Review

Diagnosis and management of status epilepticus:

improving the status quo
Jennifer V Gettings*, Fatemeh Mohammad Alizadeh Chafjiri*, Archana A Patel, Simon Shorvon, Howard P Goodkin, Tobias Loddenkemper

Status epilepticus is a common neurological emergency that is characterised by prolonged or recurrent seizures Lancet Neurol 2024
without recovery between episodes and associated with substantial morbidity and mortality. Prompt recognition Published Online
and targeted therapy can reduce the risk of complications and death associated with status epilepticus, thereby December 2, 2024
https://doi.org/10.1016/
improving outcomes. The most recent International League Against Epilepsy definition considers two important S1474-4422(24)00430-7
timepoints in status epilepticus: first, when the seizure does not self-terminate; and second, when the seizure can
*Co-first authors
have long-term consequences, including neuronal injury. Recent advances in our understanding of the
Division of Epilepsy and Clinical
pathophysiology of status epilepticus indicate that changes in neurotransmission as status epilepticus progresses Neurophysiology, Boston
can increase excitatory seizure-facilitating and decrease inhibitory seizure-terminating mechanisms at a cellular Children’s Hospital, Harvard
level. Effective clinical management requires rapid initiation of supportive measures, assessment of the cause of Medical School, Boston, MA,
USA (J V Gettings BMBS FRCPC,
the seizure, and first-line treatment with benzodiazepines. If status epilepticus continues, management should
F Mohammad Alizadeh
entail second-line and third-line treatment agents, supportive EEG monitoring, and admission to an intensive care Chafjiri MD, A A Patel MD,
unit. Future research to study early seizure detection, rescue protocols and medications, rapid treatment escalation, Prof T Loddenkemper MD);
and integration of fundamental scientific and clinical evidence into clinical practice could shorten seizure duration Guilan University of Medical
Sciences, Rasht, Iran
and reduce associated complications. Furthermore, improved recognition, education, and treatment in patients
(F Mohammad Alizadeh Chafjiri);
who are at risk might help to prevent status epilepticus, particularly for patients living in low-income and middle- University Teaching Hospitals
income countries. Children’s Hospital, Lusaka,
Zambia (A A Patel); University
Introduction classification system was proposed with four axes: College London, UCL Queen
Square Institute of Neurology
Status epilepticus is a life-threatening emergency that is semiology, cause, EEG correlates, and age. and the National Hospital for
characterised by prolonged or recurrent seizures without The updated ILAE definition acknowledges that at a Neurology and Neurosurgery,
recovery between episodes. Prompt treatment can prevent timepoint, t1, either mechanisms that lead to seizure London, UK
(Prof S Shorvon FRCP);
irreversible neuronal injury, morbidity, and mortality. In termination have failed or mechanisms that result in an
Department of Neurology and
the past 10 years, advances in status epilepticus include atypically prolonged seizure have been initiated. Once t1 Paediatrics, UVA Health,
refinements to definitions and classification systems, is reached, the seizure will persist in the absence of Charlottesville, VA, USA
improvements in conventional, quantitative, and rapid emergency treatment. If this treatment is unsuccessful (Prof H P Goodkin MD)

EEG, automated seizure detection, and development before a second timepoint, t2, long-term consequences Correspondence to:
Dr Jennifer V Gettings,
of comprehensive assessments to ascertain the cause might occur, including neuronal injury, alternations of
Division of Epilepsy and Clinical
of the seizure. Regarding treatment, intranasal rescue neuronal networks, or death. On the basis of observational Neurophysiology, Boston
medications have been developed, class 1 evidence for human studies and experimental animal studies that Children’s Hospital, Harvard
second-line medications has emerged,1–4 and novel evaluated the duration of self-limited seizures and the Medical School, Boston,
MA 02115, USA
antiseizure medications and targeted treatment for long-term consequences of seizures, t1 was defined as
jennifer.gettings@childrens.
genetic and neuroinflammatory causes are promising. 5 min for tonic-clonic seizures and 10 min for focal harvard.edu
However, disparities in care persist, particularly between seizures with impaired awareness, and t2 was defined as
high-income countries (HICs) and low-income and 30 min for tonic-clonic seizures and more than 60 min
middle-income countries (LMICs), as well as within the for focal seizures with impaired awareness. For absence
LMICs themselves. status epilepticus, t1 was defined as 10–15 min and t2 is
In this Review, we describe recent changes in the unknown.
definition of status epilepticus and discuss developments In addition to t1 and t2 in status epilepticus, stages and
in epidemiology, pathophysiology, and aetiology. We also specific syndromes are also defined in the ILAE criteria
describe recent advances in the diagnosis, treatment, and on the basis of the duration of the seizures and the
prognosis of status epilepticus. Finally, we highlight the treatment response. Early or impending status
challenges and potential future directions in global care epilepticus refers to continuous or intermittent seizures
for status epilepticus. lasting longer than 5 min without recovery of
consciousness in between seizures. Established status
Definition and specific status epilepticus epilepticus defines seizures that do not respond to
syndromes treatment with first-line benzodiazepines. When seizures
In 2015, the International League Against Epilepsy continue despite the use of two adequately dosed
(ILAE) proposed a novel definition of status epilepticus antiseizure medications (eg, a first-line benzodiazepine
that combines historical definitions based on and a second-line non-benzodiazepine antiseizure
pathophysiology with definitions that emphasise the medication), a definition of refractory status epilepticus
need for clinical intervention.5 In parallel, a diagnostic can be made. Refractory status epilepticus can be further

www.thelancet.com/neurology Published online December 2, 2024 https://doi.org/10.1016/S1474-4422(24)00430-7 1

 Review

classified in the ILAE criteria as responsive to subsequent intrinsic biological factors might contribute to these
antiseizure medications or requiring general observed disparities.
anaesthesia.6 Refractory status epilepticus that lasts Researchers from Finland found that the incidence of
longer than 24 h despite treatment with anaesthetic status epilepticus requiring intensive care unit (ICU)
agents or that recurs on anaesthetic wean is called super- admission was 3·4 per 100 000 people per year, and the
refractory status epilepticus. New-onset refractory status incidence of super-refractory status epilepticus was
epilepticus (NORSE) and febrile infection-related 0·7 per 100 000 people per year.15 The incidence of status
epilepsy syndrome (FIRES) are specific status epilepticus epilepticus that was terminated by treatment in the
syndromes within the definition of refractory status community (particularly, non-convulsive status epilepticus)
epilepticus in the ILAE criteria.7 NORSE is a clinical has not been robustly studied.
diagnosis for presentations of refractory status epilepticus
in a patient without an antecedent diagnosis of epilepsy Pathophysiology
or another neurological disorder.8 A subset of patients Dynamic processes are at play during the prolonged
with NORSE have FIRES, in which a febrile infection seizures of status epilepticus, the net effect of which is an
precedes the onset of refractory status epilepticus by 24 h atypically extended seizure that persists and places
to 2 weeks. substantial demands on homoeostatic mechanisms.
When these mechanisms fail, blood pressure drops, brain
Epidemiology perfusion and oxygenation are reduced, and concomitant
The incidence of status epilepticus depends on the respiratory and metabolic acidosis occurs.16 Animal
factors used to define it. Relevant factors comprise models of status epilepticus, in which seizures are
duration, semiology (ie, convulsive or non-convulsive), induced by electrical stimulation or administration of a
geographic location (eg, HICs or LMICs, or rural or chemoconvulsant, have elucidated molecular and cellular
urban), age distribution of the population, method of changes that affect the balance between inhibition and
case ascertainment (eg, community or hospital, excitation of seizure mechanisms.
prospective or retrospective, and clinical or registry), The changes elucidated in animal models include
cause, and inclusion and exclusion criteria (eg, exclusion reduced cellular surface expression of GABA type A
of post-anoxic cases and developmental and epileptic receptors due to an increase in the intracellular
encephalopathies). accumulation of these receptors, an increase in the
In Europe and North America, estimates from surface expression of NMDA receptors, and an alteration
observational studies of the incidence of convulsive in the subunit configuration of AMPA receptors.17 In
status epilepticus range between nine per 100 000 people addition to changes in the surface expression of
and 40 per 100 000 people per year, with higher rates in inhibitory and excitatory receptors, changes in the
children and older adults.9 For example, the incidence of intracellular and extracellular ionic environment can
status epilepticus in older people varies from occur. In animal models, neuronal injury and death have
15·5 per 100 000 people aged 60–69 years per year to been shown to result from dysregulation of calcium-
25·9 per 100 000 people older than 80 years per year.10,11 In dependent mechanisms and the build-up of reactive
LMICs, the incidence of status epilepticus is generally oxygen species.18 The preponderance of ion shifts
higher than in HICs, particularly in children in whom contributes to the self-propagation of neuronal
the leading cause is infectious diseases (eg, malaria).9 A excitability and network synchronisation.19 An example
prospective population-based study of children with of ion shifts that might occur in status epilepticus is an
status epilepticus found an incidence of increase in the intracellular concentration of chloride,
14·5 per 100 000 people per year.9 The highest age-specific resulting from chloride loading and failed extrusion of
rate, 51 per 100 000 people per year, was found in infants intracellular chloride because of internalisation of the
younger than 1 year.9 potassium chloride cotransporter KCC2. As a result,
Regarding racial and ethnicity differences, observational GABAergic signalling can shift from hyperpolarising to
studies have shown status epilepticus to be more common depolarising. In such an instance, treatment with
in African American people than in White people, and GABAergic drugs might have the paradoxical effect of
more common in both African American people and increasing neuronal excitability, with the exact response
White people than in Asian people and Hispanic people.12,13 on the network depending on the cell type and function
By sex, incidence of status epilepticus has been shown in of the cells in which the chloride has accumulated. In an
observational studies to be higher in male individuals animal model of status epilepticus, KCC2 activation
than in female individuals, although the rate of recurrence using a small molecule derived from aminopyridine
has been observed to be higher in female individuals than compounds reduced the intracellular accumulation
in male individuals.13,14 The underlying causes for these of chloride and restored the effectiveness of
differences in incidence of status epilepticus have not benzodiazepines.20 Changes in expression of cellular
been thoroughly explored, but factors such as access to receptors and ionic shifts in chloride suggest potential
care, socioeconomic status, cultural disparities, and mechanisms for why status epilepticus might become

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 Review

refractory to first-line medications such as

benzodiazepines. These mechanisms also support the Panel 1: Causes of status epilepticus, defined according to
potential use of NMDA receptor antagonists once a International League Against Epilepsy criteria5
benzodiazepine has not worked.21–23 However, as this Symptomatic
pathophysiological research is being done in animal Symptomatic status epilepticus has an identifiable cause.
models of status epilepticus, future work in patients is
Acute
required to confirm the mechanisms.
• Acute triggering factors in epilepsy (eg, withdrawal or
subtherapeutic doses of antiseizure medications, febrile
Aetiology
illness, or sleep deprivation)
The cause of status epilepticus is of particular importance
• Acute primary CNS pathology (eg, cerebrovascular
for determining appropriate treatment and prognosis.
disease, CNS infection, or head trauma)
Status epilepticus can arise from infections, vascular
• Acute secondary CNS pathology (eg, metabolic
causes, metabolic disturbances, trauma, space-occupying
disturbances, systemic infection, or fever)
lesions, genetic disorders, autoimmune disorders,
• Acute toxic causes (eg, alcohol withdrawal or drug or
iatrogenic or medication-related causes, toxic exposures,
toxin exposure)
or drug withdrawal. Causes can be classified, according to
the ILAE criteria, into symptomatic or cryptogenic.5 Remote
Symptomatic status epilepticus has an identifiable cause • Post-traumatic (eg, closed, open, or penetrating head
and is further classified into acute, remote, progressive, injury)
and status epilepticus in defined electroclinical • Post-infectious (eg, acute or chronic bacterial meningitis,
syndromes (panel 1). The heterogeneous causes of acute acute viral encephalitis, or progressive
symptomatic status epilepticus are further classified into leukoencephalopathy)
four subcategories: acute triggering factors in epilepsy, • Post-stroke (eg, ischaemic stroke, intracerebral or
acute primary CNS pathology, acute secondary CNS subarachnoid bleeding, or subdural or epidural haematoma)
pathology, and acute toxic causes.24 Among these Progressive
subgroups, acute primary CNS pathology (eg, CNS • Brain tumours
infection) has the highest risk of poor outcomes and • Progressive myoclonic epilepsies
in-hospital mortality. Conversely, acute triggering factors (eg, Unverricht–Lundborg disease and Lafora disease)
in epilepsy (eg, subtherapeutic concentrations of • Neurodegenerative disorders (eg, Alzheimer’s disease and
antiseizure medications) have the lowest risk of poor corticobasal degeneration)
outcomes and in-hospital mortality, emphasising the
Status epilepticus in defined electroclinical syndromes
importance of distinguishing these categories to tailor
• Tonic status epilepticus in early infantile developmental
treatment and address prognostic differences among
and epileptic encephalopathy, infantile epileptic spasms
subgroups.24 Additionally, a substantial proportion of
syndrome, and Lennox–Gastaut syndrome
cases comprise remote symptomatic causes, largely
• Autonomic status epilepticus in early-onset benign
structural brain lesions.
childhood occipital epilepsy
• Myoclonic status epilepticus in Alzheimer’s disease
Diagnosis
• Non-convulsive status epilepticus in Creutzfeldt–Jakob
The differential diagnosis of convulsive status epilepticus
disease
includes movement disorders (eg, dystonia and
myoclonus) and psychogenic non-epileptic seizures (also Cryptogenic
known as functional seizures),5 so diagnostic testing Cryptogenic status epilepticus has an unknown cause.
needs to exclude these disorders by identifying the cause
of the seizures. The diagnosis of convulsive status
epilepticus is largely clinical. A comprehensive history, in serum of prolactin, measured 10–20 min after a
physical examination, appropriate laboratory and seizure event, have a sensitivity of 53% and
imaging studies, and EEG are paramount to identifying specificity of 93% for diagnosis of status epilepticus and
the underlying cause (figure 1). Laboratory studies should can help to differentiate epileptic seizures from
include, at a minimum, a complete blood count, psychogenic non-epileptic seizures.27 However, the use of
measurement of glucose and electrolytes, and a this test is limited by the ability to obtain the sample
pregnancy test in patients of childbearing potential. within 20 min of a seizure event. A lumbar puncture is
Additionally, renal and liver function tests, blood gas, indicated in patients with signs of meningitis, and it
lactate, troponin, creatine kinase, and toxicology should be considered for those who appear severely ill or
screening should be performed, if possible. Investigations are younger than 18 months, have a prolonged complex
to identify treatable infectious causes include blood and febrile seizure, have an incomplete or unknown
urine cultures and appropriate microbiological testing, vaccination status (particularly for patients who are not
with consideration of local pathogens.26 Elevated amounts vaccinated against Haemophilus influenza type b or

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 Review

Essential If possible Optional or as indicated

Initial investigations

Known epilepsy patient

Antiseizure medication concentrations in blood

Serum: Blood culture, HSV PCR (if unavailable, appropriate

clinical screening)
Fever or suspected infection Urine: urine analysis, urine cultures
CSF: Cell count, protein, glucose, HSV-1 and HSV-2 PCR,
bacterial stain and culture, Gram stain
Nasopharyngeal swab for respiratory viral panel and
Ongoing altered mental status SARS-CoV-2 PCR
with concern for subtle or
non-convulsive seizures

Further evaluation, as clinically indicated based on suspected underlying cause

Consider additional diagnostics as recommended by the NORSE guidelines25

Figure 1: Diagnostic evaluation for status epilepticus

HHV=human herpes virus. HSV=human simplex virus. LGI1=leucine-rich glioma-inactivated 1. NORSE=new-onset refractory status epilepticus.

Streptococcus pneumoniae),28 or who received Although convulsive seizures are easily identifiable,
antimicrobials before a clinical evaluation. The CSF seizures can often begin or continue, particularly after
profile is helpful in uncovering an infectious, treatment, with minimal or no clinical manifestations.
inflammatory, or neoplastic cause. Elevated CSF protein These seizures are referred to as non-convulsive,
might occur in patients with seizures in the absence of subclinical, or electrographic-only seizures. Patients with
an identified underlying cause.29 Historically, CSF non-convulsive seizures can also present with confusion,
pleocytosis was attributed to prolonged seizures.30 lethargy, agitation, delirium, and speech disturbances.
However, with modern neuroimaging and laboratory EEG monitoring can be helpful in patients who do not
investigations, an infectious or immune-mediated cause return to their baseline consciousness, in whom there is
can be identified in this clinical scenario.29,31 CSF a concern for ongoing non-convulsive seizures, or in the
pleocytosis must prompt more investigation and not be setting of neuromuscular blockade or sedation that limits
attributed to the direct result of the seizure. Urgent CT clinical assessment for seizures (figure 1). Approximately
neuroimaging should be performed before lumbar half of patients with ongoing alterations in consciousness
puncture if increased intracranial pressure or a lesion after status epilepticus might show continued non-
that could cause herniation is possible.32 convulsive seizures on EEG.33 Situations that predict a

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 Review

high risk of non-convulsive seizures are admission to the required for respiratory distress, ketamine or propofol
neurointensive care unit, particularly when receiving can be used, as they have antiseizure properties. Starting
neurotoxic medications (eg, cephalosporins, ifosfamide, the treatment with a rapidly acting benzodiazepine
methotrexate, ketorolac, baclofen, lithium, opioids, and within the first 5–10 min of seizure onset (after t1) is
opioid antagonists), previous epilepsy diagnosis, a essential.42,43 If the seizure persists 5–10 min after the first
preceding generalised tonic-clonic seizure, female sex, benzodiazepine dose, a second dose should be
and history of head injury and stroke.34,35 In patients with administered. Emergency providers must take into
known epilepsy who return to baseline without concern account any doses administered before hospital arrival. A
for ongoing subclinical seizures, EEG monitoring might delay in treatment in the magnitude of minutes increases
not be needed. the risks of prolonged status epilepticus.
Limitations of EEG for monitoring of subclinical Due to their safety and efficacy, benzodiazepines are
seizures are that interpretation and reporting rely on the the first-line treatment for status epilepticus.44 In animal
labour-intensive visual analysis of digital EEG data by studies, when administered as early as 15 min after
highly trained electro­ encephalo­graphers. Moreover,
continuous EEG with simultaneous video recording is
resource-intensive and is not available in all centres, Stabilisation and resuscitation

particularly those in LMICs. In settings where continuous

EEG is unavailable, intermittent routine EEGs could be Treatment steps in adults and children Side-effects

used;36,37 however, in a quality improvement study, this

strategy missed at least 10% of subclinical seizures.38
Although intermittent EEGs can reduce the time needed
for interpretation by the electroencephalographer,
First-line

placing and replacing the EEG electrodes is not

necessarily less resource-intensive for EEG technologists.
An alternative strategy relies on computational analysis
and automated seizure detection algorithms to reduce
clinician workload. Quantitative EEG software displays
large amounts of EEG data acquired over hours or days,
in trends, allowing for fast analysis and for the detection
of gradual changes occurring over time. However, these
findings necessitate additional confirmatory review of
Second-line

the raw EEG data, and quantitative EEG detection of

seizures is subject to false positive findings, often due to
artifacts. In a prospective observational study, bedside
providers screened quantitative EEG trends for seizures,
with high sensitivity but low specificity.39 A consequence
of low specificity is potential overtreatment with
antiseizure medications.
Technologies are emerging that reduce the time and
resources required for EEG application and interpretation,
including reduced electrode montages, caps, and bands,
Third-line

which can serve as screening tools to guide whether

patients require conventional EEG monitoring.40 However,
these technologies might play a more prominent role in
settings with little access to conventional EEG. In Bhutan,
a smartphone and tablet-based EEG app in combination
with 14-electrode caps was tested as an alternative to
traditional EEG systems.41 Findings showed the app was
safe, affordable, accessible, and portable when compared
with standard EEG recordings, and sensitivity for the
detection of epileptiform discharges was 39% and
specificity was 95%.41

Management
Figure 2: Treatment algorithm for convulsive status epilepticus including medication adverse events and
Initial management of status epilepticus requires considerations for low-income and middle-income countries11
stabilisation of the patient and concurrent evaluation for *Fosphenytoin is a pro-drug of phenytoin with a higher molecular weight than phenytoin. Thus, fosphenytoin is
reversible causes. If rapid sequence intubation is dosed in phenytoin equivalents to avoid confusion.

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 Review

onset of seizures, benzodiazepines have sometimes not fosphenytoin, valproate, levetiracetam, and
terminated status epilepticus due to pharmacoresistance, phenobarbital57 within 20–40 min of status epilepticus
but a study of the effectiveness of diazepam showed that onset. The Established Status Epilepticus Treatment Trial
the cause of the seizures could determine whether (ESETT) evaluated valproic acid, levetiracetam, and
benzodiazepine pharmacoresistance will occur.45 Yet, fosphenytoin.3 The Convulsive SE Pediatric Trial
patients in status epilepticus can remain responsive to (ConSEPT)1 and Emergency Treatment with
benzodiazepines after 15 min.46,47 For these reasons, Levetiracetam or Phenytoin in Status Epilepticus in
even for prolonged status epilepticus, treatment should children (EcLIPSE)2 trials both compared levetiracetam
begin with a benzodiazepine, rapidly followed by a with phenytoin. In these randomised trials, no difference
second-line agent if needed, to avoid delays in the in efficacy was found between the agents tested, and the
transition from benzodiazepines to non-benzodiazepine response was similar when stratified by age.59 In the
treatments.19,21–23,45 Treatment of Recurrent Electrographic Non-convulsive
Benzodiazepine availability varies worldwide, which Seizures (TRENdS) randomised trial, lacosamide was
affects the optimal first-line treatment choice.44,48–51 The found to be non-inferior to fosphenytoin.60 Lacosamide
most common recommended first-line benzodiazepines and phenobarbital have been evaluated in additional
are diazepam, lorazepam, and midazolam (figure 2). longitudinal series and meta-analyses,61 none of which
Systematic reviews indicate that if clinicians have access found a compelling difference in the type of second-line
to all benzodiazepines, they prefer lorazepam over agent. Evidence for new medications with intravenous
diazepam in both adults and children.51,52 Diazepam is formulations (eg, lacosamide and brivaracetam) is
more commonly available globally53 because it is more insufficient.
affordable than midazolam and lorazepam and can be The choice of first-line or second-line agent is only
stored at room temperature. Midazolam can also be one aspect of status epilepticus management, and the
stored at room temperature. Lorazepam is heat-sensitive role of training, route of administration, and treatment
and requires refrigeration to 2–8°C, which adds to the algorithms cannot be ignored. A quality improvement
cost of storage.54,55 Rectal diazepam is widely available study showed that the implementation of acute status
globally, although it is still unavailable in 40% of low- epilepticus treatment algorithms in an inpatient setting
income countries (LICs), potentially due to cost, supply resulted in a decrease in ICU transfers from 39% to 9%.62
chain issues, or insufficient awareness or training. Another quasiexperimental cohort study of a status
Buccal midazolam is available in more than half of LICs, epilepticus alert protocol reduced the time to
but specific access might vary based on sources of administration of a second-line antiseizure medication
medications and rural or urban locations. Among from 58 min to 22 min.63
intravenous benzodiazepines, intravenous diazepam is No large randomised controlled trials have been
widely available, whereas intravenous midazolam is conducted to guide the optimal choice or dose of
available in approximately 30% of LICs, and intravenous medication for the management of refractory or super-
lorazepam is available in less than 22% of LICs.56 refractory status epilepticus. Treatment is dictated by the
Although intravenous administration is preferred when underlying cause, rational polypharmacy to target
feasible, it requires trained staff and equipment. different mechanisms of action, pharmacokinetics,
Prepackaged intranasal benzodiazepines are rarely drug–drug interactions, and mitigating side-effects in a
available in many countries.56 critically ill patient. If first-line and second-line
When benzodiazepines are unavailable, intravenous medications do not terminate status epilepticus, a
or intramuscular phenobarbital can be used as a first- continuous infusion of midazolam, propofol, or
line treatment.57 In LMICs, providing optimal pentobarbital should be considered (figure 2). In
medication dosing with a risk of respiratory depression observational studies comparing midazolam,
in the absence of continuous monitoring or pentobarbital, and propofol in patients with refractory
haemodynamic and ventilatory support can be status epilepticus, there was an association between
challenging.44 In these situations, loading doses can be pentobarbital treatment and greater seizure suppression
divided and administered cautiously in two doses. but an increased risk of hypotension.63,64 Over the past
Levetiracetam via nasogastric tube is another option: a few decades, trends have been to use propofol or
study comparing enteral levetiracetam with enteral midazolam rather than barbiturates. However, prolonged
phenobarbital in convulsive seizure management sedation with propofol increases the risk of propofol
during cerebral malaria showed equivalent efficacy to infusion syndrome (characterised by potentially
phenobarbital and a lower risk of hypotension and lethal metabolic acidosis, hyperkalaemia, hyper­
respiratory depression.58 triglyceridaemia, rhabdomyolysis, transaminitis, renal
Second-line treatment consists of non-benzodiazepine failure, and arrhythmias), particularly in children, in
antiseizure medications (figure 2). Guidelines from the which the use of the medication is restricted to less than
Neurocritical Care Society and American Epilepsy 24–48 h. Propofol is not recommended in patients with a
Society include recommendations for administering suspected underlying mitochondrial disorder or in

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 Review

patients on a concomitant ketogenic diet.65 A randomised completely unavailable is to use 24–48 h of continuous
controlled trial in super-refractory status epilepticus of infusion as a practical cutoff for the duration of therapy.
anaesthetics plus the GABA type A receptor allosteric Complications can arise from ongoing seizures and
modulator allopregnanolone, compared with standard prolonged exposure to continuous infusions, including
anaesthetics, did not show efficacy.66 Ketamine is a non- haemodynamic instability, infection, blood dyscrasias,
competitive NMDA receptor antagonist that can be used coagulopathy, metabolic derangements, and kidney and
as an alternative to propofol, benzodiazepine, or liver injury, which in turn contribute to prolonged
barbiturate infusions.67 Ketamine has a distinct hospitalisations, morbidity, and mortality. Hence, there
mechanism of action from other commonly used is considerable interest in using non-anaesthetic
antiseizure medications and does not cause therapies early during refractory status epilepticus.
haemodynamic or respiratory compromise. In settings If an immune-mediated cause of status epilepticus is
with little capacity for mechanical ventilation, small suspected, treatment with immunotherapy is recom­
doses of ketamine can be used.68 Hypothermia has not mended within 72 h of onset.25 The use of pulse-dose
been shown to confer a benefit besides standard intravenous corticosteroids or intravenous immuno­
therapies.69 globulin as first-line treatment for NORSE and FIRES is
According to an observational cohort study, treating reasonably agreed on by experts.25 Corticosteroids and a
physicians commonly treated refractory status ketogenic diet are also treatment options in patients
epilepticus by titrating anaesthetic drugs under without an underlying immune-mediated cause, to
consultation of a neurologist to induce a pharmacological target the inflammatory and immunologically mediated
coma, maintain clinical and electrographic seizure changes caused by seizures themselves or to target
suppression, and reach a burst suppression pattern on a yet unidentified immune-mediated cause. Second-
EEG. This strategy theoretically offers neuroprotection line immunotherapy options include plasmapheresis,
by reducing cerebral metabolic demands,70 but it requires rituximab, tocilizumab, cyclopho­ sphamide, and
high doses of sedatives, which can themselves be anakinra.
neurotoxic and result in hypotension, respiratory Medication availability is only one part of effective
depression, and prolonged coma. Inducing burst management of status epilepticus. Observational studies
suppression has not been shown to improve mortality in underscore the importance of training for status
retrospective observational studies of patients with epilepticus management,77 including adequate dosage,
status epilepticus.71 Burst suppression is typically timing, and route of administration.78,79 Clinicians and
maintained for 24–48 h before withdrawal of anaesthetic caregivers often delay administration or underdose
medications is attempted. To balance the negative effects benzodiazepines due to the perceived risk of respiratory
of oversedation required to reach burst suppression and depression. More than half of paediatric patients who
the goal of neuroprotection, an alternative objective is to receive benzodiazepines receive inadequate doses of
titrate continuous infusions to have seizure cessation. benzodiazepines in both prehospital and in-hospital
However, the method that is superior and whether settings.79,80 In a cross-sectional study of almost
rhythmic and periodic EEG patterns should be targeted 2500 adults with status epilepticus, none were treated
are not clear.72,73 with adequate doses of first-line midazolam.81
A long-acting antiseizure medication (eg, fosphenytoin, Benzodiazepines can cause respiratory depression in a
lacosamide, levetiracetam, phenobarbital, or valproic dose-dependent manner, but the risk of respiratory
acid) should be added to the continuous infusion for depression from ongoing status epilepticus offsets the
super-refractory status epilepticus to reach adequate risk from appropriately-dosed first-line rescue
serum concentrations, which will help to maintain benzodiazepines.81 Caregivers should be trained to
seizure control after withdrawal of the infusion. recognise seizures, administer first-line rescue
Neurophysiological signals associated with an medications (eg, rectal diazepam, buccal lorazepam, and
unsuccessful anaesthetic wean in patients with refractory buccal or intranasal midazolam), and recognise when to
status epilepticus include the presence of highly contact emergency medical services (EMS). Seizure
epileptiform bursts and burst amplitudes of 125 mV or action plans, videos, and simulations can enhance
more.74,75 The interburst interval length, burst length, and training.82,83 Additionally, wearable seizure detection
burst suppression ratios were not associated with the devices (eg, electromyography sensors, actigraphs, and
success of an anaesthetic wean in a retrospective cohort EEG-based systems) aid in the detection of seizures and
study.76 Quantitative neurophysiological signals might status epilepticus, particularly when patients are not
have a role in predicting the success of anaesthetic weans supervised.84 Ultimately, advancing first aid training
in the future.76 courses to include status epilepticus treatment
In settings without continuous monitoring for algorithms, similar to training for stroke and cardiac
electrographic seizures or burst suppression, one strategy emergencies, might improve the implementation of
is to request 20–30 min of intermittent EEG recording status epilepticus treatment algorithms outside
every 12 h (figure 2). Another strategy for when EEG is specialised centres.

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Panel 2: Priorities for management of status epilepticus in

Disparities in care worldwide
Requesting EMS support for status epilepticus with
low-income and middle-income countries
onset outside the hospital setting is common globally.85
Pre-hospital treatment EMS response times vary depending on the setting, and
• Provide individualised seizure action plans that include: data are scarce regarding response times specific to
• A description of the individual’s epilepsy and seizure status epilepticus, particularly in LMICs.86–89 EMS arrival
types times for all causes of status epilepticus can range from
• The current antiseizure medication regimen 5·9 min (in a retrospective cohort study in the USA)90 to
• Seizure precautions and any specific restrictions for 15 min (in a qualitative research study in Saudi Arabia)91
the individual’s safety in HICs, and from 7·6 min (in a retrospective descriptive
• When to seek emergency medical care and when to cross-sectional study in Iran)90 to 16·9 min (in a cross
contact the specialist managing the patient’s seizures sectional study in Ghana)92 in LMICs. These estimates do
• The care provider’s contact information not account for the differences in response times
• An emergency pathway with rescue medication and between rural versus urban areas,91 which limits
administration instructions, if available generalisability. There is a paucity of literature on gender,
• Consideration of geographic challenges and rescue racial, and socioeconomic disparities among patients
medication limitations with status epilepticus. Observational studies from
• Early recognition of status epilepticus, including (where Switzerland and the USA have suggested associations
appropriate) safe treatment plans for clustering of between the female sex and decreased odds for return to
seizures using available antiseizure medications and premorbid neurological function,93 between low income
guidance on management if antiseizure medications and status epilepticus prevalence, and between high
are unavailable income and odds of receiving EEG monitoring.94
• Improve rescue medication availability, especially nasal Attention to vulnerable populations is needed to improve
and buccal forms for ease of administration status epilepticus outcomes.
• Decrease emergency medical services arrival times
Prognosis
Trained health-care professionals and resources
Benzodiazepine treatment terminates status epilepticus
• Basic training on recognition and treatment of seizures
in approximately 70% of cases,95 although the exact
with consideration for the specific resources available in
figure varies with circumstance. If the benzodiazepine
the clinical setting in which the provider is working
does not terminate status epilepticus, treatment with
• Standardised guidelines or protocols on status epilepticus
the second-line medication is effective in approximately
tailored to locally available resources posted in every
50% of cases.3 Recovery in these early stages is excellent;
emergency unit
most patients have no long-term sequelae.96
• Status epilepticus treatment that considers availability to
The outcome in refractory status epilepticus is poorer
respiratory support for safety
than in status epilepticus. In approximately
• Education emphasising the importance of time to
50% of patients, morbidity includes epilepsy, cognitive
treatment regarding rapid escalation of antiseizure
impairment, and the consequences of prolonged
medications, early polytherapy, or early continuous
anaesthesia and ventilation in the ICU. Estimates of the
infusions during hospital management
5-year rates of seizure recurrence in adults with first-time
• Training of non-specialists on basic epilepsy management
non-hypoxic status epilepticus range from 9% for patients
and seizure action plan development
with acute toxic causes to 66% for patients with
• Access to neurologists in person or via telehealth
progressive causes.94 Risk factors for seizure recurrence
• Access to rescue medications, consistent antiseizure
after status epilepticus are progressive causes, status
medications supplies, intensive care unit facilities, and EEG
epilepticus with prominent motor phenomena evolving
monitoring for appropriate status epilepticus management
into non-convulsive status epilepticus, and non-
Public education and cultural factors convulsive status epilepticus.97 Mortality rates of
• Campaigns to improve awareness of seizures and seizure 40% or more have been reported for refractory status
first aid, destigmatise epilepsy, and debunk common epilepticus,98 and in-hospital rates might underestimate
myths of contagion the true mortality. In a retrospective cohort study from
• Education for seizure first aid among caregivers, teachers, Finland, of 395 patients with refractory status epilepticus
and community leaders who required ICU treatment, the eventual hospital
mortality rate was 7·4%, and the 1-year mortality
Seizure detection and prediction devices
rate was 25·4%.15,99 Mortality was highest in patients with
• Development of accessible and affordable seizure
the longest duration of status epilepticus, the greatest
detection and prediction devices
degree of dependency, and patients aged 80 years or
• Technology that takes advantage of widespread
older. A meta-analysis of patients with generalised
smartphone availability globally
convulsive status epilepticus found a mortality

8 www.thelancet.com/neurology Published online December 2, 2024 https://doi.org/10.1016/S1474-4422(24)00430-7

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ratio of 15·9% but, disappointingly, concluded that

mortality from convulsive status epilepticus had not Search strategy and selection criteria
improved over nearly three decades (1990–2017).100 References for this review were identified by searching
Among patients with non-hypoxic refractory status PubMed and Embase for articles published between
epilepticus, estimates of in-hospital mortality approached Sept 4, 2015, and July 1, 2024, because 2015 was the year
20% in 2023.6 Compared with patients with refractory when the International League Against Epilepsy published
status epilepticus who are responsive to antiseizure the revised definition and classification of status epilepticus.
medications, patients with refractory status epilepticus The main search terms were (“Status Epilepticus” OR “status
who require general anaesthesia have three times the epilepticus pathophysiology” OR “status epilepticus
risk of in-hospital mortality, and patients with super- epidemiology” OR “status epilepticus mortality”) OR
refractory status epilepticus have almost four times the ”antiseizure medication”. We excluded papers not written in
risk of in-hospital mortality.97 Mortality in paediatric English, conference abstracts, and case reports. Google Scholar
status epilepticus is much lower, ranging from 3–11%.101 was also searched to identify unpublished data and grey
The greatest effect on mortality and morbidity is the literature. Additionally, we included articles identified in the
underlying cause of status epilepticus, with the highest reference list of relevant articles and were ultimately selected
rates recorded in hypoxic brain injury and any other by relevance, with a preference for newer articles within the
pathology that results in large-scale neuronal destruction. search interval. The final reference list was generated on the
Among the common causes, those with acute brain injury, basis of the relevance of the search results to the topic covered
hypoxic–anoxic encephalopathy, and inflammatory or in this Review.
autoimmune disorders have especially poor outcomes.
The outcome is better for people with existing epilepsy
than for those with first-presentation status epilepticus. emergency room visits and ICU stays, and improved
Outcomes depend on the quality of ICU care, and the morbidity and mortality in status epilepticus.
longer status epilepticus remains resistant to treatment, Contributors
the greater the risk of ICU complications. Several All authors contributed to the conceptualisation, data curation, formal
prognostic scoring systems are available to predict analysis, investigation, methodology, writing of the original draft,
and review and editing of the Review.
outcomes (eg, STESS, EMSE, and END-IT scores), which
have little use in deciding on treatment approaches.15 Declaration of interests
JVG receives research funding from the National Institutes of Health
(NIH). FMAC was partly funded by the Epilepsy Research Fund.
Conclusions and future directions AAP receives research support from the NIH and National Institute of
Status epilepticus and its associated morbidity and Neurological Disorders and Stroke (NINDS); serves on the advisory board
mortality are potentially preventable. Effective treatment of ROW Foundation; and is a consultant for the WHO Brain Health Unit.
HPG receives salary support from the NIH and NINDS. TL receives
is crucial to control seizures and prevent refractory and research funding from NIH, Epilepsy Research Fund, and Epitel;
super-refractory status epilepticus.62,84 Strategies for received data for separate research from Sumitomo Pharma; receives
improved outpatient care include better detection and travel support and speaker honoraria for Grand Rounds at academic
prediction, accessible rescue medications, and seizure centres and national and international meetings; is part of patent
applications to detect and predict clinical outcomes and to detect,
action plans, particularly in settings where timely access manage, diagnose, and treat neurological conditions, epilepsy, and
to EMS can be a barrier, such as LMICs. Key seizures; serves as the consortium principal investigator of the Pediatric
interventions in LMICs might include providing Status Epilepticus Research Group; serves on various committees and
medications at the point of care, enhancing education, roles in national societies; and received device donations from Epitel and
Empatica. While working in his laboratory, some of TL’s trainees received
implementing seizure action plans, and using salary support from international foundations and societies and academic
diagnostic tools such as mobile apps, wearables, and centres. SS declares no competing interests.
portable EEG systems (panel 2). A detailed hub-and- Acknowledgments
spoke network of acute neurological care centres and FMAC and TL were in part supported by the Epilepsy Research Fund.
telemedicine approaches, akin to stroke networks, References
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