Definition and Classification
The classical definition of convulsive status epilepticus (CSE) is continuous seizure activity for at least 30 minutes, or two or more recurrent convulsive seizures with incomplete recovery of consciousness between seizures.1 Recently, the definition of CSE was revised in accordance with the various evidences of neuronal injury and changes in clinical settings. Currently, the most acceptable duration of continuous seizure activities is 5 minutes.2,3 In fulfilment of the revised definition and classification of status epilepticus (SE), the 2015 International League Against Epilepsy (ILAE) task force stressed that SE is either the failure of the mechanism responsible for seizure termination or the initiation of a mechanism leading to abnormally prolonged seizures, which can have long-term consequences.4 The framework of the new classification is based on four axes: 1) semiology, 2) etiology, 3) electroencephalogram (EEG) correlates, and 4) age (Table 1).
The definition of nonconvulsive SE (NCSE) is more controversial. The most common definition is electrographic seizure activity lasting for at least 30 minutes without visible convulsive movement.5,6 The essential element of the definition of NCSE is that neurological abnormalities are induced by a prolonged period of epileptic activity.4 The two key components of NCSE classification are absence SE (ASE) and complex partial SE (CPSE) (Table 2).7 NCSE can also be classified according to the age of onset (Table 3).8 ASE is a type of NCSE in which continuous or recurrent generalized epileptiform discharges are associated with a varying degree of consciousness impairment.4,9 It is most commonly diagnosed in patients with known idiopathic generalized epilepsy. However, it may also be the first presentation of epilepsy. De novo ASE occurs in middle-aged or elderly patients without a history of epilepsy and is precipitated by systemic factors with a toxic or metabolic basis. The commonest age of these patients is in the sixth decade. Sometimes, high-dose psychotropic drugs or sudden psychotropic drug withdrawal are related to this phenomenon. In these cases, de novo ASE can be categorized as an acute symptomatic seizure.10,11 NCSE with bilateral ictal discharges often presents asymmetricity. Some of these cases may represent CPSE of frontal lobe origin (ASE with focal features) and it may not be appropriate to describe them as ASE. Atypical ASE is observed in patients with symptomatic or cryptogenic generalized epilepsy such as Lennox-Gastaut syndrome.12 CPSE can be described as having abnormalities of consciousness with or without behavioral change with lateralized epileptiform discharges.13 The change of consciousness ranges from impairment of higher cortical function to frank coma. It is also characterized by seizures involving long-lasting stupor, staring, and unresponsiveness. This is sometimes accompanied by automatisms or focal motor phenomena, such as eye twitching.7
The definition of refractory SE (RSE) involves either clinical or electrographic seizures that persist after adequate doses of an initial benzodiazepine (BZD) and acceptable second-line antiseizure medication.14 Super-refractory SE (SRSE) is seizures continuing to recur 24 hours or more after the onset of anesthetic therapy.15 Subtle SE is the end stage of prolonged generalized tonic-clonic seizures (GTCS).16,17 Clinical features include focal or multifocal myoclonic movements, coma, periodic lateralized epileptiform discharges (PLEDs) with low voltage background, or continuous, rapid generalized epileptiform discharges with occasional flat periods. With advancing disease, these flat periods become longer. As an advanced stage of convulsive SE, the prognosis is poor. There is a controversy whether subtle SE should be regarded as a type of NCSE.
Clinical Manifestation and Diagnosis
The clinical manifestation of CSE is overt. However, the diagnosis of NCSE is sometimes difficult and may be dependent on some important clues.8,18 NCSE may be followed by GTCS or CSE. Some stuporous patients show subtle signs such as twitching, blinking, and nystagmus. If otherwise unexplained stupor or confusion is observed, especially in older people, a diagnosis of NCSE should be considered. Sometimes, a history of seizures and a new medical or surgical stress can also provide clues to the diagnosis of NCSE. Some stroke patients show inappropriate altered mentality not fully explained by the lesion. This condition is called “stroke plus,” which suggests that its symptoms were compromised with NCSE symptoms.
The criteria for the diagnosis of NCSE are controversial.19,20 NCSE can be summarized as a diminished level of consciousness or other neurologic deficit associated with epileptiform EEG of typical discrete seizures or continuous discharges. The response to antiepileptic drugs (AEDs) can be included in the diagnostic criteria. However, many NCSEs are refractory to AEDs both on EEG and on clinical presentation. Typical ASE has been described as an epileptic twilight state or spike-wave stupor. Three-quarters of patients are younger than 20 years of age. The onset is abrupt, without warning, and is sometimes associated with perioral or eyelid myoclonia, or limb myoclonus. Patients may be unaware of their environment with ambulatory automatism, poor communication, and variable amnesia. However, the clinical manifestations of atypical ASE present with fluctuating confusion with tonic, clonic, or sometimes focal-onset seizures. EEGs show bilateral asymmetric discharges of <3 Hz.9
CPSE is also known as prolonged epileptic fugue or prolonged epileptic twilight status.21–23 The change in consciousness ranges from mild clouding to unresponsive coma. There may be recurrent complex partial seizures with incomplete clearing between events or more continuous seizure activity and obtundation. CPSE may be associated with a twilight state with amnestic reactivity, complex reactive automatism, occasional alimentary automatism, perseverative gesticulation, and vocalizations. While symptoms of CPSE and ASE overlap considerably, some semiological differences may provide clues to the correct diagnosis. The cyclicity of semiology and the presence of fear, anxiety, irritability, aggression, and complex automatism favor the diagnosis of CPSE. Lip smacking, lateralized automatism, eye deviation, and nystagmus are also usually associated with CPSE. However, total unresponsiveness, speech arrest, cyclic behavior, and stereotypic nonlateralized automatism may also be present in both CPSE and ASE.9,24 The categorization based on the clinical characteristics of patients such as the level of consciousness and ability to ambulate may sometimes be helpful to decide the urgency or the best types of drug to treat SE (Fig. 1).
The use of the EEG is critical in the diagnosis and treatment of NCSE. However, there are a wide range of EEG abnormalities in NCSE. Sometimes less-prominent semirhythmic slowing is the only EEG finding in NCSE. Some EEG findings are more suggestive of NCSE, while others are less suggestive (Fig. 2).19,20,25,26 The typical finding is focal or generalized spike-and-slow activity that usually waxes and wanes at a frequency of >2 Hz. Localized rhythmic delta and theta activity are also frequently found. While triphasic waves are the marker of metabolic encephalopathy, they also indicate the presence of NCSE.27 The response of triphasic waves to BZD may be helpful in the differential diagnosis between metabolic encephalopathy and NCSE. However, triphasic waves can be suppressed by BZD, even in metabolic encephalopathy. PLEDs on EEG classically suggest an acute destructive brain lesion. Triphasic waves can also be caused by the ictal rhythm itself. PLEDs are periodic epileptiform discharges, usually at a frequency of <1 Hz, often every 1–2 seconds, some with intervals up to 10 seconds. Nine out of 10 patients have clinical seizures, usually a few days before the EEG is taken, and two-thirds had some form of SE before the appearance of PLEDs.28,29 They may not have a manifestation of seizures at the time. Notably, more rapid periodic discharges are typically seen in acute clinical seizures (>1 Hz or >1.5 Hz) although there is no absolute frequency criterion (Fig. 3).
Various conditions can mimic NCSE:13,30 e.g., neurologic disorders, such as mitochondrial encephalopathy, transient global amnesia, posttraumatic amnesia, complex migraine, and vascular disorders; toxic and metabolic conditions, such as toxic and metabolic encephalopathy, alcohol withdrawal symptoms, hypo- or hyperglycemia, neuroleptic malignant syndrome, serotonin syndrome; and various drug intoxication and psychiatric conditions, such as psychiatric non-epileptic seizures.
Treatment of CSE
Both the Neurocritical Care Society and the American Epilepsy Society (AES) have suggested a paradigm to treat CSE (Fig. 5, Table 4).31,32 These two paradigms share almost identical frameworks that recommend similar AEDs with only slight differences in the administered dose. The AES recommends a time difference in dosing based on evidence derived from real-world situations.
The first-line treatment of CSE with BZD is well-established. The second-line treatment comprises intravenous (IV) fosphenytoin (phenytoin), valproate, phenobarbital, levetiracetam, or midazolam. Several studies have compared the efficacy of various AEDs in this situation (Table 5).33–38 IV lorazepam was superior to IV phenytoin for the control of CSE in a randomized controlled trial.33 IV lorazepam and diazepam showed equal efficacy,34 although lorazepam was favored because of its prolonged binding to GABA receptors. Midazolam was superior to lorazepam in one study, probably because of the shorter injection time of midazolam.35 IV levetiracetam was equally effective as IV lorazepam. Meta-analysis showed that IV valproate, phenobarbital, and levetiracetam were superior to IV phenytoin.36,37 Children, adults, and older adults with established SE respond similarly to phenytoin, valproate, and levetiracetam (about 50%) in prospective randomized controlled trials. Levetiracetam and fosphenytoin were equally effective in the prevention of recurrent seizures after the control of CSE.38 Midazolam given via the intranasal, buccal, or intramuscular route may be as safe and effective as IV or rectal diazepam in terminating early-onset SE in children and potentially in adults.39
Treatment of NCSE
There is no universal consensus about how aggressively to treat NCSE. The etiology of NCSE is the most important prognostic factor in this disease.40 As a result, it is difficult to assess the effect of NCSE alone on neuronal damage in human subjects. However, there is much evidence in animal models of neuronal damage in prolonged NCSE.41,42 The treatment paradigm is similar to CSE. In addition, when or how to apply anesthetic treatment of refractory NCSE is controversial.
Although fosphenytoin (phenytoin) and valproate are commonly used in NCSE,43 the effectiveness of AEDs on NCSE has not been well studied. New AEDs such as IV levetiracetam and lacosamide can also be used to treat NCSE with fewer side effects and fewer drug-drug interactions. The efficacy of lacosamide (usually 200–400 mg, IV) to treat SE has been assessed by systemic review43 and was found to be 61% for CSE and 57% for NCSE. The effectiveness of lacosamide to treat recurrent electrographic nonconvulsive seizure was compared with fosphenytoin (IV lacosamide 400 mg vs. fosphenytoin 20 mg; phenytoin equivalent/kg). This was a noninferiority, prospective, multicenter, randomized controlled trial that found lacosamide to be superior to fosphenytoin (63.3% vs. 50%) in preventing seizure recurrence (p=0.02).44
Treatment of RSE and SRSE
For RSE, general anesthesia with IV midazolam, propofol, pentobarbital, or thiopental is recommended (Fig. 6). Continuous EEG monitoring is mandatory. When RSE is not controlled after 24-hour use of anesthesia, other options are available. Ketamine,45 megadose phenobarbital46 therapy, and multiple combinations of various AEDs including high-dose oral AEDs can be considered.47–49 Oral AEDs such as topiramate, oxcarbazepine, and perampanel can also be used with a loading or high dose (Table 6).
The effect of BZD or other GABA agonists to control RSE is limited because GABA receptor internalization occurs50,51 after repeated seizures or continuous SE, which makes it impossible for GABA agonists to reach their receptors. High-dose phenobarbital may clear this hurdle. The advantage of megadose phenobarbital therapy is that less respiratory depression occurs compared with other anesthetic therapy; therefore, it is suitable for long term use. Other special methods can also be considered for SRSEs that are resistant to these treatments, including application of hypothermia; electroconvulsive therapy; ketogenic diet; and emergency epilepsy surgery (Table 7).
Immunotherapy
Autoimmune processes have a vital role to play in SE. For example, some viral infections of the central nervous system can result in SE. Furthermore, the etiology of a recent increase in the number of SE cases can be explained by autoimmune encephalitis.52 Two special circumstances of SE are closely aligned with autoimmune processes.53–55 New-onset refractory SE (NORSE) is a clinical presentation that occurs in patients without active epilepsy or other preexisting relevant neurological disorder and no clear acute or active structural, toxic or metabolic disorder. Febrile infection-related epilepsy syndrome is a subcategory of NORSE. In both cases, a preceding febrile infection starts between 2 weeks and 24 hours before the onset of RSE. Other features suggesting an autoimmune etiology include acute or subacute onset, a history of preceding infection or trauma, the presence of anti-GABA A receptor antibodies, and a progressive course not responding to standard AEDs, but responsive to immunotherapy.
AEDs alone are largely ineffective in the treatment of SE in autoimmune encephalitis. Immunotherapy such as steroid, immunoglobulin, rituximab, or tocilizumab can be effective. In one study of six patients, NORSE was treated, without recurrence with one or two doses of tocilizumab with a median interval of 3 days from initiation.56
