ABSTRACT

This review explores the pathophysiology of status epilepticus in adults, along with its incidence and key clinical considerations. We present a comprehensive treatment approach, emphasizing both emergent and urgent therapies. Additionally, we examine the role of newer agents such as clobazam and brivaracetam. This review also includes dosing strategies and potential drug-drug interactions of commonly used antiseizure medications in critically ill patients. Treatment strategies for refractory and super-refractory status epilepticus are also discussed. Finally, we provide a practical algorithm for a structured management approach, along with dosing and titration guidelines for sedatives following seizure cessation.

Introduction

Definition and Clinical Considerations

Status epilepticus (SE) is a medical emergency requiring immediate intervention to prevent long-term consequences arising from sustained seizure activity. Historically, SE was defined as seizure activity or the occurrence of two or more seizures without recovery of consciousness, lasting beyond five minutes. However, in 2015, the International League Against Epilepsy (ILAE) and the Commission on Epidemiology introduced a precise operational definition, incorporating two critical time points: T1 and T2 (1).

•T1 (Seizure Onset): For bilateral tonic-clonic (convulsive) SE, treatment should commence at 5 minutes, as seizures are unlikely to resolve spontaneously. In focal SE, with or without impaired consciousness, this threshold extends to 10 minutes.

•T2 (Risk of Neuronal Damage): This marks the maximum time window for effective seizure control to prevent long-term complications. For convulsive SE, the threshold is 30 minutes, while for focal SE, it is 60 minutes.

This definition underscores the necessity of prompt treatment to mitigate the risks associated with SE. Status epilepticus arises from either the failure of mechanisms responsible for seizure termination or the activation of mechanisms leading to abnormally prolonged seizures. After T1, seizure activity generally requires medical intervention to halt progression. Beyond T2, the risk of significant neuronal damage increases, necessitating aggressive management to prevent irreversible harm.

The ILAE’s operational framework for SE emphasizes the importance of timely recognition and intervention to reduce the risk of lasting neurological consequences (1).

Incidence

The global incidence of SE varies significantly across different regions and populations. According to a meta-analysis, the pooled crude annual incidence rate of SE is approximately 12.6 per 100,000 persons (2). The incidence of all types of SE in the USA ranges from 18.3 to 41 per 100,000 people per year. The incidence of convulsive SE (CSE), specifically, has increased from 3.5 per 100,000 in 1979 to 12.5 per 100,000 in 2010 (3). The goal of therapy is the rapid termination of both clinical and electrical seizure activity, since appropriate and timely therapy of status epilepticus reduces the associated mortality and morbidity. Delayed treatment can lead to neuronal injury, irreversible damage to vulnerable regions in the hippocampus, thalamus, and neocortex, and in some cases, brain tissue hypoxia, and increased intracranial pressure.

Risk Factors

Common causes for status epilepticus have been listed in Table 1 below. In children, the most common causes for status epilepticus are remote structural disease, acute symptomatic disease, and febrile seizures. In adults, the most common causes for status epilepticus are acute symptomatic disease such as stroke and metabolic derangements (4, 5).

Pathophysiology

During SE, typical seizure termination mechanisms fail, or abnormal excitatory mechanisms are activated, resulting in prolonged seizure activity. As seizures persist, changes in neurotransmitter receptor dynamics progressively reduce the efficacy of termination strategies. A retrospective study in adults found that 80% of patients treated within the first 30 minutes of seizure activity experienced successful seizure termination, whereas this response rate dropped to less than 40% after 2 hours of seizure activity (6). Animal studies further demonstrate that prolonged seizures induce changes in neuronal membrane receptors, making seizure activity increasingly resistant to termination over time.

At the molecular level, benzo-diazepam sensitive synaptic gamma-aminobutyric acid, g-aminobutyric acid (GABA, gamma sub-unit), is internalized during prolonged seizures, leading to a reduction in membrane receptor density. This poses a challenge for treatment particularly with benzodiazepines, which are the first-line therapy for seizure termination. Conversely, prolonged seizure activity promotes the translocation of N-methyl-D-aspartate (NMDA) receptors to the synaptic membrane, increasing excitatory signaling. These receptor changes can occur within as little as 5 minutes of seizure onset. Figure 1 explains additional factors that exacerbate ongoing seizure activity, including the release of peptides, neuroinflammation, and the breakdown of the blood-brain barrier, all contributing to the increasing difficulty of terminating seizures over time (7).

During convulsive SE, significant physiological changes occur, including alterations in heart rate, blood pressure, respiratory rate, blood glucose levels, body temperature, and electrolyte balance. The repetitive muscle contractions associated with convulsions impose extreme metabolic demands on the body. As convulsions persist, a shift to anaerobic metabolism occurs, resulting in increased lactic acid levels. Animal studies suggest that compensatory mechanisms begin to fail after 20 to 40 minutes of continuous seizure activity. Inadequate ventilation leads to hypoxia, which, coupled with pulmonary edema, contributes to respiratory acidosis. Simultaneously, metabolic acidosis develops due to lactic acid accumulation. Prolonged convulsions can also result in hyperthermia and rhabdomyolysis (7).

Prolonged SE can cause neuronal injury through mechanisms such as hypoxia, hyperthermia, acidosis, and hypoglycemia. This damage may lead to hippocampal sclerosis, characterized by the loss of neurons in the dentate nucleus and pyramidal layer of the hippocampus. Hippocampal sclerosis can serve as a focal point for seizures and epilepsy, perpetuating a vicious cycle of recurrent seizures and further neuronal injury (8).

Treatment

First-line (emergent) therapy: Effective initial therapy, also known as emergent therapy, according to the Neurocritical Care Society (NCS), depends on multiple factors, including drug choice, dosage, and timing. Benzodiazepines are considered a first-line treatment, with lorazepam being the preferred option in hospitals due to its proven efficacy in clinical trials (9). Clinical trials have shown that IV lorazepam is more effective than IV phenytoin and at least as effective as phenobarbital or diazepam plus phenytoin. In an out-of-hospital setting, IV lorazepam has a slightly better response than IV diazepam and is comparable to intramuscular (IM) midazolam (10). IM midazolam enters the systemic circulation quickly, providing a seizure cessation action like IV lorazepam. This is a viable alternative when IV access is delayed (Table 2).

Timely and appropriate dosing is crucial for effective benzodiazepine therapy in status epilepticus. A lorazepam dose of 0.1 mg/kg (maximum 4 mg) is effective, while 10 mg of IM midazolam is appropriate for patients over 40 kg, when IV access is unavailable. Concerns about respiratory compromise and airway management with benzodiazepines are countered by evidence suggesting a lower intubation rate in treated patients compared to those left untreated.

Second line (urgent) therapy: Although various antiseizure medications are available for urgent therapy in status epilepticus, no clinical trials definitively support one agent over another in terms of efficacy. Studies reveal suboptimal response rates, with less than 50% seizure cessation for phenytoin or phenobarbital, and variable responses for valproate (70-88%) and phenytoin (25-84%) (11, 12). More recently the ESETT trial showed no difference in efficacy when levetiracetam, valproate, or phenytoin were utilized as second line agent for the management of status epilepticus (13). In this study, status epilepticus was stopped in approximately 50% of patients in each treatment group. It is, therefore, important to consider individual medication and patient-specific factors when choosing the second-line agent. Traditional agents such as phenobarbital and (fos)phenytoin have limitations, including prolonged infusion times and risks such as hypotension, respiratory depression, and arrhythmias, often necessitating airway protection and cautious infusion rates to mitigate adverse effects. Propylene glycol in these drugs can cause toxicity, including severe metabolic acidosis. Fosphenytoin allows faster administration but is still constrained by cardiovascular risks and in vivo conversion time. In contrast, newer agents such as levetiracetam and lacosamide can be infused more quickly, offering practical benefits such as reduced monitoring time and faster therapeutic concentrations. They also have fewer drug-drug interactions. Finally, valproate with a broad mechanism of action may be helpful in controlling seizures as a second-line agent. Valproate should be avoided in those with thrombocytopenia, severe liver disease, or pregnancy or of childbearing age. Additionally, the combination of valproate and carbapenem should be avoided, as it results in subtherapeutic valproate concentrations (Table 3). Therapeutic drug monitoring should be performed when available to help guide therapeutic decision making (Table 4).

In recent years, novel antiseizure medications such as clobazam and brivaracetam have gained popularity. The exact mechanism by which brivaracetam exerts its antiseizure effects remains unknown, though it is a high-affinity ligand of synaptic vesicle protein 2A (SV2A).

Compared to levetiracetam, brivaracetam binds to SV2A with 10- to 30-fold greater affinity. Its rapid onset of action and availability in an intravenous (IV) formulation make it an appealing option for the treatment of SE, refractory SE (RSE), and super-refractory SE (SRSE). While animal studies suggest potential benefits of this agent in SE, clinical evidence remains limited. Phase III trials in epilepsy have shown that adding brivaracetam to ongoing levetiracetam therapy does not provide additional therapeutic benefit. Notably, patients who had not been exposed to levetiracetam responded better to brivaracetam. Among those previously treated with levetiracetam, efficacy was greater in patients who discontinued it due to adverse effects rather than due to insufficient response. Future randomized trials are needed to clarify the role of brivaracetam when co-administered with levetiracetam in SE (14).

Clobazam, a 1,5-benzodiazepine, enhances GABA-A receptor activity with greater selectivity for subunits involved in anxiolytic and anticonvulsant effects than for those mediating sedation. Its ease of administration, rapid onset, and favorable safety profile make it a viable option for SE treatment in patients with enteral access (14). However, given the limited clinical evidence, the potential role of this agent as an early add-on oral therapy for SE should be further explored through prospective randomized trials. Table 3 summarizes dosing and clinical pearls regarding these novel antiseizure medications.

Finally, the pathophysiology of status epilepticus highlights the importance of rapid seizure cessation to prevent neurological and metabolic complications. Prolonged status epilepticus can reduce the effectiveness of traditional treatments and increase the risk of refractory status epilepticus. Animal models indicate that benzodiazepine receptors undergo endocytosis after about 30 minutes, resulting in benzodiazepine refractoriness, while increased NMDA-glutamate receptor expression sustains an excitatory brain state and thereby elevates metabolic demands. This highlights the interest in starting anti-NMDA agents such as perampanel (enteral) or ketamine (intravenous) earlier in the course of status epilepticus therapy (15). Figure 2 demonstrates a practical approach to choosing antiseizure medications in status epilepticus. Individual patient factors such as organ function and drug-drug interactions should be prioritized when choosing the antiseizure medication(s). Table 5 summarizes important landmark clinical trials in urgent and emergent management of status epilepticus.

Refractory Status Epilepticus and Super Refractory Status Epilepticus

RSE is defined as SE that persists despite at least two appropriately dosed parenteral ASMs, while SRSE is SE that persists either for at least 24 hours after the onset of continuous anesthetic medications (i.e., midazolam, propofol, pentobarbital, and ketamine) or during the weaning of these medications. However, it is important to note that, prolonged requirement for anesthetic coma was strongly associated with poor functional outcomes and functional decline. Mechanical ventilation was required in more than 90% of cases, one-third of which ultimately required tracheostomy. Longer duration of mechanical ventilation was associated with mortality. Additionally, cardiac arrhythmias requiring intervention, and pneumonia predicted poor functional outcome (17).

Recent case reports (18, 19) have shown that ketamine represents a safe and effective treatment option for refractory seizures without intubation, and thus has the potential to reduce morbidity associated with intubation in a carefully selected patient population. Early initiation may increase the likelihood of success. Table 6 summarizes appropriate dosing of anesthetics in this context.

Discontinuation of Anesthetics

Once under the anesthetic, patients are monitored on continuous EEG and targeted for burst suppression. This is aimed to last for at least 24-28 hours. Once achieved, the anesthetic can be weaned every 3 hours by 20-50% (Table 6) (20). If brief seizures progress to SE, anesthetic tapering should be stopped, and the dose should be increased to the prior, effective level. In addition, another anti-seizure medication can be added to aid in weaning anesthetic. Another 24-48 hours period of electrographic stability should be achieved before attempting an anesthetic withdrawal.

While deep sedation and burst suppression are well-described interventions for refractory status epilepticus, the specifics on weaning sedation are based on expert opinion, small observational studies, and standard critical care principles rather than large, dedicated randomized controlled trials. For now, clinicians rely on continuous EEG monitoring, gradual tapering, and strong maintenance antiseizure drug coverage to prevent rebound seizures and optimize outcomes.

Conclusion

SE presents a significant clinical challenge due to its potential for rapid progression to irreversible neuronal damage. The ILAE’s operational framework underscores the importance of early recognition and time-sensitive treatment. Delayed intervention increases the risk of mortality and long-term morbidity, evidenced by the steep decline in treatment efficacy beyond 30 minutes of seizure activity.

Recent insights into the pathophysiological mechanisms of SE provide a basis for targeted interventions. The role of receptor dynamics (e.g., GABA-A receptor internalization and NMDA receptor externalization) has informed the use of benzodiazepines and highlighted the need for alternative therapies in benzodiazepine-resistant cases.

Advances in ASM pharmacokinetics, newer agents like brivaracetam, clobazam, and perampanel, and adjunctive therapies like ketamine offer hope for better outcomes in refractory cases. However, the management of SRSE remains complex, requiring careful balancing of sedation, ventilation, and systemic support to minimize complications. Further research is needed to refine treatment algorithms for RSE and SRSE, identify biomarkers predicting treatment response, and develop neuroprotective agents to mitigate long-term neuronal damage.

In conclusion, managing SE requires a multidisciplinary approach, combining prompt intervention with an understanding of its complex pathophysiology. Standardized protocols and emerging therapies promise to improve patient outcomes, especially in refractory and super-refractory cases.

Footnotes