Status epilepticus in adults: a clinically oriented review of etiologies, diagnostic challenges, and therapeutic advances

Status epilepticus (SE) is the second most common neurological emergency following ischemic stroke [1]. Its incidence rate varies among countries, ranging from 4.6 to 41 per 100,000 per year [2]. Mortality rates in adults with SE can reach 30% [2]. The discrepancy in the epidemiological data is partly explained by the great variety of study designs and inclusion criteria. Prompt recognition and urgent treatment are thus necessary to reduce morbidity and mortality [1].

In this updated review, we provide an overview of the SE definition, physiopathology, diagnostic challenges, and recent treatment advances.

Because of the high mortality rate related to SE and in order to optimize management, concerted efforts have been made to standardize the definition, classification, and treatment protocols [2].

The American Epilepsy Society defined SE as either continuous seizure activity lasting more than 5 min or the occurrence of two or more sequential seizures without complete recovery of consciousness between them [3]. A few years earlier, the Neurocritical Care Society provided a definition for SE as “ongoing clinical or electrographic activity,” specifying that SE is characterized by either “(i) continuous clinical and/or electrographic seizure activity lasting 5 min or more” or “(ii) recurrent seizure activity without recovery between seizures” [4]. The inadequacy of both definitions lies in their failure to account for the various types of SE, such as non-convulsive, focal, and absence seizures. In 2015, the International League Against Epilepsy (ILAE) formed a task force consisting of the Commission on Classification and Terminology and the Commission on Epidemiology to develop a new definition and classification system for SE [5]. As a result, a new definition was proposed stating that SE arises from either the failure of mechanisms responsible for terminating seizures or the activation of mechanisms that lead to abnormally prolonged seizures (after time point t1). This condition can result in long-term consequences (after time point t2), such as neuronal death, neuronal injury, and disruption of neuronal networks, which vary depending on the type and duration of the seizures. This definition considers the pathophysiology of SE and sets the time points for treatment decision-making, with t1 defining the time of treatment initiation and t2 addressing the aggressiveness of the treatment approach required to prevent long-term consequences. The time points (t1 and t2) vary according to the type of seizure ([5]; Fig. 1).

In the same effort, a novel diagnostic classification system for SE has been suggested, aiming to guide the clinical diagnosis, investigation, and treatment of each patient. According to the ILAE, SE characterization should follow a four-axis approach. The axes include semiology, etiology, electroencephalogram (EEG) correlates, and age ([5]; Table 1). Semiologic assessment and patient age are easily evaluated, while the identification of etiology may require more time. The EEG recordings may not always be available, especially during the initial presentation. Nonetheless, EEG patterns significantly impact treatment and prognosis, so that early testing is recommended. Although some experts propose that determining the “clinical context”— such as SE occurring in individuals with no history of epilepsy or in those with epilepsy, may be more critical than identifying the etiology to facilitate a faster diagnostic evaluation and management [5]—it is important to remember that up to 42% of SE episodes might require a specific treatment targeting its etiology [6].

The pathophysiology of SE involves several mechanisms that ultimately lead to neuronal injury and death. Animal studies showed that prolonged convulsive seizures lead to modifications in bodily functions such as significant alterations in blood pressure, heart rate, respiratory performance, electrolyte levels, blood sugar, and body temperature [7, 8]. During the initial phase of convulsive SE, the cerebral blood flow increases, accompanied by tachycardia, higher blood pressure, and dilation of cerebral blood vessels [8]. Although glycemia increases initially, there is a subsequent surge in lactate levels and acidosis due to the greater demand for energy, leading to increased anaerobic metabolism [8]. In non-human primates, compensatory mechanisms gradually fail about 20–40 min after the onset of convulsive SE [8]. This leads to a progressive decline in blood pressure, cerebral perfusion, brain oxygenation, and glycemia. At this point, non-mechanically ventilated primates are at risk of frequent arrhythmias and cardiovascular collapse [8]. According to the literature available on the physiological changes that occur during prolonged seizures and convulsive SE, it appears that humans experience compensatory responses that are comparable to those observed in animal models [9].

In non-human primates, the cortex, cerebellum, and hippocampus are susceptible to lesions caused by prolonged convulsive seizures, which exhibit a similar pattern to that observed in cases of circulatory arrest, systemic hypotension, or hypoglycemia [10]. Although some neuronal damage occurs as a result of physiological dysregulation, injury can also occur in a physiologically stable but seizing brain. The excessive activation of glutamate receptors and subsequent Ca²⁺ influx into the neuron caused by epileptic activity alone can result in neuronal injury and death [11].

At the level of neurotransmitters, different research groups reported that prolonged seizures or seizure-like activity leads to the internalization and subsequent reduction of γ‑aminobutyric acid B (GABA_A) receptors in the synapse [9]. The internalization process of GABA_A receptors was shown to be modulated by neuronal activity, with recurrent bursting enhancing it and blockade of neuronal activity reducing it. This internalization was associated with a decreased response to GABA, while inhibition of internalization was linked to an increased response to GABA. Conversely, N-methyl-d-aspartate (NMDA) receptors were found to accumulate in the synapse during SE. This resulted in a progressive decrease in functionally active GABA_A receptors and an increase in functionally active NMDA receptors in the postsynaptic membrane soon after the onset of SE. These findings might clarify the gradual pharmacoresistance to GABA_A receptor allosteric modulators and the increasing pharmacosensitivity to NMDA antagonists observed in animal models [9].

The classification of SE can be based on its semiology, duration, and underlying etiology. Since SE is defined basically as a prolonged seizure, there can be as many forms of SE as there are types of seizures. To simplify and emphasize the severe form of SE, the Neurocritical Care Society proposed a classification based on two semiology criteria: the presence or absence of motor symptoms and the retention or impairment of consciousness [4].

Generalized convulsive status epilepticus (GCSE) is characterized by tonic–clonic movements of the extremities and impairment of mental status, such as coma, confusion, or lethargy [4]. Focal neurological deficits can be observed in the postictal period. Convulsive SE makes up 37–70% of all forms of SE [12].

Non-convulsive status epilepticus (NCSE) is characterized by seizure activity detected on an EEG, but without observable prominent motor symptoms. This type of SE is complex since there are several types ranging from an “absence SE” to an “NCSE in coma” complicating a severe brain injury [13]. Furthermore, NCSE might also be seen after uncontrolled GCSE and is common in the intensive care setting [4]. It is important to recognize all NCSE subtypes such as absence, aphasic, autonomic, and subtle SE because each requires a different management approach and might be related to very different outcome. However, they all require the use of EEG for diagnosis.

Patients who fail to respond to standard treatment regimens for SE are considered to have refractory SE (RSE), which involves appropriate doses of an initial benzodiazepine (BZD) followed by an ASM [4].

Super-refractory SE is defined as “status epilepticus that continues 24 h or more after the onset of anesthesia, including those cases in which the status epilepticus recurs on the reduction or withdrawal of anesthesia” [14].

While ASM have been widely studied for their ability to stop seizures, it is also crucial to promptly diagnose and address any underlying causes. Various underlying factors, such as alcohol withdrawal or intoxication, infections, severe metabolic disturbances, cerebrovascular events, and brain tumor-related events require immediate and specific treatment beyond ASMs. A timely identification of the underlying cause of seizure activity would facilitate more targeted treatment [6].

Trinka and colleagues proposed in the second axis of the classification system for SE a categorization of the underlying causes, making it easier for physicians from different specialties to communicate with one another [5]. The etiology of SE is divided into two groups: (i) known or symptomatic, and (ii) unknown or cryptogenic.

Within the symptomatic group, the cause can be acute symptomatic, remote symptomatic, or progressive symptomatic, depending on the temporal relationship between the cause and the onset of SE [5, 15]. The known disorder can be caused by a structural, metabolic, inflammatory, infectious, toxic, or genetic factors ([5]; Fig. 2).

Acute symptomatic causes are the leading etiologies, making up approximately 48–63% of all SE. Among these cases, stroke emerges as the leading cause, accounting for 14–22% of SE in adults. Furthermore, in older adults, prior strokes play a significant role as a contributing factor [16].

Overall, a significant proportion of patients diagnosed with SE have a prior history of epilepsy, ranging from 30% to 44% [17]. Also, SE may occur in individuals who have previously been diagnosed with epilepsy or in those who experience it as their first symptom (sometimes called “de novo SE”). Among adults with a history of epilepsy, the primary cause of SE is typically low levels of ASM.

In most cases of SE, the underlying cause can be determined. However, there is a subset of cases, roughly 5%, where the cause cannot be identified despite a comprehensive work-up [6]. This category is now referred to as “cryptogenic SE” in the updated ILAE classification system.

The term “unknown origin” or “cryptogenic” is used in its original sense of having an unknown cause, without presuming it to be symptomatic or genetic [5]. The terms “idiopathic” or “genetic” are not applicable to the underlying etiology of SE because even in genetic epilepsy syndromes, the cause of SE may not be the same as the disease. Metabolic, toxic, or intrinsic factors (such as sleep deprivation) can trigger SE in these syndromes [5, 15].

The term “new-onset refractory status epilepticus” (NORSE) was coined to describe a group of patients who share certain commonalities and yet are often found to have varying etiologies. A multidisciplinary team of experts came together to develop a clear definition for NORSE: “a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other pre-existing relevant neurological disorder, with a new onset of RSE without a clear acute or active structural, toxic, or metabolic cause” [18]. Febrile-infection-related epilepsy syndrome (FIRES) is a type of NORSE that is characterized by a febrile infection that occurred between 2 weeks to 24 h before the onset of RSE. This febrile infection may or may not be present during the onset of SE [19].

Recently, a systematic review and meta-analysis examining the etiology and mortality of NORSE was published. The study revealed that cryptogenic causes were responsible for 49.9% of cases, while autoimmune factors accounted for 36.2%, making it the second most prevalent cause [20]. Approximately 10% of NORSE cases are caused by infections, with viruses being the most commonly implicated pathogen, depending on the region’s endemic agents. The onset of NORSE can be attributed to genetic and congenital disorders, along with toxic, vascular, and degenerative conditions that have also been reported [21]. The overall mortality rate was recorded at 22%. Frequently employed treatments encompassed the administration of ASM (with a median of 5), general anesthesia, as well as immunotherapies such as corticosteroids, intravenous immunoglobulin, and plasma exchange. The average duration of intensive care unit stay was recorded as 33.4 days, and upon discharge, approximately 52% of patients were diagnosed with epilepsy. Neurocognitive impairment emerged as a prevalent consequence of NORSE [20].

It has been shown that 42.5% of SE cases require specific treatment for the underlying cause, in addition to stopping seizures and providing symptomatic treatment [6]. It is crucial to quickly identify the underlying cause of SE. Sometimes, a thorough evaluation may be necessary, especially in cases of SE occurring in patients with “de novo” SE [22].

Approximately half of SE cases occur in patients with epilepsy, while the other half are new-onset cases [6]. It is essential to determine whether the patient has a history of epilepsy or not, and thus a comprehensive medical history and a complete neurological examination are imperative. Focal abnormalities may suggest a structural brain lesion. Vital signs and a general physical examination, including a skin examination, may be informative in revealing indirect signs of drug intoxication, injection sites (toxic), or purpura [23].

It is necessary to perform brain imaging for all patients and conduct basic laboratory tests to rule out major acid-base disturbances, electrolyte imbalances, acute organ failure, and intoxications [22]. Whenever possible, magnetic resonance imaging (MRI) should be favored over other imaging techniques as it is more sensitive in diagnosing certain underlying causes. In some cases, MRI can provide physiopathological insights, such as detecting evidence of ictal or postcritical neuronal damage [24]. In such cases, there are usually visible T2 hyperintensities involving the cortex (especially in the hippocampus), adjacent white matter, basal ganglia, thalamus (pulvinar), corpus callosum, and cerebellum, indicating vasogenic and sometimes cytotoxic edema [25]. In patients with a known history of epilepsy and rapid and favorable evolution, brain imaging might not be required.

In patients with epilepsy who experience occasional breakthrough seizures and for whom no other underlying cause for their SE has been identified through medical history, basic laboratory investigations, and neuroimaging, a lumbar puncture might be considered [22]. In patients presenting with de novo SE, the threshold for performing a lumbar puncture should be set even lower. Additionally, any patient with a suppressed immune system or exhibiting antecedent infectious symptoms or language difficulties, such as fever or hypothermia, should undergo cerebrospinal fluid (CSF) analysis to rule out central nervous system infection [22].

The interpretation of the CSF analysis results may be subject to debate, especially in the presence of moderate pleocytosis. Pleocytosis and an increased concentration of lactate and albumin CSF/serum ratio in the CSF are sometimes described in the postictal phase in the absence of any infectious or vascular pathology. However, this pleocytosis remains moderate (< 25 elements/mm³), rare (6% of patients), early (< 24 h), and is not influenced by the duration or type of seizure [26].

It is imperative to obtain an EEG at the earliest opportunity. The EEG plays a crucial role in determining the treatment options, aggressiveness, and prognosis. Also, certain types of SE can only be accurately diagnosed through EEG evaluation [5]. In convulsive forms of SE, the EEG is often affected by movement and muscle artifacts, making its interpretation difficult. However, in the case of NCSE, where clinical signs are often subtle and nonspecific, the EEG becomes essential for accurate diagnosis [5, 27].

In the case of NORSE, a thorough investigation (Table 2) is necessary. The most frequently encountered etiologies are non-paraneoplastic autoimmune pathologies (19%) and paraneoplastic autoimmune pathologies (18%) associated with various synaptic or intraneuronal autoantibodies [21].

Antibodies directed against neuronal cell surface antigens are inherently pathogenic. This category includes antibodies that bind, for example, to NMDA receptor, leucine-rich glioma-inactivated 1 (LGI1), and GABA_B receptor [28]. The mechanisms underlying seizure generation remain partially elusive, but research suggests that anti-NMDA receptor antibodies have the potential to trigger receptor internalization, anti-LGI1 antibodies may cause disturbances in synaptic protein localization, and antibodies against GABA_B receptor can serve as antagonists for neurotransmitters [28].

Antibodies against glutamate decarboxylase (GAD), as well as classic onconeural antibodies that target intracellular neural antigens, such as antibodies against Hu, Yo, Ri, Ma2, SRY-box transcription factor 1 (SOX1), and amphiphysin, have varying degrees of association with different types of tumors. Unlike antibodies that bind to neuronal cell surface antigens, onconeural antibodies are believed to primarily reflect the epiphenomenon of the underlying immune cascade, in which cellular immunity, specifically cytotoxic T cell infiltration and granzyme B‑mediated damage, may play the leading role [28, 29]. Although auto-immune and inflammatory etiologies have received a lot of attention recently, it is important to remember that they represent only 2.5% of SE overall [30]. It is thus important to look for it in the right clinical context.

Rare mitochondrial diseases, such as MELAS, MERRF, or POLG1, may initially present as a de novo SE in adults [23].

Given the variety of underlying causes of SE, the use of a diagnostic guide may be useful. The SEEIT (Status Epilepticus Etiology Identification Tool) questionnaire has been developed for use at the patient’s bedside in an emergency setting [6]. The SEEIT questionnaire was evaluated in a cohort of 212 cases of all types of SE in adults. Based solely on information available in the emergency department, it was able to correctly identify the underlying cause in 88.7% of cases (kappa coefficient of 0.88). Additionally, the results were reproducible in 83.3% of cases (kappa coefficient of 0.81) among physicians with different levels of training and specialties.

The principle of “time is brain” holds utmost significance when dealing with convulsive SE. Quick administration of symptomatic treatment (seizures control) is imperative and may need to be escalated to anesthetics to avert severe metabolic disorders and long-lasting effects beyond time point t2 [4].

The basis for the recommended staged treatment approach lies in the pathomechanisms of SE characterized by the malfunctioning of GABA-ergic neurotransmission and the overactivity of glutamatergic signaling. The treatment plan suggests that BZDs should be administered immediately after diagnosing SE as a first-line treatment via intravenous (IV) or alternative routes, followed by IV non-sedating ASM [19, 31]. The primary treatment in advanced stages is the use of anesthetic drugs to induce a therapeutic coma [31]. Furthermore, critical care management along with other therapeutic options, such as immune therapies and dietary interventions, offer crucial supplementary treatments [32].