilepticus; GCSE: Generalized convulsive status epilepticus; GTCSE: Generalized tonic–clonic status epilepticus; h: Hours; KET: Ketamine; LCM: Lacosamide; LEV: levetiracetam; M: Male; MDZ: Midazolam; NCSE: Non-convulsive status epilepticus; NORSE: New-onset refractory status epilepticus; PHT: Phenytoin; RSE: Refractory status epilepticus; SE: Status epilepticus; SPSE: Simple partial(motor/versive/aura) status epilepticus; TPM: Topiramate.
[72]
Retrospective study 122 2005
24.4 months (0.5–197.4 months) F (51); M (71)
Unknown
Idiopathic (46); acute symptomatic (24); progressive neurologic (3); remote symptomatic (5); febrile (44)
MDZ, PHT Unknown GCSE
[17]
LEV 3.4 days (0–12 days) Complex partial (7); Tonic–clonic (2); Subtle (2) Retrospective study 11 2009
2.5 months (2 days–9 years) F (2); M (9)
Unknown
Cerebrovascular accidents (3); brain tumors (2); CNS infections (3); unknown (1); congenital brain malformation (1); history of perinatal hypoxic-ischemic encephalopathy (1)
The main drug of combination therapy SE duration prior to combination therapy SE type Etiology of RSE Study type History of epilepsy Age/sex Patients (n) Year
Table 1. Demographics and clinical data of combination drug therapy in SE/RSE (cont.).
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Ref.
Combination drug therapy for the treatment of SE
Review
Indications
Combination therapy with LEV is mainly used to treat SE or RSE in adults and RSE or ESES syndrome in children [16–18,60]. Mode of administration
The treatment should start with benzodiazepines and then proceed with LEV. When LEV is used in combination with benzodiazepines in adult SE and RSE, the recommended dose is 2500 mg LEV administered iv. (>5 min) [16,60,61]. Rossetti et al. [62] also found that the early use of LEV was more effective than the later use of LEV. In a study by Uges et al. [16], patients received 2500 mg LEV iv. (>5 min) while taking standard treatments of first-line and/or second-line drugs, such as benzodiazepines and phenytoin. The median time from hospital admission to the use of LEV was 36 (15–90) min. Nine patients received LEV combined with benzodiazepines as the initial treatment. Another two patients received LEV as an addon therapy in the late stage of SE when successive use of benzodiazepines, phenytoin and valproate was ineffective. In all of the patients, SE was completely controlled within 24 h after the use of LEV; one patient died 9 days later due to multiple organ failure, which was independent of LEV. There were also no obvious side effects related to LEV. In children with RSE, the recommended dose is 15–70 mg/kg LEV administered iv. [63]. Gallentine et al. [17] retrospectively analyzed 11 children with RSE who were treated with LEV as an add-on therapy for RSE. When LEV was being used, other AEDs were continuously used or concomitantly added or adjusted (e.g., midazolam, pentobarbital, valproic acid, phenobarbital, phenytoin, diazepam). Four patients were administered 15–60 mg/kg LEV by nasal feeding or orally, six received 15–62.5 mg/kg LEV iv. and one was administered 70 mg/kg LEV rectally followed by 20 mg/kg LEV by nasal feeding. This treatment strategy was 73% (8/11) effective. The average time for the termination of RSE from the administration of LEV was 1.5 (1–8) days with no obvious side effects. This study showed that the effective dose of LEV was more than 30 mg/kg/d (median: 40 mg/kg/d). The recommended initial dose of LEV in combination therapy was 30 mg/kg/d for the treatment of children with RSE and LEV could be administered orally, iv. or by nasal feeding. The early use of LEV was more effective than the later use of LEV [62]. To examine combination therapy in children with ESES syndrome, Su et al. [18] analyzed 15 patients diagnosed with ESES syndrome with benign childhood epilepsy with centrotemporal spikes. The early use of LEV monotherapy was ineffective for both the EEG and clinical signs. Later, the children received LEV (20–40 mg/kg/d) orally, combined with CZP orally, at bedtime for 2 months (for the first month, 0.02–0.03 mg/kg CZP once per day; for the second month, 0.02–0.03 mg/kg CZP once every other day). Except for one patient who had seizures and a recurrence of ESES, all of the other children showed no clinical seizures, and their sleep EEGs revealed normal or only a small amount of low-amplitude discharge in the 643
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Wang, Jin & Chen
central temporal region. Before treatment, all of the patients had some of the following symptoms: language impairment, decline in academic performance and hyperactivity. After treatment, their neuropsychological function obviously improved. The study found that in children with ESES, the combination of LEV and CZP was more effective for seizure control compared with monotherapy with either LEV or CZP.
strong synergistic effect in the treatment of SE. The application of ketamine combined with AEDs has also been used clinically [15].
The effective time
Indications
Uges et al. [16] study showed that SE stopped within 24 h of LEV use in adults. Gallentine et al. [17] found that the average time that it took for RSE to stop in children was 1.5 days after LEV was given.
Combined administration of ketamine is mainly suitable for adult patients with RSE [15,42,66,67]. Synowiec et al. [15] retrospectively analyzed 11 RSE patients who used iv. ketamine as an add-on drug when other AEDs were ineffective. Ketamine was used in combination with other AEDs, such as lorazepam and phenytoin. Ketamine was used for 4–28 days. Six patients (6/7) who needed vasopressors to maintain blood pressure at the early stage of treatment ceased the use of vasopressors after the use of ketamine. Eventually, the RSE of all patients (11/11) was completely controlled with no obvious side effects.
Adverse reactions
Uges et al. [16] reported that one patient exhibited allergic reactions, including face flushing, which returned to normal in a short time; five patients exhibited mental confusion 24 h after SE termination, which might have been an adverse reaction to LEV. Gallentine et al. [17] reported that one patient had rectal bleeding with the administration of LEV and valproate rectally, but rectal bleeding stopped when LEV was used alone by nasal feeding. Precautions
Patients who are allergic to LEV, pyrrolidine derivatives or any other component of LEV cannot use LEV. The animal experiments by Mazarati et al. [59] supported the idea that the characteristics of combination therapy with diazepam and LEV include synergistic effects, quick effects, minor toxic effects and nerve protection. Uges et al. [16–18] demonstrated that the clinical administration of LEV combined with other AEDs to treat SE, RSE and ESES syndrome is safe and feasible. Because the present clinical use of LEV combined with other AEDs includes a small sample size and the follow-up time is limited, further research expanding the sample size for the clinical application of combination therapy is necessary. Navarro et al. [60] are currently conducting a Phase III clinical trial to compare the efficacy of iv. LEV combined with CZP and CZP monotherapy in treating GCSE. The results of the study will help determine the exact efficacy of combination therapy.
Combination therapy with ketamine
Ketamine are used as an add-on treatment when the first-line or second-line drug is ineffective for SE [15].
Mode of administration
Treatment should start with benzodiazepines and then proceed with ketamine. Synowiec et al. [15] used ketamine as an add-on treatment together with other AEDs (such as lorazepam and phenytoin) to control RSE. The administration of ketamine was a 1–2 mg/kg iv. load, followed by 1.3 mg/kg/h (0.45– 2.1 mg/kg/h) continuous iv. administration. The maximum dose was 1392–4200 mg/d. The RSE of all patients (11/11) was completely controlled. The effective time
The study by Synowiec et al. [15] defined the termination of RSE as termination at the behavioral level and/or at the electrographic level 24 h after drug withdrawal. The average time after ketamine was used until the termination of RSE was observed was 9.8 (4–28) days. Adverse reactions
Zeiler et al. [68] found that the adverse reactions related to ketamine included psychiatric symptoms, increases in intracranial pressure and intraocular pressure and arrhythmia, but these reactions were rare. Synowiec et al. [12] found no acute side effects related to ketamine.
Ketamine
Ketamine is a noncompetitive NMDA receptor antagonist [42] that blocks NMDA transmission and protects neurocytes [64]. Ketamine can also stabilize hemodynamics, so that hypotension will not occur [15,42]. One study [36] found that as the seizures repeated and the time of SE was prolonged, the number and activity of GABA receptors in the postsynaptic membrane decreased, while the number and activity of NMDA receptors increased; these changes led to an increase in the frequency of RSE. The application of ketamine in combination with other AEDs to treat SE is being explored. Animal experiments [5,13,65] have found that diazepam combined with ketamine has a 644
Precautions
[69]
First, slow administration and a gradual increase in the amount of ketamine are necessary. Pruss et al. [66] reported a young female with malignant SE who was resistant to benzodiazepines, phenytoin, thiopental and propofol. The RSE was finally controlled by the combined use of midazolam (0.6 mg/kg/h iv.) and ketamine. Ketamine was administered as a 0.5 mg/kg iv. load (>1 min), followed by 0.4 mg/kg/h continuous administration iv., which was increased to 1.6 mg/kg/h over 3 h and then to 2.4–3.2 mg/kg/h after 48 h for an additional 8 days. Eventually, the RSE terminated, and the EEG seizures Expert Rev. Neurother. 15(6), (2015)
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Combination drug therapy for the treatment of SE
disappeared with no side effects. Second, the close monitoring of patient vital signs is needed. Mechanical ventilation could be used when necessary. Third, coronal CT should be used to exclude intracranial lesions that may increase intracranial pressure. Fourth, the use of ketamine should be considered when SE is caused by alcohol intoxication. In addition, skeletal muscle tension caused by ketamine should be distinguished from tonic–clonic seizure. Animal experiments [5,13] have demonstrated that the combined administration of ketamine and benzodiazepines can correct two types of changes during the progression of SE: the reduction of GABA’s inhibiting effect and the enhancement of NMDA effects. The synergistic action of ketamine and diazepam seemed to be model-independent. Martin et al. [65] showed that the combination of ketamine and diazepam was strongly effective in diazepam-refractory SE induced by cholinergic stimulation, while monotherapy had small effects. This synergistic effect offered more advantages compared to monotherapy in the treatment of RSE. The clinical study by Synowiec et al. [15] demonstrated that the combination therapy of ketamine and other AEDs is relatively safe and effective for the treatment of RSE. Additionally, the beneficial cardiovascular effect of ketamine is an advantageous characteristic that no other AEDs possess. Of course, further study is needed to determine the best time for the administration of ketamine, the dosage and its effect on the intracranial pressure and cerebral blood flow. Midazolam
Midazolam is a water-soluble benzodiazepine. It inhibits the excitability of GABA neurons through allosteric modulation of the GABA receptor. It can rapidly penetrate the blood– brain barrier and has a short onset time [70,71]. Midazolam is effective for the treatment of SE in children, with a low mortality rate [72–74] and a high recurrence rate [42,75]. Monotherapy always has a poor response in children with SE and RSE [17], so progressive sequential therapy with midazolam and other AEDs has certain advantages compared with monotherapy [72,76].
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(20 mg/kg) or a bolus of midazolam (0.15 mg/kg iv.) is given. If the SE continues, the dose of iv. midazolam is increased every 5 min (up to 0.6 mg/kg/min) to stop the epilepsy, and this increased dose is continued for 24 h. Then, the delivery rate is decreased by 0.05 mg/kg/min every 6 h. If the seizure continues after 60 min of the infusion (0.6 mg/kg/min), the amount of iv. midazolam is increased to 1.2 mg/kg/min (monitor the vital signs). If the seizures continue for 60–90 min, an infusion of propofol (1 mg/kg/h) is introduced. The author analyzed 27 children with SE, 9 (33%) of whom had RSE (the seizure lasted >60 min). The SE of two patients was controlled by the first step, six by the second step, 18 by the third step and one by the fourth step. The maximum maintenance dose for iv. midazolam is 1.2 mg/kg/min. Twenty-two people (including nine RSE patients) used diazepam and midazolam administered sequentially, and it was effective in 21 of 22 (p < 0.01, 95% CI) episodes. There were no obvious side effects. Brevoord et al. [72] advocate for the following progressive sequential therapy for children’s GCSE: First, 0.5 mg/kg midazolam is given rectally or 0.1 mg/kg midazolam iv. Ten minutes later, 0.1 mg/kg midazolam is administered iv. If the seizures continue, 10 min later, 20 mg/kg phenytoin is iv. administered over 20 min. If the seizures persist, 0.2 mg/kg midazolam is administered iv., followed by 0.1 mg/kg/h midazolam iv., which is increased by 0.1 mg/kg/h every 10 min (up to 1 mg/kg/min). Before midazolam reaches the maximum amount in the third step, doctors can also include the following step early according to the clinical presentation: 20 mg/kg phenobarbital iv. or a 2–5 mg/kg iv. load of pentobarbital followed by 1–2 mg/kg/h continuously iv. The author analyzed 122 children from 1995 to 2001. In 58 patients, SE was controlled by the first step, and in 19, SE was controlled by the second step. In 32 patients, SE was controlled by the third step, and the amount of iv. midazolam reached 0.05–0.8 mg/ kg/h. In 13 patients, SE was controlled by the fourth step, with the amount of iv. midazolam reaching 0.1–1.0 mg/kg/h. Therefore, 89% of patients who were given midazolam and phenytoin obtained full control of SE. Clinical practice
The combination therapy with midazolam
The strategy for combination drug therapy is progressive sequential therapy of midazolam combined with other AEDs [72,76]. Indications
Combined therapy with midazolam applies mainly to children with convulsive SE [72,76]. Administration
Some authors have advocated the use of sequential therapy. A study by Saz et al. [76] describes four-step therapy in children: During the first 10 min of the episode, 0.5 mg/kg of rectal diazepam is given twice if the seizure continues more than 5 min. After 15 min of episodes, either iv. phenytoin informahealthcare.com
Saz et al. [76] analyzed 27 children with convulsive SE to assess a sequential therapy called the Ege Pediatric SE Protocol (EPSEP). Nine (33%) of them had RSE (seizures continued >60 min). Eleven (40%) patients had meningitis or encephalitis. Seven (26%) patients underwent febrile convulsions. Five (19%) patients had cortical dysplasia, and three (11%) patients had hypoxic-ischemic encephalopathy. One patient had trauma. Twenty-two people (including nine patients with RSE) were administered diazepam and midazolam sequentially, and it was effective in 21/22 (95%) patients with no obvious side effects. Brevoord et al. [72] studied 122 children who were taking the second treatment program described above. The age of the patients ranged from 0.5 to 197.4 months. Forty-six (37.7%) patients had idiopathic seizures, and 44 (36.1%) patients had febrile convulsion. In 89% of the patients who were 645
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administered the drugs in a stepwise approach, combining midazolam and phenytoin was clinically effective.
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Adverse reactions
The adverse reactions of midazolam included hypotension, respiratory tract secretion, increased heart rate, disturbance of consciousness and urinary retention [77]. Saz et al. [76] used EPSEP therapy; three patients had mild hypotension, which is normal after iv. infusion, and one patient had transient desaturation, which is normal when using an oxygen mask. No one died after 1 year of follow-up. Brevoords et al’s study [72] showed that 52 patients required artificial ventilation and 39 patients had respiratory insufficiency after being treated with midazolam. Seven patients died, with no direct relationship with GCSE. Precautions
thought the study above had certain defects. The anticonvulsant effects of lorazepam are stronger than those of diazepam, but the control group in this study was the combination of diazepam and phenytoin. The efficacy of lorazepam combined with phenytoin and lorazepam monotherapy is unclear. Perhaps further prospective studies comparing monotherapy and combination therapy can be conducted. Outin et al. [81] concluded that the treatment of GCSE should be based on the duration of SE. If SE has lasted 5–30 min, CZP is first administered alone; subsequently, if SE does not terminate, it should be followed 5 min later with CZP together with fosphenytoin or phenobarbital. If SE has lasted for more than 30 min before treatment, monotherapy is always ineffective, and CZP should be immediately combined with fosphenytoin or phenobarbital. This treatment proposal requires further prospective studies to determine the clinical feasibility and the curative dose.
Midazolam should be slowly administered and gradually increased. Close monitoring of vital signs, including respiration and blood pressure, is needed. Mechanical ventilation could be used when necessary. The progressive sequential therapy of midazolam combined with other AEDs has more advantages than monotherapy in the treatment of children with SE. Using the drugs step-by-step can be effective and can reduce the side effects. It can also prevent the irregular use of AEDs (including unreasonable medication time, drug changes and drug withdrawal) [72,76]. Large-scale and multicenter studies are needed to improve the standard sequential therapy for children.
Stiripentol is an allosteric regulation drug that selectively regulates GABA receptor subunits. To date, it has been used as adjunct therapy for the treatment of severe myoclonic epilepsy in infancy (SMEI, Dravet syndrome) in Europe [82]. Stiripentol not only strongly potentiates receptors containing a3 or d subunits on the postsynaptic membrane, but it also increases the release of GABA by acting on the presynaptic membrane. Its unique pharmacological action suggests the potential utility of stiripentol combined with AEDs in the treatment of established SE and benzodiazepine-resistant SE [38,83,84].
Phenytoin, fosphenytoin & barbiturates
Animal experiments
Phenytoin, fosphenytoin and barbiturates are commonly used as second-line AEDs. Phenytoin and fosphenytoin inhibit the uptake of GABA in nerve terminals and induce hyperplasia of the GABA receptors. Barbiturates [42] can depress neuronal excitability by enhancing g-aminobutyric acid-coupled responses. These drugs can be used together with benzodiazepines to produce synergistic effects. The animal experiments by Bankstahl et al. [78,79] found that sequential injection or combination therapy with benzodiazepines and barbiturates terminates SE more effectively than monotherapy. Treiman et al. [80] conducted a randomized, double-blind, controlled clinical trial of SE. The study analyzed 570 patients with generalized convulsive SE over 5 years. All of the patients were administered one of four types of iv. infusion therapy as the initial treatment: diazepam (0.15 mg/kg) + phenytoin (18 mg/kg), lorazepam (0.1 mg/kg), phenytoin (18 mg/kg) and phenobarbital (15 mg/kg). One therapy was thought to be efficient if the SE was terminated at both the behavioral level and the electrographic level within 20 min after the administration of the drug and no seizures recurred within 40 min after SE terminated. The analysis showed that there were no obvious differences among the therapies of diazepam + phenytoin, lorazepam and phenobarbital, and these three therapies were superior to phenytoin monotherapy. However, Chen et al. [4]
Grosenbaugh et al. [84] used the pilocarpine model and found that stiripentol is effective for RSE. Stiripentol can strengthen GABAergic inhibitory postsynaptic currents and tonic GABAergic currents. Stiripentol selectively acts on the a3 or d subunits (non-benzodiazepine binding subunits) of the GABA receptor, which is a special pharmacological property that produces therapeutic effects with no serious side effects [85]. The anticonvulsant effect of stiripentol is more effective in young animals. This finding is probably because a3 subunit expression occurs mostly in the immature brain [38,83].
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Stiripentol
Application
The present study [38] showed that benzodiazepines and stiripentol have synergistic effects. The simultaneous use of the two drugs can increase the inhibitory effect of GABA neurons and improve the diversity of the GABA receptor. Stiripentol can be used as an addon therapy for RSE. The clinical application of stiripentol is mainly for SMEI, and its anticonvulsant effect is age-dependent. Stiripentol may be more effective for SE in children [38,83]. At present, further clinical trials are needed to determine its clinical application. Immunomodulating therapy
Immunomodulating therapy includes steroids, plasmapheresis and iv. immune globulin [86]. In recent years, SE caused by Expert Rev. Neurother. 15(6), (2015)
Combination drug therapy for the treatment of SE
some special types of encephalitis (such as anti-NMDA-receptor encephalitis) and new-onset refractory SE (NORSE) syndrome have gradually been recognized [87–89], and the cause of NORSE syndrome is probably some unknown infection or immune mechanism. These patients are resistant to most AEDs [86,90]. Immunomodulating therapy combined with AEDs can both terminate the SE and improve the prognosis of patients.
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The combination therapy with immunomodulating therapy
Combination therapy comprises the use of immunomodulating therapy and AEDs simultaneously [86,90]. Indications
Immunomodulating therapy is indicated in RSE caused by autoimmune encephalitis [86] or NORSE syndrome (new onset of refractory SE in patients with no clear etiology or no history of seizures) [90]. Gall et al. [90] retrospectively analyzed five patients in the ICU with NORSE syndrome, and all of the patients were young healthy adults. They all had nonspecific symptoms 2–7 days before their seizures and then developed RSE. All of the patients were resistant to AEDs and narcotics. Three patients received AEDs together with steroids and immunoglobulin early, and their RSE was gradually controlled. Their prognoses were quite good, with no serious neuropsychological defects, and two of these three patients resumed full-time work. One patient without immunomodulating therapy died of ICU-related complications. One patient’s prognosis was unknown because he returned to his city of residence after being treated with thiopental. Finne et al. [86] retrospectively analyzed a juvenile patient with long-term SE caused by autoimmune encephalitis. Immunomodulating therapy (including corticosteroids, plasma exchange and immunoglobulin) was combined with AEDs. Eventually, the patient’s RSE terminated, and the prognosis was good. Mode of administration
Treatment should start with benzodiazepines and then proceed with immunomodulating therapy. Gall et al. [90] retrospectively analyzed a 26-year-old patient with NORSE syndrome with a history of hyperthyroidism. He had no risk factors for epilepsy. In addition to the positive anti-TPO antibody, his auxiliary examination, including cranial MRI, serological examination of viral and autoimmune antibodies, and cerebrospinal fluid examination, was normal. Premonitory symptoms of the patient were headache and vomiting. Five days later, he was admitted to the hospital because of generalized tonic–clonic seizures and complex partial seizures. Then, he gradually developed refractory GCSE and was admitted to the ICU for treatment with general anesthesia. The patient was treated with propofol, phenytoin, valproic acid, LEV, thiopental and phenobarbital, but the epilepsy continued. Because SE may be caused by immune factors when infectious factors are excluded, the patient received steroids on the 12th day in the hospital. The patient was first treated with iv. methylprednisolone (1 g/d) for 3 days, followed by oral prednisone (60 mg/d), and finally with iv. immunoglobulin (5 days for a total volume of 150 g) on the eighteenth day in the informahealthcare.com
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hospital. After 2 months of hospital treatment, the patient recovered and was discharged from the hospital. He continued to take immunosuppressors and AEDs after discharge to prevent the recurrence of epilepsy. Finne et al. [86] retrospectively analyzed a 17-year-old patient with long-term SE caused by anti-NMDA receptor encephalitis. The patient had no history of epilepsy. The MRI examination and general examination for tumor screening were negative. He had premonitory symptoms of fatigue and cold 2 days prior to the onset of the change in consciousness and partial seizures. Then, he gradually developed SE, and AEDs and anesthetics were ineffective. The patient was later diagnosed as having anti-NMDA receptor encephalitis because specific antibodies were found in the serum and cerebrospinal fluid. He was immediately given immunotherapy while AEDs were continued. He was first treated with iv. methylprednisolone 1 g/day for 5 days with oral tapering, then five instances of plasma exchange and finally iv. immunoglobulin (0.4 g/kg) for 5 days. After 86 days of intensive treatment, the patient recovered consciousness, and the SE was completely controlled. After discharge, he continued taking immunosuppressants (azathioprine or mycophenolate mofetil) and AEDs. The patient recovered completely after a year of rehabilitation treatment and continued to attend high school. Precautions
Discharged patients should continue to use immune inhibitors (azathioprine or mycophenolate mofetil) and AEDs for at least 1 year [86,90] to prevent the recurrence of epilepsy. Lacosamide
Lacosamide (LCM) is a promising new AED that is involved in the regulation of calcium channels and sodium channels. LCM has few drug interactions, and it may provide some neuroprotective effects [91]. Its enteral and iv. formulations were approved in 2009. A few studies [92] and case reports [93,94] have reported on LCM as an add-on treatment for SE and RSE. The combination therapy with lacosamide
A strategy for combination therapy is the use of LCM as an add-on treatment when the first- or second-line drugs are ineffective for SE [91]. Indications
Combined administration of LCM is mainly suitable for adult patients with RSE [91,94–97]. Sutter et al. [91] retrospectively analyzed 111 adult RSE patients treated between 2005 and 2011, 53% of whom used iv. LCM as an add-on drug after the failure of first- and second-line AEDs (excluding 25 patients with hypoxicischemic encephalopathy). LCM was used simultaneously with other AEDs, such as lorazepam and LEV. Patients with LCM tended to have more frequent seizure control (odds ratio, OR: 2.34; 95% CI: 0.5–10.1, p = 0.252). Among all patients who received LCM as the last AED (23/45), seizure control was achieved in 91% (21/23), with no adverse events related to LCM. The duration of SE in patients with iv. LCM 647
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was 87.2 ± 159.4 h, and the duration of SE in patients without iv. LCM was 134.3 ± 188.7 h.
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Mode of administration
The treatment should start with benzodiazepines and then proceed with LCM. Sutter et al. [91] used LCM as an add-on treatment together with other AEDs (such as lorazepam and LEV) to control RSE. The administration of LCM was 200 mg twice daily. Patients with renal failure received LCM twice a day with 150 mg per application (creatinine clearance 30–50 ml) or 100 mg twice daily (creatinine clearance less than 30 ml). The administration of LCM to an obese patient (110 kg) was 600 mg per day. Adverse reactions
Sutter et al. [91] found no acute side effects related to LCM. The clinical study by Sutter et al. [91] demonstrated that a combination therapy with LCM and other AEDs is relatively safe and effective for the treatment of RSE. Additionally, the administration of LCM decreased the mortality of RSE. Prospective studies with larger sample sizes are warranted to further elucidate the efficacy of LCM for the treatment of RSE. Topiramate
Topiramate is a new broad-spectrum AED that is involved in the regulation of the ionotropic glutamatergic a-amino-3hydroxy-5-methyl-4-isoxazole-propionic acid receptor [98]. It has characteristics that include fast absorption, linear pharmacokinetics and long elimination half-life. Topiramate is metabolized more quickly if phenytoin or carbamazepine is coadministered. Its enteral and oral formulations are currently available. A few case reports in adults [99–101] and children [102–108], as well as case series [109,110], have reported on topiramate as an add-on treatment for SE and RSE. The combination therapy with topiramate
A strategy for combination therapy is the use of topiramate as an add-on treatment when the first-line or second-line drug is ineffective for SE. Indications
The combined administration of topiramate is mainly suitable for adult patients with RSE (90–94). Hottinger et al. [98] retrospectively analyzed 35 (median age = 60.5 (19–84) years) RSE patients administered topiramate enterally between 2004 and 2011. Topiramate was used as an add-on drug enterally after the failure of first- and second-line AEDs, and it was administered simultaneously with other AEDs, such as lorazepam and LEV. After the administration of topiramate, seizure control was achieved in 71% within 72 h and 9% within 24 h. The mortality was 31%, and the cause was not RSE but the underlying etiology of RSE. Mode of administration
Treatment should start with benzodiazepines and then proceed with topiramate. The recommended initial dosing is 648
200–400 mg (nasogastric or by mouth). The administration rate and alternative dosing recommendation is 300–1600 mg/day orally (divided two to four times daily) [111]. Hottinger et al. [98] used topiramate enterally as an add-on treatment. Based on the topiramate dose, patients were divided into three groups in this study: the 800 mg/day group, the 400–799 mg/day group and the
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Combination drug therapy for the treatment of status epilepticus Expert Rev. Neurother. 15(6), 639–654 (2015)
Xuefeng Wang*, Jing Jin‡ and Rong Chen‡ Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China *Author for correspondence: Tel.: +86 136 2835 9876 Fax: +86 023 8901 2878 [email protected]
Status epilepticus (SE) is a common neurological emergent disease with high mortality and disability rates. Rapidly and effectively controlling seizures is key to saving the lives of patients and improving their prognoses. Traditional antiepileptic drugs for SE are ineffective in 30–40% of cases. In light of the diverse etiology and complex pathogenesis of SE, combination drug therapy for SE might be more conducive for the treatment of all patients because the combined use of drugs can produce synergistic effects via different mechanisms. This review summarizes combination drug therapies used for SE in animal experiments and clinical practice, the potential advantages of combination drug therapy and specific combination drug therapies using different antiepileptic drugs. The aim is to help researchers seek better treatments for early termination of SE. KEYWORDS: AEDs . animal experiment . clinical practice . combination drug therapy . monotherapy . SE . seizure
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Joint first authors
Status epilepticus (SE) is a common neurological emergency and severe disease. Controlling seizures early is key to saving lives and improving prognoses [1,2]. Currently, the traditional antiepileptic drugs (AEDs) for SE are widely used in the clinical setting. Although they are effective in 60–70% of cases of SE, the remaining 30–40% of patients do not benefit from the currently available treatment [3]. Combination drug therapy for SE may be more conducive for the treatment of all patients because the combined use of drugs can produce synergistic effects via different mechanisms, which might ensure the effective application of AEDs to terminate SE early. Because experimental and clinical evidence of the effectiveness of combination drug therapy over monotherapy for improving the prognosis of patients with SE is absent, exploring combination drug therapies for SE may be of value [4,5]. Combination therapy was defined as any one of the following: . .
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two or more types of AEDs are used simultaneously (including add-on treatments); progressive sequential therapy: the intentional use of a first drug, and then the administration of a second drug when the pharmacological effects of the prior drug still exist (the intention is for the two drugs to produce a combined effect);
10.1586/14737175.2015.1045881
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combination of an AED with non-pharmacological strategies, neuromodulation drugs or immunomodulating therapy. The add-on treatment can also be considered as combination therapy for SE as the long half-lives of most of the compounds used before the add-on treatment will interact with the addon drugs during sequential treatment.
Materials & methods
We performed a review of the recent literature on the treatment of SE and refractory status epilepticus (RSE), summarized the current combination therapy for commonly utilized AEDs and provided an argument for early combination therapy in SE/RSE. A PubMed and Medline literature search was performed for relevant articles published prior to 2015 using the following search terms: ‘status epilepticus plus drug therapy’, ‘status epilepticus plus add-on treatment’, ‘status epilepticus plus combination’. Clinical trials, animal experiments, review articles and practice guidelines were all included. Combination drug therapy for SE in animal experiments
Mazarati et al. [6] used an experimental model of self-sustaining SE (SSSE) in rats that was induced by electrical stimulation of the
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ISSN 1473-7175
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perforant path [7,8]. Once this model was induced, the rats were resistant to traditional AEDs, such as diazepam and phenytoin. Ten minutes after the perforant path stimulation, the following drugs were separately administered by intraperitoneal injection: levetiracetam (LEV) (50, 200, 500 and 1000 mg/kg), diazepam (1, 5 mg/kg), a combination of diazepam (5 mg/kg) and LEV (1, 3, 10 and 200 mg/kg) and a combination of diazepam (1 mg/kg) and LEV (25, 50 and 200 mg/kg). The study found that 200 mg/kg LEV shortened the seizure duration and spike frequency by 50%. The combination of LEV (200 mg/kg) and an individually ineffective dose of diazepam (1 mg/kg) shortened the seizure duration by 99% and the spike frequency by 97%. An analysis of the average termination time for SSSE in each experimental group indicated that the length of time for the different doses of the combination of LEV and diazepam was significantly shorter than the time for monotherapy. Even when the doses of both drugs were far below the therapeutic doses, these combinations still had a significant curative effect, and there were fewer side effects. However, higher doses are usually required for rodents compared to humans per unit weight. As there is a lack of studies about the tolerability of high doses of LEV in humans, it is difficult to precisely compare toxicity in rodents versus humans. Some animal experiments [7,9,10] have found that combinations of LEV and other AEDs can produce a synergetic effect and that LEV can enhance the anticonvulsant action of other AEDs. Kaminski et al. [11] found that LEV can significantly enhance the inhibitory effect of other AEDs in seizures in the amygdala in a rat model. LEV can also enhance the seizure suppression of other AEDs in audiogenic susceptible mice [9]. A combination of a noncompetitive N-methyl-D-aspartic (NMDA) receptor antagonist with diazepam was found to be superior to diazepam monotherapy in many animal experiments. One study found that a combination of a single dose of MK 801 (4 mg/kg) with diazepam (10 mg/kg) administered 60 min after SE onset stopped SE more easily than diazepam alone [12]. Wasterlain et al. [5] used a model of severe SE induced by cholinergic agents, which might apply to battlefield or terrorism situations as these agents are components in some bioweapons. The following drugs were separately administered by intraperitoneal injection: monotherapy with ketamine (10 mg/kg), valproate (30 mg/kg), brivaracetam (10 mg/kg) or diazepam (1, 5 or 10 mg/kg); combination therapy with diazepam (1 mg/kg), ketamine (10 mg/kg) + valproate (30 mg/kg) and combination therapy with diazepam (1 mg/kg), ketamine (10 mg/kg) + brivaracetam (10 mg/kg). Some data from this study have not been published, but ‘toxicity score’ data and the number of post-treatment seizures have been presented in the literature. ‘Toxicity score’ (analysis of ataxia, righting reflex, response to tail pinch and corneal reflex) was used to measure drug toxicity during the first hour. The number of posttreatment seizures was used to measure SE outcome. Monotherapy with ketamine, valproate, brivaracetam, diazepam and other AEDs failed to stop SE. The available data indicated that the combina-tions were significantly more effective and less toxic 640
than monotherapy in this model. In the kainic acid-induced post-SE model, another widely used and well-characterized animal model for temporal lobe epilepsy, Vermoesen et al. [13] treated the rats with the following drugs by intraperitoneal injection after the SE had continued for 90 min: diazepam (10, 20 mg/kg), ketamine (50 mg/kg), the combination of ketamine (50 mg/kg) and diazepam (10 mg/kg) or the combination of ketamine (50 mg/kg) and diazepam (20 mg/kg). A 10 mg/kg dose of diazepam terminated 28% of SE, 20 mg/kg diazepam terminated 50% of SE, the combination of ketamine (50 mg/kg) and diazepam (10 mg/kg) terminated 33% of SE and ketamine (50 mg/kg) did not terminate SE and increased the spike frequency. The combina-tion of ketamine (50 mg/kg) and diazepam (20 mg/kg) terminated SE at both the behavioral level and the electrographic level in all rats. Francois et al. [14] used a model of lithium–pilocarpineinduced SE, leading to spontaneous recurrent seizures (SRS). The following drugs were administered by intraperitoneal injection: combination therapy with topiramate (10, 30 or 60 mg/kg) at the onset of SE and 10 h later and diazepam (2.5 and 1.25 mg/kg) at 2 and 10 h after SE, followed by topiramate twice daily for 6 days. For other rats, two injections of diazepam were administered on the day of SE. The cell count data, the occurrence and frequency of SRS and the MRI T2-weighted signal in the hippocampus and ventral cortices were precisely collected and analyzed. The results showed that the combination therapy of topiramate and diazepam could partly protect the hippocampus and ventral entorhinal cortex, both of which are crucial to epileptogenesis. However, diazepam–topiramate treatment had no impact on the latency and frequency of SRS, which indicates that the antiepileptogenic effects of the diazepam–topiramate combination were not sufficient. However, animal experiments have their limitations. Animal experiments are flawed as animal models do not completely simulate human function. It is also very difficult to distinguish between cause and effect as the lesions or stimuli inducing seizures may produce neuronal damage. Whether the outcomes of animal experiments can be used in humans is always unclear. More clinical trials are still needed to support the results of animal experiments. Clinical practice with combination drug therapy for SE
Synowiec et al. [15] retrospectively analyzed 11 benzodiazepineresistant SE patients in 2003–2011, using ketamine as an add-on drug. Seven patients had systemic or central nervous system infections. One patient had metabolic disease. In three patients, SE was thought to be caused by an insufficient initial dose of AEDs. RSE was defined as terminated if the clinical signs and/or the electroencephalo-graph (EEG) seizures disappeared after ketamine withdrawal for 24 h. All patients with SE resistant to AEDs received ketamine iv., in combination with other drugs, such as lorazepam or phenytoin. In all patients (11/11), RSE was completely controlled with no obvious side effects. Uges et al. [16] designed a prospective, single center, no-control, non-blinded study to evaluate the efficacy and safety of LEV added to a standard therapy scheme of SE. The study included 11 adults Expert Rev. Neurother. 15(6), (2015)
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Combination drug therapy for the treatment of SE
(median age: 60 years) with SE, five of whom had generalized convulsive SE (GCSE), five had partial seizures and one had non-convulsive SE. SE etiology was identified in all subjects, including stroke, meningoencephalitis, malignant glioma and acute subdural hematoma. All of the patients were treated with LEV combined with other AEDs. One patient died for reasons unrelated to LEV; in the rest of the patients, SE was fully controlled within 24 h with no obvious side effects. Gallentine et al. [17] retrospectively analyzed LEV as an add-on treatment in children with RSE. The study included 11 children (median age: 2.5 months) in 2000–2007. RSE etiology was identified in all subjects, including perinatal hypoxic ischemic encephalopathy, transfer of neural tube cells, brain tumor and congenital malformation. LEV as an add-on therapy was effective in 45% of patients (5/11), and the effect was uncertain in 27% (3/11). The average time between LEV use and the cessation of RSE was 1.5 (1–8) days without obvious side effects. Su et al. [18] analyzed 15 children who were diagnosed with electrical SE of sleep (ESES) syndrome. Compared with clonazepam (CZP) or LEV monotherapy, LEV combined with CZP more effectively controlled the clinical seizures and sleep epileptiform discharges. The combination therapy also led to fewer adverse reactions. Rossetti et al. [19] retrospectively analyzed 31 instances of RSE in 27 adult patients from 1997 to 2002. All of the patients were treated with iv. propofol. To maintain the lowest effective dose of propofol, other AEDs (mainly CZP or phenytoin) were continuously used, and six patients later used thiopental as an addon drug. The average speed of propofol infusion was 4.8 (2.1– 13) mg/kg/d. The duration of treatment was 3 (1–9) days, and the ICU stay was 7 (2–42) days. CZP or phenytoin combined with propofol terminated 21 (67%) episodes, and the thiopental follow-up effectively terminated three (10%) episodes. No serious side effects occurred.
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was prolonged, the activity of GABA receptors on the postsynaptic membrane decreased, and the number and activity of NMDA receptors increased. This repeated and prolonged exposure induces an increasing incidence of RSE [37]. The combined application of drugs that act on different neurotransmitters may have more advantages. Particularly, the use of some new AEDs as additive drugs may improve the prognosis of patients [3,4,16,36,38,45] Combination therapy may improve brain damage
Sustained seizures cause substantial damage to the brain [4,25,35,37,46], including neuronal loss and cerebral edema. For example, Vespa et al. [47,48] studied patients with posttraumatic non-convulsive electrographic seizures. These in-depth studies found that severe traumatic brain injury might cause frequent non-convulsive seizures, which seemed to be related to long-term hippocampal atrophy. In addition, non-convulsive electrographic post-traumatic seizures might cause an increase in both intracranial pressure and the microdialysis lactate/ pyruvate ratio, which indicates a poor prognosis for patients with traumatic brain injury. Combination therapy may shorten SE duration
The delayed treatment of SE is a risk to patients, and the early use of AEDs that affect multiple mechanisms is conducive to terminating SE early to improve the prognosis [1,39,44,49–54]. In a review [55], the author assembled data on outcome factors in SE. One of the most studied risk factors for death in SE was SE duration after SE onset. The studies of SE outcome showed that a critical determining factor for mortality was an SE duration of more than 1 h, and increases in mortality and hospital stay were apparent when the number of hours of seizure activity increased. Combination drug therapy with different AEDs
The potential advantages of combination therapy for SE
Both the animal experiments and clinical studies above support the rationale of combination therapy for SE. Cook et al. [20] also found that the clinical practice of combination therapy for SE and RSE is much more prevalent than reported in the literature, and wider attention is currently paid to it. The following reasons support the use of combination therapy for SE. Combination therapy may have multiple mechanisms of action
SE is a multifactorial and heterogeneous disease. SE not only has many causes, but it also has a very complicated mechanism [21–30]. The combined application of AEDs with various mechanisms of action may be preferred in clinical practice over benzodiazepine monotherapy with a single mechanism of action [4,5,7,31].
At present, combination drug therapy mainly involves drugs such as LEV, ketamine, midazolam, phenytoin, barbiturates, stiripentol, immunomodulatory drugs, lacosamide, topiramate, non-pharmacological strategies and neuromodulation drugs (TABLE 1). Levetiracetam
LEV is a broad-spectrum antiepileptic drug that is involved in the regulation of calcium channels, NMDA receptors and GABA transportation [16,17,42,56–58]. The characteristics of LEV include rapid action, linear pharmacokinetics, nerve protection, little impact on cognition and few drug interactions [16,17,56,59]. Mazarati et al. [59] found, in animal experiments, that combination therapy with diazepam and LEV for the treatment of SE had strong synergistic effects. In clinical practice, combination therapy with LEV for SE has gradually increased in frequency [16–18,60].
Combination therapy may act on different neurotransmitters
The combination therapy with LEV
SE is a continuous disease process, and the pathogenesis might not be identical at different time points [32–35]. Wasterlain et al. [36] found that as the seizures repeated and the duration of SE
First, LEV and benzodiazepines are used simultaneously. Second, LEV is used as an add-on treatment when the first-line or second-line drugs fail [16–18,60].
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641
642
45
11
1
5
35
27
2013
2013
2013
2013
2012
2012
60 years (44–75 years) F (4); M (7)
3.8 years (2.5 months–11 years) F (10); M (17)
60.5 years (19–84 years) F (16); M (19)
27 years (22–34 years) F (2); M (3)
17 years M (1)
52 years (22–82 years) F (4); M (7)
64.7 years (49.5–80 years) F (25); M (20)
8 years (8.5–13.5 years) F (6); M (9)
Age/sex
Retrospective study
Unknown
Prospective study
Retrospective study
Yes (11) No (24)
Yes (6) No (5)
Case series
Retrospective study
Yes (6); No (5)
No (5)
Retrospective study
Yes (15); No (30)
Case report
Retrospective study
Yes (15)
No (1)
Study type
History of epilepsy
Metabolic problems (3); cerebrovascular accidents (4); meningoencephalitis (1); glioblastoma (2); pyramidal tetraparesis (1)
Meningitis or encephalitis (11); febrile SE (7); cerebral cortical dysgenesis (5); hypoxic ischemic encephalopathy (3); Trauma (1)
Cerebrovascular accidents (12); brain tumors (8); hypoxic brain damage (5);CNS infections (4); metabolic problems (4); Dandy–Walker syndrome (1); malcompliance 1(1)
Unknown
Anti-N-Methyl-D-Aspartate receptor encephalitis
CNS infection (2); Metabolic disturbance (1); Low AED levels (3); Sepsis (2); Systemic infection (3)
Acute symptomatic seizures (25); remote symptomatic unprovoked seizures (17); unprovoked seizures of unknown etiology (3)
Unknown (13); febrile history (1); family history of epilepsy (1)
Etiology of RSE
LEV, DZP
MDZ, DZP
Within hours Initial SE (8); established SE (10); RSE (9)
36 min (15–90 min)
TPM
2 days (2–23 days) NCSE (17); GCSE (4); SPSE (14)
NCSE (1); GCSE (5); FCSE (5)
Immunomodulating therapy
Immunomodulating therapy 12 days (1); Unknown (4)
32 days
KET
NORSE syndrome
GTCSE (1)
5 days (1–11 days)
LCM
Unknown
Simple partial/ complex/ absence (17); GCSE (1); NCSE (27) GTCSE (6); NCSE (5)
LEV, CBZ
The main drug of combination therapy
Unknown
SE duration prior to combination therapy
ESES syndrome
SE type
[16]
[76]
[98]
[90]
[86]
[15]
[91]
[18]
Ref.
CBZ: Carbamazepine; CNS: Central nervous system; DZP: Diazepam; F: Female; FCSE: Focal convulsive status epilepticus; GCSE: Generalized convulsive status epilepticus; GTCSE: Generalized tonic–clonic status epilepticus; h: Hours; KET: Ketamine; LCM: Lacosamide; LEV: levetiracetam; M: Male; MDZ: Midazolam; NCSE: Non-convulsive status epilepticus; NORSE: New-onset refractory status epilepticus; PHT: Phenytoin; RSE: Refractory status epilepticus; SE: Status epilepticus; SPSE: Simple partial(motor/versive/aura) status epilepticus; TPM: Topiramate.
11
15
2014
2009
Patients (n)
Year
Table 1. Demographics and clinical data of combination drug therapy in SE/RSE.
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Expert Rev. Neurother. 15(6), (2015)
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CBZ: Carbamazepine; CNS: Central nervous system; DZP: Diazepam; F: Female; FCSE: Focal convulsive status epilepticus; GCSE: Generalized convulsive status epilepticus; GTCSE: Generalized tonic–clonic status epilepticus; h: Hours; KET: Ketamine; LCM: Lacosamide; LEV: levetiracetam; M: Male; MDZ: Midazolam; NCSE: Non-convulsive status epilepticus; NORSE: New-onset refractory status epilepticus; PHT: Phenytoin; RSE: Refractory status epilepticus; SE: Status epilepticus; SPSE: Simple partial(motor/versive/aura) status epilepticus; TPM: Topiramate.
[72]
Retrospective study 122 2005
24.4 months (0.5–197.4 months) F (51); M (71)
Unknown
Idiopathic (46); acute symptomatic (24); progressive neurologic (3); remote symptomatic (5); febrile (44)
MDZ, PHT Unknown GCSE
[17]
LEV 3.4 days (0–12 days) Complex partial (7); Tonic–clonic (2); Subtle (2) Retrospective study 11 2009
2.5 months (2 days–9 years) F (2); M (9)
Unknown
Cerebrovascular accidents (3); brain tumors (2); CNS infections (3); unknown (1); congenital brain malformation (1); history of perinatal hypoxic-ischemic encephalopathy (1)
The main drug of combination therapy SE duration prior to combination therapy SE type Etiology of RSE Study type History of epilepsy Age/sex Patients (n) Year
Table 1. Demographics and clinical data of combination drug therapy in SE/RSE (cont.).
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Ref.
Combination drug therapy for the treatment of SE
Review
Indications
Combination therapy with LEV is mainly used to treat SE or RSE in adults and RSE or ESES syndrome in children [16–18,60]. Mode of administration
The treatment should start with benzodiazepines and then proceed with LEV. When LEV is used in combination with benzodiazepines in adult SE and RSE, the recommended dose is 2500 mg LEV administered iv. (>5 min) [16,60,61]. Rossetti et al. [62] also found that the early use of LEV was more effective than the later use of LEV. In a study by Uges et al. [16], patients received 2500 mg LEV iv. (>5 min) while taking standard treatments of first-line and/or second-line drugs, such as benzodiazepines and phenytoin. The median time from hospital admission to the use of LEV was 36 (15–90) min. Nine patients received LEV combined with benzodiazepines as the initial treatment. Another two patients received LEV as an addon therapy in the late stage of SE when successive use of benzodiazepines, phenytoin and valproate was ineffective. In all of the patients, SE was completely controlled within 24 h after the use of LEV; one patient died 9 days later due to multiple organ failure, which was independent of LEV. There were also no obvious side effects related to LEV. In children with RSE, the recommended dose is 15–70 mg/kg LEV administered iv. [63]. Gallentine et al. [17] retrospectively analyzed 11 children with RSE who were treated with LEV as an add-on therapy for RSE. When LEV was being used, other AEDs were continuously used or concomitantly added or adjusted (e.g., midazolam, pentobarbital, valproic acid, phenobarbital, phenytoin, diazepam). Four patients were administered 15–60 mg/kg LEV by nasal feeding or orally, six received 15–62.5 mg/kg LEV iv. and one was administered 70 mg/kg LEV rectally followed by 20 mg/kg LEV by nasal feeding. This treatment strategy was 73% (8/11) effective. The average time for the termination of RSE from the administration of LEV was 1.5 (1–8) days with no obvious side effects. This study showed that the effective dose of LEV was more than 30 mg/kg/d (median: 40 mg/kg/d). The recommended initial dose of LEV in combination therapy was 30 mg/kg/d for the treatment of children with RSE and LEV could be administered orally, iv. or by nasal feeding. The early use of LEV was more effective than the later use of LEV [62]. To examine combination therapy in children with ESES syndrome, Su et al. [18] analyzed 15 patients diagnosed with ESES syndrome with benign childhood epilepsy with centrotemporal spikes. The early use of LEV monotherapy was ineffective for both the EEG and clinical signs. Later, the children received LEV (20–40 mg/kg/d) orally, combined with CZP orally, at bedtime for 2 months (for the first month, 0.02–0.03 mg/kg CZP once per day; for the second month, 0.02–0.03 mg/kg CZP once every other day). Except for one patient who had seizures and a recurrence of ESES, all of the other children showed no clinical seizures, and their sleep EEGs revealed normal or only a small amount of low-amplitude discharge in the 643
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Wang, Jin & Chen
central temporal region. Before treatment, all of the patients had some of the following symptoms: language impairment, decline in academic performance and hyperactivity. After treatment, their neuropsychological function obviously improved. The study found that in children with ESES, the combination of LEV and CZP was more effective for seizure control compared with monotherapy with either LEV or CZP.
strong synergistic effect in the treatment of SE. The application of ketamine combined with AEDs has also been used clinically [15].
The effective time
Indications
Uges et al. [16] study showed that SE stopped within 24 h of LEV use in adults. Gallentine et al. [17] found that the average time that it took for RSE to stop in children was 1.5 days after LEV was given.
Combined administration of ketamine is mainly suitable for adult patients with RSE [15,42,66,67]. Synowiec et al. [15] retrospectively analyzed 11 RSE patients who used iv. ketamine as an add-on drug when other AEDs were ineffective. Ketamine was used in combination with other AEDs, such as lorazepam and phenytoin. Ketamine was used for 4–28 days. Six patients (6/7) who needed vasopressors to maintain blood pressure at the early stage of treatment ceased the use of vasopressors after the use of ketamine. Eventually, the RSE of all patients (11/11) was completely controlled with no obvious side effects.
Adverse reactions
Uges et al. [16] reported that one patient exhibited allergic reactions, including face flushing, which returned to normal in a short time; five patients exhibited mental confusion 24 h after SE termination, which might have been an adverse reaction to LEV. Gallentine et al. [17] reported that one patient had rectal bleeding with the administration of LEV and valproate rectally, but rectal bleeding stopped when LEV was used alone by nasal feeding. Precautions
Patients who are allergic to LEV, pyrrolidine derivatives or any other component of LEV cannot use LEV. The animal experiments by Mazarati et al. [59] supported the idea that the characteristics of combination therapy with diazepam and LEV include synergistic effects, quick effects, minor toxic effects and nerve protection. Uges et al. [16–18] demonstrated that the clinical administration of LEV combined with other AEDs to treat SE, RSE and ESES syndrome is safe and feasible. Because the present clinical use of LEV combined with other AEDs includes a small sample size and the follow-up time is limited, further research expanding the sample size for the clinical application of combination therapy is necessary. Navarro et al. [60] are currently conducting a Phase III clinical trial to compare the efficacy of iv. LEV combined with CZP and CZP monotherapy in treating GCSE. The results of the study will help determine the exact efficacy of combination therapy.
Combination therapy with ketamine
Ketamine are used as an add-on treatment when the first-line or second-line drug is ineffective for SE [15].
Mode of administration
Treatment should start with benzodiazepines and then proceed with ketamine. Synowiec et al. [15] used ketamine as an add-on treatment together with other AEDs (such as lorazepam and phenytoin) to control RSE. The administration of ketamine was a 1–2 mg/kg iv. load, followed by 1.3 mg/kg/h (0.45– 2.1 mg/kg/h) continuous iv. administration. The maximum dose was 1392–4200 mg/d. The RSE of all patients (11/11) was completely controlled. The effective time
The study by Synowiec et al. [15] defined the termination of RSE as termination at the behavioral level and/or at the electrographic level 24 h after drug withdrawal. The average time after ketamine was used until the termination of RSE was observed was 9.8 (4–28) days. Adverse reactions
Zeiler et al. [68] found that the adverse reactions related to ketamine included psychiatric symptoms, increases in intracranial pressure and intraocular pressure and arrhythmia, but these reactions were rare. Synowiec et al. [12] found no acute side effects related to ketamine.
Ketamine
Ketamine is a noncompetitive NMDA receptor antagonist [42] that blocks NMDA transmission and protects neurocytes [64]. Ketamine can also stabilize hemodynamics, so that hypotension will not occur [15,42]. One study [36] found that as the seizures repeated and the time of SE was prolonged, the number and activity of GABA receptors in the postsynaptic membrane decreased, while the number and activity of NMDA receptors increased; these changes led to an increase in the frequency of RSE. The application of ketamine in combination with other AEDs to treat SE is being explored. Animal experiments [5,13,65] have found that diazepam combined with ketamine has a 644
Precautions
[69]
First, slow administration and a gradual increase in the amount of ketamine are necessary. Pruss et al. [66] reported a young female with malignant SE who was resistant to benzodiazepines, phenytoin, thiopental and propofol. The RSE was finally controlled by the combined use of midazolam (0.6 mg/kg/h iv.) and ketamine. Ketamine was administered as a 0.5 mg/kg iv. load (>1 min), followed by 0.4 mg/kg/h continuous administration iv., which was increased to 1.6 mg/kg/h over 3 h and then to 2.4–3.2 mg/kg/h after 48 h for an additional 8 days. Eventually, the RSE terminated, and the EEG seizures Expert Rev. Neurother. 15(6), (2015)
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Combination drug therapy for the treatment of SE
disappeared with no side effects. Second, the close monitoring of patient vital signs is needed. Mechanical ventilation could be used when necessary. Third, coronal CT should be used to exclude intracranial lesions that may increase intracranial pressure. Fourth, the use of ketamine should be considered when SE is caused by alcohol intoxication. In addition, skeletal muscle tension caused by ketamine should be distinguished from tonic–clonic seizure. Animal experiments [5,13] have demonstrated that the combined administration of ketamine and benzodiazepines can correct two types of changes during the progression of SE: the reduction of GABA’s inhibiting effect and the enhancement of NMDA effects. The synergistic action of ketamine and diazepam seemed to be model-independent. Martin et al. [65] showed that the combination of ketamine and diazepam was strongly effective in diazepam-refractory SE induced by cholinergic stimulation, while monotherapy had small effects. This synergistic effect offered more advantages compared to monotherapy in the treatment of RSE. The clinical study by Synowiec et al. [15] demonstrated that the combination therapy of ketamine and other AEDs is relatively safe and effective for the treatment of RSE. Additionally, the beneficial cardiovascular effect of ketamine is an advantageous characteristic that no other AEDs possess. Of course, further study is needed to determine the best time for the administration of ketamine, the dosage and its effect on the intracranial pressure and cerebral blood flow. Midazolam
Midazolam is a water-soluble benzodiazepine. It inhibits the excitability of GABA neurons through allosteric modulation of the GABA receptor. It can rapidly penetrate the blood– brain barrier and has a short onset time [70,71]. Midazolam is effective for the treatment of SE in children, with a low mortality rate [72–74] and a high recurrence rate [42,75]. Monotherapy always has a poor response in children with SE and RSE [17], so progressive sequential therapy with midazolam and other AEDs has certain advantages compared with monotherapy [72,76].
Review
(20 mg/kg) or a bolus of midazolam (0.15 mg/kg iv.) is given. If the SE continues, the dose of iv. midazolam is increased every 5 min (up to 0.6 mg/kg/min) to stop the epilepsy, and this increased dose is continued for 24 h. Then, the delivery rate is decreased by 0.05 mg/kg/min every 6 h. If the seizure continues after 60 min of the infusion (0.6 mg/kg/min), the amount of iv. midazolam is increased to 1.2 mg/kg/min (monitor the vital signs). If the seizures continue for 60–90 min, an infusion of propofol (1 mg/kg/h) is introduced. The author analyzed 27 children with SE, 9 (33%) of whom had RSE (the seizure lasted >60 min). The SE of two patients was controlled by the first step, six by the second step, 18 by the third step and one by the fourth step. The maximum maintenance dose for iv. midazolam is 1.2 mg/kg/min. Twenty-two people (including nine RSE patients) used diazepam and midazolam administered sequentially, and it was effective in 21 of 22 (p < 0.01, 95% CI) episodes. There were no obvious side effects. Brevoord et al. [72] advocate for the following progressive sequential therapy for children’s GCSE: First, 0.5 mg/kg midazolam is given rectally or 0.1 mg/kg midazolam iv. Ten minutes later, 0.1 mg/kg midazolam is administered iv. If the seizures continue, 10 min later, 20 mg/kg phenytoin is iv. administered over 20 min. If the seizures persist, 0.2 mg/kg midazolam is administered iv., followed by 0.1 mg/kg/h midazolam iv., which is increased by 0.1 mg/kg/h every 10 min (up to 1 mg/kg/min). Before midazolam reaches the maximum amount in the third step, doctors can also include the following step early according to the clinical presentation: 20 mg/kg phenobarbital iv. or a 2–5 mg/kg iv. load of pentobarbital followed by 1–2 mg/kg/h continuously iv. The author analyzed 122 children from 1995 to 2001. In 58 patients, SE was controlled by the first step, and in 19, SE was controlled by the second step. In 32 patients, SE was controlled by the third step, and the amount of iv. midazolam reached 0.05–0.8 mg/ kg/h. In 13 patients, SE was controlled by the fourth step, with the amount of iv. midazolam reaching 0.1–1.0 mg/kg/h. Therefore, 89% of patients who were given midazolam and phenytoin obtained full control of SE. Clinical practice
The combination therapy with midazolam
The strategy for combination drug therapy is progressive sequential therapy of midazolam combined with other AEDs [72,76]. Indications
Combined therapy with midazolam applies mainly to children with convulsive SE [72,76]. Administration
Some authors have advocated the use of sequential therapy. A study by Saz et al. [76] describes four-step therapy in children: During the first 10 min of the episode, 0.5 mg/kg of rectal diazepam is given twice if the seizure continues more than 5 min. After 15 min of episodes, either iv. phenytoin informahealthcare.com
Saz et al. [76] analyzed 27 children with convulsive SE to assess a sequential therapy called the Ege Pediatric SE Protocol (EPSEP). Nine (33%) of them had RSE (seizures continued >60 min). Eleven (40%) patients had meningitis or encephalitis. Seven (26%) patients underwent febrile convulsions. Five (19%) patients had cortical dysplasia, and three (11%) patients had hypoxic-ischemic encephalopathy. One patient had trauma. Twenty-two people (including nine patients with RSE) were administered diazepam and midazolam sequentially, and it was effective in 21/22 (95%) patients with no obvious side effects. Brevoord et al. [72] studied 122 children who were taking the second treatment program described above. The age of the patients ranged from 0.5 to 197.4 months. Forty-six (37.7%) patients had idiopathic seizures, and 44 (36.1%) patients had febrile convulsion. In 89% of the patients who were 645
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administered the drugs in a stepwise approach, combining midazolam and phenytoin was clinically effective.
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Adverse reactions
The adverse reactions of midazolam included hypotension, respiratory tract secretion, increased heart rate, disturbance of consciousness and urinary retention [77]. Saz et al. [76] used EPSEP therapy; three patients had mild hypotension, which is normal after iv. infusion, and one patient had transient desaturation, which is normal when using an oxygen mask. No one died after 1 year of follow-up. Brevoords et al’s study [72] showed that 52 patients required artificial ventilation and 39 patients had respiratory insufficiency after being treated with midazolam. Seven patients died, with no direct relationship with GCSE. Precautions
thought the study above had certain defects. The anticonvulsant effects of lorazepam are stronger than those of diazepam, but the control group in this study was the combination of diazepam and phenytoin. The efficacy of lorazepam combined with phenytoin and lorazepam monotherapy is unclear. Perhaps further prospective studies comparing monotherapy and combination therapy can be conducted. Outin et al. [81] concluded that the treatment of GCSE should be based on the duration of SE. If SE has lasted 5–30 min, CZP is first administered alone; subsequently, if SE does not terminate, it should be followed 5 min later with CZP together with fosphenytoin or phenobarbital. If SE has lasted for more than 30 min before treatment, monotherapy is always ineffective, and CZP should be immediately combined with fosphenytoin or phenobarbital. This treatment proposal requires further prospective studies to determine the clinical feasibility and the curative dose.
Midazolam should be slowly administered and gradually increased. Close monitoring of vital signs, including respiration and blood pressure, is needed. Mechanical ventilation could be used when necessary. The progressive sequential therapy of midazolam combined with other AEDs has more advantages than monotherapy in the treatment of children with SE. Using the drugs step-by-step can be effective and can reduce the side effects. It can also prevent the irregular use of AEDs (including unreasonable medication time, drug changes and drug withdrawal) [72,76]. Large-scale and multicenter studies are needed to improve the standard sequential therapy for children.
Stiripentol is an allosteric regulation drug that selectively regulates GABA receptor subunits. To date, it has been used as adjunct therapy for the treatment of severe myoclonic epilepsy in infancy (SMEI, Dravet syndrome) in Europe [82]. Stiripentol not only strongly potentiates receptors containing a3 or d subunits on the postsynaptic membrane, but it also increases the release of GABA by acting on the presynaptic membrane. Its unique pharmacological action suggests the potential utility of stiripentol combined with AEDs in the treatment of established SE and benzodiazepine-resistant SE [38,83,84].
Phenytoin, fosphenytoin & barbiturates
Animal experiments
Phenytoin, fosphenytoin and barbiturates are commonly used as second-line AEDs. Phenytoin and fosphenytoin inhibit the uptake of GABA in nerve terminals and induce hyperplasia of the GABA receptors. Barbiturates [42] can depress neuronal excitability by enhancing g-aminobutyric acid-coupled responses. These drugs can be used together with benzodiazepines to produce synergistic effects. The animal experiments by Bankstahl et al. [78,79] found that sequential injection or combination therapy with benzodiazepines and barbiturates terminates SE more effectively than monotherapy. Treiman et al. [80] conducted a randomized, double-blind, controlled clinical trial of SE. The study analyzed 570 patients with generalized convulsive SE over 5 years. All of the patients were administered one of four types of iv. infusion therapy as the initial treatment: diazepam (0.15 mg/kg) + phenytoin (18 mg/kg), lorazepam (0.1 mg/kg), phenytoin (18 mg/kg) and phenobarbital (15 mg/kg). One therapy was thought to be efficient if the SE was terminated at both the behavioral level and the electrographic level within 20 min after the administration of the drug and no seizures recurred within 40 min after SE terminated. The analysis showed that there were no obvious differences among the therapies of diazepam + phenytoin, lorazepam and phenobarbital, and these three therapies were superior to phenytoin monotherapy. However, Chen et al. [4]
Grosenbaugh et al. [84] used the pilocarpine model and found that stiripentol is effective for RSE. Stiripentol can strengthen GABAergic inhibitory postsynaptic currents and tonic GABAergic currents. Stiripentol selectively acts on the a3 or d subunits (non-benzodiazepine binding subunits) of the GABA receptor, which is a special pharmacological property that produces therapeutic effects with no serious side effects [85]. The anticonvulsant effect of stiripentol is more effective in young animals. This finding is probably because a3 subunit expression occurs mostly in the immature brain [38,83].
646
Stiripentol
Application
The present study [38] showed that benzodiazepines and stiripentol have synergistic effects. The simultaneous use of the two drugs can increase the inhibitory effect of GABA neurons and improve the diversity of the GABA receptor. Stiripentol can be used as an addon therapy for RSE. The clinical application of stiripentol is mainly for SMEI, and its anticonvulsant effect is age-dependent. Stiripentol may be more effective for SE in children [38,83]. At present, further clinical trials are needed to determine its clinical application. Immunomodulating therapy
Immunomodulating therapy includes steroids, plasmapheresis and iv. immune globulin [86]. In recent years, SE caused by Expert Rev. Neurother. 15(6), (2015)
Combination drug therapy for the treatment of SE
some special types of encephalitis (such as anti-NMDA-receptor encephalitis) and new-onset refractory SE (NORSE) syndrome have gradually been recognized [87–89], and the cause of NORSE syndrome is probably some unknown infection or immune mechanism. These patients are resistant to most AEDs [86,90]. Immunomodulating therapy combined with AEDs can both terminate the SE and improve the prognosis of patients.
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The combination therapy with immunomodulating therapy
Combination therapy comprises the use of immunomodulating therapy and AEDs simultaneously [86,90]. Indications
Immunomodulating therapy is indicated in RSE caused by autoimmune encephalitis [86] or NORSE syndrome (new onset of refractory SE in patients with no clear etiology or no history of seizures) [90]. Gall et al. [90] retrospectively analyzed five patients in the ICU with NORSE syndrome, and all of the patients were young healthy adults. They all had nonspecific symptoms 2–7 days before their seizures and then developed RSE. All of the patients were resistant to AEDs and narcotics. Three patients received AEDs together with steroids and immunoglobulin early, and their RSE was gradually controlled. Their prognoses were quite good, with no serious neuropsychological defects, and two of these three patients resumed full-time work. One patient without immunomodulating therapy died of ICU-related complications. One patient’s prognosis was unknown because he returned to his city of residence after being treated with thiopental. Finne et al. [86] retrospectively analyzed a juvenile patient with long-term SE caused by autoimmune encephalitis. Immunomodulating therapy (including corticosteroids, plasma exchange and immunoglobulin) was combined with AEDs. Eventually, the patient’s RSE terminated, and the prognosis was good. Mode of administration
Treatment should start with benzodiazepines and then proceed with immunomodulating therapy. Gall et al. [90] retrospectively analyzed a 26-year-old patient with NORSE syndrome with a history of hyperthyroidism. He had no risk factors for epilepsy. In addition to the positive anti-TPO antibody, his auxiliary examination, including cranial MRI, serological examination of viral and autoimmune antibodies, and cerebrospinal fluid examination, was normal. Premonitory symptoms of the patient were headache and vomiting. Five days later, he was admitted to the hospital because of generalized tonic–clonic seizures and complex partial seizures. Then, he gradually developed refractory GCSE and was admitted to the ICU for treatment with general anesthesia. The patient was treated with propofol, phenytoin, valproic acid, LEV, thiopental and phenobarbital, but the epilepsy continued. Because SE may be caused by immune factors when infectious factors are excluded, the patient received steroids on the 12th day in the hospital. The patient was first treated with iv. methylprednisolone (1 g/d) for 3 days, followed by oral prednisone (60 mg/d), and finally with iv. immunoglobulin (5 days for a total volume of 150 g) on the eighteenth day in the informahealthcare.com
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hospital. After 2 months of hospital treatment, the patient recovered and was discharged from the hospital. He continued to take immunosuppressors and AEDs after discharge to prevent the recurrence of epilepsy. Finne et al. [86] retrospectively analyzed a 17-year-old patient with long-term SE caused by anti-NMDA receptor encephalitis. The patient had no history of epilepsy. The MRI examination and general examination for tumor screening were negative. He had premonitory symptoms of fatigue and cold 2 days prior to the onset of the change in consciousness and partial seizures. Then, he gradually developed SE, and AEDs and anesthetics were ineffective. The patient was later diagnosed as having anti-NMDA receptor encephalitis because specific antibodies were found in the serum and cerebrospinal fluid. He was immediately given immunotherapy while AEDs were continued. He was first treated with iv. methylprednisolone 1 g/day for 5 days with oral tapering, then five instances of plasma exchange and finally iv. immunoglobulin (0.4 g/kg) for 5 days. After 86 days of intensive treatment, the patient recovered consciousness, and the SE was completely controlled. After discharge, he continued taking immunosuppressants (azathioprine or mycophenolate mofetil) and AEDs. The patient recovered completely after a year of rehabilitation treatment and continued to attend high school. Precautions
Discharged patients should continue to use immune inhibitors (azathioprine or mycophenolate mofetil) and AEDs for at least 1 year [86,90] to prevent the recurrence of epilepsy. Lacosamide
Lacosamide (LCM) is a promising new AED that is involved in the regulation of calcium channels and sodium channels. LCM has few drug interactions, and it may provide some neuroprotective effects [91]. Its enteral and iv. formulations were approved in 2009. A few studies [92] and case reports [93,94] have reported on LCM as an add-on treatment for SE and RSE. The combination therapy with lacosamide
A strategy for combination therapy is the use of LCM as an add-on treatment when the first- or second-line drugs are ineffective for SE [91]. Indications
Combined administration of LCM is mainly suitable for adult patients with RSE [91,94–97]. Sutter et al. [91] retrospectively analyzed 111 adult RSE patients treated between 2005 and 2011, 53% of whom used iv. LCM as an add-on drug after the failure of first- and second-line AEDs (excluding 25 patients with hypoxicischemic encephalopathy). LCM was used simultaneously with other AEDs, such as lorazepam and LEV. Patients with LCM tended to have more frequent seizure control (odds ratio, OR: 2.34; 95% CI: 0.5–10.1, p = 0.252). Among all patients who received LCM as the last AED (23/45), seizure control was achieved in 91% (21/23), with no adverse events related to LCM. The duration of SE in patients with iv. LCM 647
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Wang, Jin & Chen
was 87.2 ± 159.4 h, and the duration of SE in patients without iv. LCM was 134.3 ± 188.7 h.
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Mode of administration
The treatment should start with benzodiazepines and then proceed with LCM. Sutter et al. [91] used LCM as an add-on treatment together with other AEDs (such as lorazepam and LEV) to control RSE. The administration of LCM was 200 mg twice daily. Patients with renal failure received LCM twice a day with 150 mg per application (creatinine clearance 30–50 ml) or 100 mg twice daily (creatinine clearance less than 30 ml). The administration of LCM to an obese patient (110 kg) was 600 mg per day. Adverse reactions
Sutter et al. [91] found no acute side effects related to LCM. The clinical study by Sutter et al. [91] demonstrated that a combination therapy with LCM and other AEDs is relatively safe and effective for the treatment of RSE. Additionally, the administration of LCM decreased the mortality of RSE. Prospective studies with larger sample sizes are warranted to further elucidate the efficacy of LCM for the treatment of RSE. Topiramate
Topiramate is a new broad-spectrum AED that is involved in the regulation of the ionotropic glutamatergic a-amino-3hydroxy-5-methyl-4-isoxazole-propionic acid receptor [98]. It has characteristics that include fast absorption, linear pharmacokinetics and long elimination half-life. Topiramate is metabolized more quickly if phenytoin or carbamazepine is coadministered. Its enteral and oral formulations are currently available. A few case reports in adults [99–101] and children [102–108], as well as case series [109,110], have reported on topiramate as an add-on treatment for SE and RSE. The combination therapy with topiramate
A strategy for combination therapy is the use of topiramate as an add-on treatment when the first-line or second-line drug is ineffective for SE. Indications
The combined administration of topiramate is mainly suitable for adult patients with RSE (90–94). Hottinger et al. [98] retrospectively analyzed 35 (median age = 60.5 (19–84) years) RSE patients administered topiramate enterally between 2004 and 2011. Topiramate was used as an add-on drug enterally after the failure of first- and second-line AEDs, and it was administered simultaneously with other AEDs, such as lorazepam and LEV. After the administration of topiramate, seizure control was achieved in 71% within 72 h and 9% within 24 h. The mortality was 31%, and the cause was not RSE but the underlying etiology of RSE. Mode of administration
Treatment should start with benzodiazepines and then proceed with topiramate. The recommended initial dosing is 648
200–400 mg (nasogastric or by mouth). The administration rate and alternative dosing recommendation is 300–1600 mg/day orally (divided two to four times daily) [111]. Hottinger et al. [98] used topiramate enterally as an add-on treatment. Based on the topiramate dose, patients were divided into three groups in this study: the 800 mg/day group, the 400–799 mg/day group and the
