Diagnosis and Treatment of Status Epilepticus.

The definition of status epilepticus (SE) was revised recently in accordance with the various evidences of neuronal injury and changes in clinical settings. Currently, the most acceptable duration of continuous seizure activity is 5 minutes. In 2015, the International League Against Epilepsy Task Force, which was convened to develop a definition and classification of SE, presented a new classification based on four axes: 1) semiology, 2) etiology, 3) electroencephalogram (EEG) correlates, and 4) age. The essential element of nonconvulsive SE (NCSE) is the presence of neurological abnormalities induced by a prolonged epileptic process. The definition of refractory SE involves either clinical or electrographic seizures that persist after adequate doses of an initial benzodiazepine and acceptable second-line antiseizure drugs. The use of EEG is critical in the diagnosis and treatment of NCSE. However, there are a wide range of EEG abnormalities in NCSE. Both the Neurocritical Care Society and the American Epilepsy Society have suggested a paradigm for treating convulsive SE (CSE). The first-line treatment of CSE with benzodiazepine is well-established. The second-line treatment comprises intravenous (IV) doses of fosphenytoin (phenytoin), valproate, phenobarbital, levetiracetam, or midazolam. Although fosphenytoin (phenytoin) and valproate are commonly used in NCSE, the effectiveness of antiepileptic drugs (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 drug-drug interactions. For refractory SE, general anesthesia with IV midazolam, propofol, pentobarbital, or thiopental could be applied. Use of ketamine, megadose phenobarbital therapy, and multiple combinations of various AEDs including high doses of oral AEDs can also be considered. New-onset refractory status epilepticus (NORSE) and its subcategory, febrile infection-related epilepsy syndrome, involve autoimmune processes. AEDs alone are poorly effective in the treatment of SE in autoimmune encephalitis. Immunotherapy such as steroids, immunoglobulin, rituximab, or tocilizumab can be effective.

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).

Table 1

Classification of status epilepticus by the ILAE task force4

Semiology	Presence or absence of prominent motor symptoms	A. Prominent motor symptoms - Convulsive SE - Myoclonic SE - Focal motor status - Tonic status - Hyperkinetic SE
	Degree of impaired consciousness	B. Without prominent motor symptoms - NCSE with coma - NCSE without coma
		Generalized: Typical or atypical absence status
		Focal: Without impairment of consciousness (e.g., aura continua)
		Aphasic status
		With impairment of consciousness
		Unknown whether focal or generalized
		Autonomic SE
Etiology	Known	Acute (e.g., stroke, intoxication, encephalitis, etc.)
		Remote
		Progressive
		SE in defined electroclinical syndrome
	Unknown	Cryptogenic
EEG	Six categories of EEG terminology	Location, pattern, morphology, time-related features, modulation, effect of intervention
Age		Neonatal, infancy, childhood (>2 to 12 years), adolescence and adulthood, elderly ≥60 years

ILAE, International League Against Epilepsy; SE, status epilepticus; NCSE, nonconvulsive status epilepticus; EEG, electroencephalogram.

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

Table 2

Simple classification of status epilepticus

Generalized NCSE
ASE	Atypical ASE
Typical ASE
De novo ASE
Partial SE
CPSE	Simple partial SE
Frontal CPSE	Epilepsia partialis continua
Temporal CPSE
CPSE originated from other lobes
Subtle SE

NCSE, nonconvulsive status epilepticus; SE, status epilepticus; ASE, absence status epilepticus; CPSE, complex partial status epilepticus.

Table 3

Classification of NCSE according to age

NCSE in the neonatal and infantile epilepsy syndromes
West syndrome	SMEI
Ohtahara syndrome	NCSE in other forms
NCSE occurring only in childhood
Panayiotpoulos syndrome	ESES
NCSE in other forms of childhood epileptic encephalopathy	Landau-Kleffner syndrome
NCSE occurring in both childhood and adult life
With epileptic encephalopathy	Without epileptic encephalopathy
NCSE in Lennox-Gastaut syndrome	Typical absence status epilepticus
Atypical absence status epilepticus	Complex partial status epilepticus
Tonic status epilepticus	Limbic
Other forms of NCSE with learning disability or cerebral development	Non-limbic
	NCSE in postictal phase of tonic-clonic seizures
	Subtle status epilepticus
	Aura continua

NCSE, nonconvulsive status epilepticus; SMEI, severe myoclonic epilepsy in infancy; ESES, electrical status epilepticus in sleep.

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).

Figure 1

Categorization of SE according to the patient’s status, such as level of consciousness and ability to ambulate. SE, status epilepticus; NCSE, nonconvulsive status epilepticus.

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).

Figure 2

EEG of NCSE showing the increasing possibility of NCSE when approaching the left end. NCSE, nonconvulsive status epilepticus; EEG, electroencephalogram; PLED, periodic lateralized epileptiform discharge.

Figure 3

Example of periodic lateralized epileptiform discharges. See the periodic sharp waves at the frequency of 1 Hz in the right posterior area.

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

Although clear features have not been identified, especially in NCSE, much experimental evidence indicates that irreversible brain damage arises after prolonged seizures. As a result, the 2015 ILAE task force recommended the 5-minute time point for the start of treatment (Fig. 4).4

Figure 4

Acceptable time of initial treatment for various SE types recommended by the ILAE task force.4 GCSE, generalized convulsive status epilepticus; SE, status epilepticus; ILAE, International League Against Epilepsy.

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.

Figure 5

Treatment algorithm for convulsive status epilepticus by the Neurocritical Care Society and the American Epilepsy Society.31,32 ABC, airway, breathing, circulation; IV, intravenous; AED, antiepileptic drug; SE, status epilepticus; IM, intramuscular; EEG, electroencephalogram.

Table 4

Recommended dose of AEDs in CSE

Drugs	Neurocritical Care Society	American Epilepsy Society
Lorazepam	0.1 mg/kg up to 4 mg	0.1 mg/kg up to 4 mg
Midazolam	0.2 mg/kg up to 10 mg	10 mg if >40 Kg
Midazolam continuous infusion	0.2 mg/kg; infusion rate 2 mg/min
Diazepam	0.15 mg/kg up to 10 mg	0.15-0.2 mg/kg up to 10 mg
Fosphenytoin/phenytoin	20 mg/kg phenytoin equivalent	20 mg/kg phenytoin equivalent up to 1,500 mg
Valproate	20–40 mg/kg	40 mg/kg up to 3,000 mg
Phenobarbital	20 mg/kg	15 mg/kg
Levetiracetam	1,000–3,000 mg	60 mg/kg up to 4,500 mg
Pentobarbital	5–15 mg (5–10 mg additional dose); infusion rate ≤50 mg/min
Propofol	1–2 mg/kg; infusion rate 20 mcg/kg/min
Thiopental	2–7 mg/kg; infusion rate ≤50 mg/min

AED, antiepileptic drug; CSE, convulsive status epilepticus.

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

Table 5

AED comparison in the treatment of CSE

Study	AEDs	Results (efficacy)
US Department of VA cooperative study:33 RCT	IV lorazepam 0.1 mg/kg vs. IV phenytoin	Lorazepam > phenytoin
Leppik et al.34 (double blind study)	IV diazepam 10 mg vs. IV lorazepam 4 mg	Equal efficacy (diazepam 76% vs. lorazepam 89%)
RAMPART35	10 mg midazolam vs. 4 mg lorazepam	Midazolam > lorazepam (probably rate dependent)
Yasiry and Shorvon36 (meta-analysis)	IV valproate, IV phenobarbital, IV levetiracetam, IV phenytoin (BZD refractory CSE)	VPA (75.7%), phenobarbital (73.6%), levetiracetam (68.5%) > phenytoin (50%)
ESETT (ongoing):37 prospective RCT	Phenyoint, vlaporate, levetiracetam (BZD refractory CSE)
Nakamura et al.38	Recurred seizure after control of SE by BZD: levetiracetam vs. fosphenytoin	Equal efficacy

AED, antiepileptic drugs; CSE, convulsive status epilepticus; RCT, randomized controlled trial; IV, intravenous; BZD, benzodiazepine; VPA, valproic acid; SE, status epilepticus.

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).

Figure 6

Suggested treatment algorithm for refractory status epilepticus and super-refractory status epilepticus. IV, intravenous; EEG, electroencephalogram; AED, antiepileptic drugs; ECT, electroconvulsive therapy.

Table 6

Oral antiepileptic drugs used in status epilepticus

AEDs	Loading dose	Peak level after a single dose
Topiramate	400–800 mg	1.5–2 hours
Oxcarbazepine (MHD)	30 mg/kg	5–6 hours (therapeutic range within 2 hours)
Perampanel	4–32 mg	0.25–2 hours

AED, antiepileptic drugs; MHD, monohydroxy derivatives.

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).

Table 7

Other treatment options

Method	Consideration
Ketamine	Early use may have better prognosis
Isoflurane	No sustained effect
Ketogenic diet	Difficult compliance
Hypothermia	Coagulation disorders
Electroconvulsive therapy
Mega dose phenobarbital
Epilepsy surgery: focal resection

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