The basic goals of treatment for patients with persistent epilepsy are rapid seizure control and prevention of complications. Seizure symptoms should first be controlled, and benzodiazepines are used for rapid SE control and are also commonly used to control refractory persistent epilepsy. three Cochrane trials have confirmed that benzodiazepines are the only effective evidence-based treatment. A more aggressive treatment approach is still advocated considering the systemic or systemic damage associated with persistent seizures in generalized convulsive RSE; in contrast, treatment of non-convulsive SE without significant impairment of consciousness should be more conservative, and the timing of treatment-induced coma in focal complex epilepsy remains debated.
1. Intravenous anti-successive status epilepticus drugs
Therapeutically, there is no significant difference between intravenous midazolam, propofol, and pentobarbital. However, a randomized trial showed that propofol and barbiturates required a longer duration of mechanical assisted ventilation, despite no significant difference in efficacy
(1) Midazolam
Midazolam is an injectable benzodiazepine with a rapid onset of action, rapid penetration of the blood-brain barrier and short duration of action. The mechanism is positive variant modulation of γ-aminobutyric acid type A receptors and inhibition of neuronal excitability. Midazolam is hydroxylated in the liver and metabolites are excreted by the kidneys, so drug concentrations are affected by hepatic drug metabolism isoenzymes and hepatic and renal insufficiency.
Several studies have reported the effect of midazolam (using different doses and therapeutic targets) in refractory status epilepticus. A meta-analysis of 111 children with RSE treated with midazolam versus other coma-inducing drugs showed equal efficacy and lower mortality (midazolam: 0%). A multicenter, retrospective study suggested the effectiveness of a single loading dose injection of midazolam and continuous infusion. A high dose of midazolam 0.4 mg/kg/h resulted in shorter seizure duration, lower mortality, and fewer recurrent seizures after withdrawal compared with a conventional dose of 0.2 mg/kg/h. Studies comparing midazolam and Valium in the treatment of RSE in children have shown similar efficacy rates, but midazolam has a higher recurrence rate (57% vs. 16%) and a higher mortality rate (38% vs. 10.5%).
The efficacy of midazolam is rapid, occurring within 0.3-1.1 hours. An initial single injectable dose of 0.1-0.5 mg/kg followed by an infusion concentration of 1-2ug/kg/min, which can be increased to 30ug/kg/min as needed, is recommended to control refractory persistent epilepsy in most children. Higher initial doses and faster dosing may be associated with more rapid symptom control. Midazolam has few side effects, but sudden reoccurrence of seizures can occur and hypotension is rare.
(2) Propofol
Propofol is an intravenous hydroxy-phenol general anesthetic that modulates γ-aminobutyric acid receptors and has a rapid onset of action and is easily titrated. It is primarily metabolized in the liver and usually has a short half-life, allowing for rapid awakening after drug interruption. Propofol infusion syndrome, manifesting as heart failure, rhabdomyolysis, metabolic acidosis, renal failure and sometimes death, can occur with long-term propofol application. Risk factors include high doses, prolonged use, use of catecholamines and corticosteroid support therapy and possible low body mass index, and death has also been reported when a ketogenic diet is combined with propofol injection.
Comparing the published randomized trials to date, propofol does not differ significantly in efficacy from other intravenous antiepileptic drugs. However, hypotension and the development of propofol infusion syndrome PRIS need to be considered during the use of propofol. The presentation of propofol infusion syndrome varies, and one retrospective study estimated the incidence of the syndrome to be 7% (fatal) and 38% (nonfatal) in refractory status epilepticus. However this rate is quite different from the conclusions reached in another retrospective and prospective study showing an incidence between 0-7%, a result that could be due to selective bias [26]. In a report of 31 RSE patients treated with propofol, three developed unexplained respiratory cardiac arrest,and 11 developed non-life-threatening propofol infusion syndrome. There were two reports of 27 patients treated with propofol and 31 patients who did not develop propofol infusion syndrome. In adults, propofol infusion resulted in termination of seizures in 67% of patients, with onset of action within 35 minutes followed by continuous titration to suppress the seizure. 50-70% of patients required vasopressors to maintain blood pressure. Careful monitoring of serum lactate concentrations during dosing to stop this complication early, as well as the use of benzodiazepines may reduce the dose of propofol, and the combination may reduce the risk of this syndrome.
(3) Barbiturates
Pentobarbital has a long history of use in the treatment of refractory persistent epilepsy. It is an intravenous anesthetic barbiturate that inhibits neuronal excitability by enhancing the gamma-aminobutyric acid coupling response. Pentobarbital is the first metabolite of thiopental sodium. Compared to luminal, pentobarbital has a faster penetration into the brain and a shorter half-life, although accumulation can occur with prolonged dosing due to lipid solubility. Pentobarbital has been associated with respiratory depression, myocardial failure, hypotension and low cardiac output.
A meta-analysis covering 193 adults with refractory persistent epilepsy compared the effects of pentobarbital, midazolam, and propofol. Pentobarbital was associated with significantly lower rates of short course treatment failure, sudden re-seizures, and treatment changes. In 33% of patients with refractory epilepsy in children treated with pentobarbital, there was complete control and no recurrence, and most of the 66.7% of patients with recurrence still achieved complete control. 66% of patients had concurrent infections, 10% had metabolic acidosis, 10% had pancreatitis, and 33% had poor prognosis due to death or concurrent encephalopathy. However, its disadvantages such as the need for long-term blood pressure maintenance and continuous mechanical assisted ventilation limit its use.
2.Ketamine
Ketamine has been less frequently reported for the treatment of refractory persistent epilepsy. It is a noncompetitive NMDA receptor antagonist, and animal models have demonstrated that ketamine is effective at 1 hour of persistent epilepsy rather than at the early 15-minute mark, suggesting that ketamine is ineffective before receptor alterations occur and may be effective in the later stages of refractory persistent epilepsy. Ketamine is neurotoxic and this toxicity is related to its inability to selectively block extrasynaptic and intrasynaptic NMDA receptors therefore some suggest that ketamine should be combined with GABAergic drugs to achieve synaptic synergism. Ketamine is metabolized by hepatic p450 enzymes, so its drug levels can be influenced by other antiepileptic drugs. In one case report, a patient with RSE improved after ketamine was given intravenously on hospital day 58 after successive treatment failures with midazolam, propofol, and sodium thiopental. In another case report, a patient with RSE who was resistant to midazolam, propofol, and phenytoin improved after receiving ketamine intravenously on day 9 of hospitalization and controlled relapses with oral ketamine maintenance therapy. In another study, patients with persistent status epilepticus were controlled by midazolam in combination with ketamine.
3. Other antiepileptic drugs
(1) Lacosamide
Both cases suggest that lacosamide may be effective as an add-on drug for persistent epilepsy, but this is still controversial. Two studies described successful treatment with 400 mg of lacosamide given intravenously after failure of lorazepam for aphasic status epilepticus and effective treatment with 300 mg given via gastroepidermal fistula after failure of diazepam, etomidate, midazolam, lorazepam, and levetiracetam for GCSE, respectively.
(2) Levetiracetam
Levetiracetam can be used in some patients with complex episodes after failure of benzodiazepines, but it needs more clinical support to become an adjunctive agent. A retrospective analysis suggested that 36 patients with RSE who failed to respond to at least one antiepileptic drug received levetiracetam intravenously with a success rate of 69%. 4 studies from Germany showed that levetiracetam given intravenously was effective in 44-88% of RSE. Levetiracetam is used because side effects such as nausea, vomiting, and elevated liver enzymes are rare, despite the administration of large doses such as 1000-20,000 mg or even 3000 mg/d intravenously. Patients are usually not quiet but also do not require vasopressure and mechanical assist ventilation. In a study that potentially analyzed the pharmacokinetics of levetiracetam, 10 patients with RSE had symptom control within 5 minutes of intravenous administration of 250 mg of levetiracetam.
(3) Pregabalin
In a study of 23 patients with RSE developing from brain tumors, 70% of patients had seizure control after the addition of a third antiepileptic drug, i.e., a combination of phenytoin, levetiracetam, and pregabalin, and their mean seizure duration was 24 hours. In addition to intravenous medication, a retrospective study demonstrated the effectiveness of oral pregabalin for RSE in most patients with partial persistent epilepsy, and a 450 mg dose of pregabalin was effective in 5/11 patients, and possibly in three others, with no side effects.
4. Inhalational anesthetics
Few articles have been reported on inhalational anesthetics for the treatment of RSE. Inhalational anesthetics such as isoflurane and desflurane at concentrations of 1.2-5% have been used to obtain EEG burst suppression in SE patients who have failed to respond to intravenous anesthetics and can control seizure activity within minutes. An earlier report on isoflurane treatment of RSE suggested that all nine RSE patients were cured but six of them died, and a 2004 article reported seven RSE patients treated by isoflurane, four of whom had a good prognosis while the other three died. Several reports have found central nervous system toxicity with isoflurane in refractory persistent epilepsy, particularly in the thalamus and cerebellar regions. In one case, the patient showed no significant abnormalities on early cranial MRI, while on day 14 and day 29 of treatment with isoflurane a repeat cranial MRI showed the presence of multiple lesions in the T2 phase, and in another case, this infant patient also showed no significant abnormalities on early cranial MRI, and on follow-up MRI every 4 days after isoflurane use, a high signal shadow in the thalamic region in the T2 phase was seen. In a 7-patient report, two patients with RSE had a T2-phase high signal shadow in the cerebellar tonsils on day 34 and day 85 of treatment with isoflurane, respectively, on follow-up cranial MRI. The main limitation of inhaled anesthetics is that they have a high recurrence rate after use and patients often need to be admitted to the ICU.
5.Lidocaine (lidocaine)
Lidocaine regulates Na ion channels and stabilizes the cell membrane potential, thereby preventing the spread of epileptic discharges, and may be effective in persistent epilepsy where phenobarbital treatment is ineffective. A retrospective study of 37 patients with refractory status epilepticus showed a 36% response rate to lidocaine, and no major adverse effects or deaths were reported. However, the use of lidocaine carries the risk of decreased heart rate, atrioventricular block, and even cardiac arrest, and should be used under close cardiac monitoring. Lidocaine is effective against epilepsy at low concentrations, but the blood concentration above 5mg/L can promote seizures.
6.Isoprodine
Isoptin can inhibit multi-resistant transporter protein, which improves the effectiveness of antiepileptic drugs in the brain. Some reports believe that its use is effective, but need to be under cardiac monitoring, the daily dose of 360mg is safe.
7, magnesium
Magnesium in physiological conditions to block NMDA receptors, has been mentioned in relation to refractory persistent epilepsy, but serum concentrations of only 14 mmol/L, in addition to a report on 2 patients with mitochondrial encephalopathy. Notably, high doses may cause neuromuscular blockade, thereby masking clinical seizures.
8. Ketogenic diet
The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet that may be effective in some RSE patients by metabolizing acetone and thus affecting K+ channels. It requires accurate nutritional calculations and is administered via parenteral nutrition. Most complications are mild and reversible, such as hypoglycemia, acidosis, hyperlipidemia, and rare complications can occur with primary cardiomyopathy and pancreatitis. The ketogenic diet is recommended for refractory persistent epilepsy in individual healthcare settings, but studies are lacking in this area. A recent retrospective analysis of the role of the ketogenic diet in RSE (mostly in pediatric patients) demonstrated its promise for the treatment of RSE.
9. Steroids/immunotherapy
Immunomodulation is sometimes used in the treatment of refractory persistent epilepsy, either alone or in combination with corticosteroids, pro-adrenocorticosteroids, ion exchange, and immune-requested proteins after exclusion of infectious factors, and these treatments may be effective in refractory persistent epilepsy caused by Rasmussen’s encephalitis, vasculitis, and anti-NMDA receptor encephalitis. A recent article reviewed and analyzed the use of steroids and immunotherapy in patients with RSE, and this author concluded that immunotherapy is gradually being used more because of our increased understanding of the etiology of RSE including NMDA and the growing evidence of the role of immune factors in epilepsy.