NEUROINTENSIVE CARE
Update on the
management of status
epilepticus
Marco Paris
Ugan Reddy
Abstract
Status epilepticus (SE) it is widely recognized as the second most com-
mon and life-threatening neurological emergency after stroke, which
carries a high mortality and morbidity. The main goal of treatment is
to emergently stop clinical and electrographic seizure activity. Most au-
thorities agree on three-line treatment for SE with administration of ben-
zodiazepines followed by longer-acting anti-epileptic agents and finally,
if seizures persist, the administration of general anaesthetic agents.
Keywords EEG monitoring; epilepsy; new anti-epileptic medication;
refractory status epilepticus; status epilepticus
Royal college of Anaesthetists CPD Matrix: 2F00; 3F00
Introduction
Status epilepticus (SE) it is widely recognized as the second-most
common and life-threatening neurological emergency after stroke,
which carry a high mortality and morbidity. Its annual incidence
is 10e41 per 100,000 people. SE definition has recently changed
and keeps doing so as new evidence emerges. SE was defined as
continuous seizure activity lasting longer than 5 minutes.
Recently, SE have been re-defined depending upon the classifi-
cation as whether this was convulsive (CSE), focal (FSE) or absent
status epilepticus (ASE) with different timelines defined with
respectively 5 minutes, 10 minutes and 10e15 minutes for absent
status epilepticus. This new definition was considering the evi-
dence that after these timelines the seizure activity was unlikely to
stop spontaneously and therefore the need to aggressively treat
such complex pathology. The importance of this new definition is
related with the type of seizure, as the time after which a patient
has long-term consequences vary.
Classification of SE
SE is defined as time after which if seizures do not terminate
patient is considered in SE and therefore the initial therapy phase
as to commence. The timeline is different as the patient is in a
state of convulsive status epilepticus (CSE) (5 minutes), focal
status epilepticus with impaired consciousness (10 minutes) and
absent status epilepticus (10e15 minutes) generally known as
Marco Paris MD is a Clinical Fellow in Neurosurgery and Neurocritical
Care at the National Hospital for Neurology and Neurosurgery,
London, UK. Conflicts of interests: none declared.
Ugan Reddy BSc MB ChB FRCA FFICM is a Consultant in Neurocritical
Care and Neuroanaesthesia at the National Hospital for Neurology
and Neurosurgery, London, UK. Conflicts of interests: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 19:3
Learning objectives
After reading this article, you should understand:
C
C
the new classification and aetiology of status epilepticus
the new guideline on drugs used in the treatment of status
epilepticus
C the future directions on treatment of status epilepticus
non-convulsive SE (NCSE). This new classification is important
because the time after which the ongoing seizures have long-
term consequences differ. CSE has consequences as permanent
neuronal damage after 30 minutes of its onset. NCSE or FSE with
impaired consciousness have consequences after 60 minutes
while absent SE timelines as to permanent consequences is un-
known. Seizure activity that persists after first-line treatment
(benzodiazepines has become a standard of care for early status
epilepticus) is defined as established status epilepticus (ESE) and
widely treated with second-line medications. SE that persists
after a first-line and second-line agents is defined as refractory
status epilepticus (RSE). Super refractory status epilepticus
(SRSE) is defined as continuous seizure activity despite anaes-
thetic therapy or recurrence of seizure upon withdrawal of
anaesthetic therapy.
Aetiology of SE
SE is a dynamic entity and its pathophysiology is still poorly
understood. SE is often a manifestation of pre-existing epilepsy
and the main causes are low blood concentrations of antiepileptic
drugs in patients with chronic epilepsy (34%), or consequence of
multitude cerebral insults such as remote symptomatic causes
(24%), cerebrovascular accidents (22%), anoxia or hypoxia
(w10%), metabolic causes (w10%), and alcohol and drug
withdrawal (w10%) (see Box 1).
Complications of SE
Central nervous system
Seizure activity results in sympathetic stimulation leading to an
increase in cerebral blood flow and blood glucose levels. This
initially meets the needs of the increased metabolic demand of
neurones; however, as seizures continue, these compensatory
mechanisms become exhausted; anaerobic metabolism in-
tervenes and results in cerebral hypoxia and neuronal damage.
The safeguarding of homoeostasis is essential for the prevention
of neuronal injury, and maximizing the supply of oxygen and
glucose to the brain, by maintaining cerebral blood flow and
blood gases, is as essential as reducing cerebral metabolic needs
by restricting seizures and hyperthermia.
Systemic effects
Systemic effects are related to a massive catecholamine release
and hyper adrenergic state that may result in neuro-cardiogenic,
pulmonary and, sometimes, musculoskeletal or renal injury
(see Box 2).
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 NEUROINTENSIVE CARE

Emergency management of SE
Aetiology of status epilepticus
Management of SE consists of:
C New manifestation of epilepsy  resuscitation and diagnostic evaluation
C Cerebrovascular diseases  rapid termination of seizures
C CNS infection  treatment of life-threatening underlying cause.
C Neurodegenerative diseases The main goal of treatment is to emergently stop clinical and
C Intracranial tumours electrographic seizure activity. Most seizure activities self-
C Cortical dysplasia terminate within 5 minutes, therefore the initial treatment strat-
C Head trauma egy consists in stabilizing the patient while assessing and man-
C Alcohol withdrawal or chronic consumption aging airway, breathing, and circulation, administering oxygen,
C Intoxication gaining intravenous (IV) access and monitoring cardiac activity.
C Withdrawal or low level AED If the patient needs respiratory assistance, perform tracheal
C Cerebral hypoxia or anoxia intubation when necessary. Along with resuscitation, a diag-
C Metabolic disturbances (e.g. electrolyte imbalances, glucose im- nostic work-up is necessary with finger stick glucose, electrolyte,
balances, organ failure, acidosis, renal failure, hepatic encepha- haematology, toxicology screen and anticonvulsant levels.
lopathy, etc.) Lumbar puncture can be performed if appropriate clinical picture
C Autoimmune disorder is suspected once the patient is stabilized.
C Mitochondrial diseases Owing to lack of well-conducted and appropriately powered
C Chromosomal aberrations and genetic anomalies randomized controlled studies, protocols of treatment of SE have
C Neurocutaneous syndrome remained almost unchanged, despite promising results in pre-
C Metabolic disorders clinical animal models and some human trials for newer drugs.
C Others (Malignant hyperpyrexia, eclampsia, sepsis etc) Most authorities agree on three-line treatment for SE.

Box 1 Initial therapy phase (First line treatment): a benzodiazepine

(specifically IM midazolam, IV lorazepam, or IV diazepam) is
recommended as the initial therapy of choice, given their
Complications of status epilepticus
demonstrated efficacy, safety and tolerability. Compared to pre-
vious guideline, IV phenobarbital it is now established as effi-
Central nervous system
cacious and well tolerated as initial therapy.
C Cerebral oedema
C Cerebral venous thrombosis
Established status epilepticus SE (Second line treatment):
C Cerebral hypoxia
Patients who respond to benzodiazepine therapy are started on
C Cerebral haemorrhage
longer acting anti-epileptic drugs (AED) to prevent the re-
emergence of further seizures following benzodiazepine ther-
Cardiovascular apy. Similarly, those patients who do not respond, and those
C Hyper/hypotension patients which seizure activity persist after initial therapy phase,
C Cardiac arrest are given AEDs to try and control their SE. However, there is only
C Cardiogenic shock a 7% chance that continuing SE will respond to second line
C Myocardial infarction treatment. Treatment for estabilished status epilepticus includes,
C Arrhythmias phenytoin, fosphenytoin, valproic acid and levetiracetam. Most
of the recent effort and advances of medications for SE are
concentrating on new drugs able to be effective in established
Respiratory
status epilepticus, when initial therapy phase with benzodiaze-
C Pulmonary oedema
pine fail. Seizure activity that persist after first and second line
C Respiratory failure
treatment are considered to be in refractory status epilepticus
(see Box 3).
Metabolic
C Hyponatraemia Refractory status epilepticus RSE (Third line treatment): is
C Hyperkalaemia defined as the persistence of seizure activity, or failure to
C Hypoglycaemia respond to first and second line treatments. Intravenous anaes-
C Metabolic acidosis thetic therapy is the standard of care to treat RSE. When RSE is
evident, the patient requires transfer to intensive care, with the
goal of CEEG monitoring and systemic support with tracheal
Other
intubation and cardiovascular support.
C Rhabdomyolysis
Preferred agents used include propofol, thiopental, mid-
C Fractures
azolam and pentobarbital. While on CEEG monitoring, anaes-
C Acute tubular necrosis
thetic agents are titrated to produce at least 10-seconds EEG burst
Box 2 interval suppression. Usually anaesthetic agents are maintained

ANAESTHESIA AND INTENSIVE CARE MEDICINE 19:3 84 Crown Copyright Ó 2018 Published by Elsevier Ltd. All rights reserved.
 NEUROINTENSIVE CARE

Diagnosis and treatment of SE C midazolam (0.2 mg/kg loading dose then 0.05e3 mg/kg/h)
C pentobarbital (5 mg/k loading over 10 minutes then 1e5 mg/kg/h
Diagnostic evaluation for 24 hours)
In all patients: All with continuous EEG monitoring.

C Take history Box 3

C Glucose dipstick
C Laboratory testing of: glucose, electrolytes (especially sodium,
potassium, calcium), full blood count, renal and hepatic profiles, for 24e48 hours while longer acting agents are given before the
anti-epileptic drug levels patient is woken to assess CEEG electrical activity.
C Toxicology screen: alcohol, cocaine, antidepressant drugs etc

Depending on clinical suspicion: Super-refractory SE

C CT/MRI scan
C Lumbar puncture
Treatment of SE
Stabilization phase:
C A, B, C, D with neurological examination
C Time seizure from onset and monitor vital signs
C Give oxygen
C ECG monitor
C Administer 100 mg thiamine IV and then 50 ml D50W IV if finger
stick glucose <60 mg/dl
C IV access and blood sample
Initial therapy phase (first-line treatment):
C IM midazolam (10 mg for >40 kg, 5 mg for 13e40 kg, single
dose)
C IV lorazepam (0.1 mg/kg/dose, max 4 mg/dose, may repeat dose
once)
C IV diazepam (0.15e0.2 mg/kg/dose, max 10 mg/dose, may repeat
dose once)
C IV phenobarbital (15 mg/kg/dose, single dose) if none of three
option above available
Established status epilepticus (second-line treatment):
C IV fosphenytoin (20 mg PE/kg, max 1500 mg PE/dose, single
dose)
C IV valproic acid (40 mg/kg, max 3000 mg/dose, single dose)
C IV levetiracetam (60 mg/kg, max 4500 mg/dose, single dose)
C IV phenobarbital (15 mg/kg/dose, single dose) if none of three
option above available
Refractory status epilepticus (third-line treatment):
C Repeat second-line treatment or anaesthetic doses
C Propofol (1e2 mg/kg loading dose over 5 minutes then up to 10
e12 mg/kg/min)
C thiopental (2 mg/kg loading then 0.5e5 mg/kg/h)
Super-refractory SE is defined as the persistence of seizure
activity, or failure to respond to first, second and anaesthetic
therapy. The lack of standardized treatment of SRSE is due to
the little controlled and randomized study data; therefore the
basis of therapeutic management tends to be expert opinion,
clinical reports and assumptions arising from experimental
data.
Monitoring of SE
Electroencephalography (EEG) is essential to detect electrical
seizures and to document their duration and response to therapy.
When considering SE, CSE do not necessarily need EEG moni-
toring as its diagnosis is clinical. This becomes fundamental and
urgent when patients are not waking up after cessation of clinical
seizure in order to rule out NCSE. Particularly important is
continuous monitoring (CEEG) when the patient does not
respond to second-line treatment and therefore is in a RSE. RSE is
almost exclusively non-convulsive and require further treatment
to stop ongoing electrographic seizures that are not clinically
evident. We recommend urgent (within 60 minutes) CEEG in
patients with RSE.
Prognosis of SE
SE is a frequent neurological emergency with overall mortality
rates ranging from 7.6 to 39 %. One of the main predictors of
prognosis of SE is the related underlying aetiology, age, loss of
consciousness, duration, EEG pattern, comorbidities and pop-
ulations. Refractory SE has a mortality of up to 60% with higher
morbidity. Currently, a prognostic score for SE exist, and this is
the Epidemiology based mortality score (EMSE) in status
epilepticus.
Future directions on treatment of SE
Many recent randomized control trials have tried to compare
different treatment regimen but failed to give clear indication to
guide treatment. Despite lack of prospective study supporting a
specific regimen, new data continue to improve understanding of

ANAESTHESIA AND INTENSIVE CARE MEDICINE 19:3 85 Crown Copyright Ó 2018 Published by Elsevier Ltd. All rights reserved.
 NEUROINTENSIVE CARE
management options in SE. We now summarize all recent
advancement in the critical care management of SE.
Brivaracetam (BRV) is the latest approved AED, which exceeds
levetiracetam (LEV)’s binding potential by between 10-fold and
30-fold. A number of factors, such as increased availability as IV
solution, speed of onset of action and increased efficacy, point to
BRV as an alternative second or third line RSE and SRSE
therapy.
Lacosamide is an AED with established efficacy as adjunctive
treatment for partial-onset seizures, recently a review of 136
cases showed that lacosamide given as loading dose of 10e12
mg/kg at an infusion rate of 0.4 mg/kg/min is well tolerated and
will produce levels at least 15 mcg/ml, which showed a suc-
cessful rate of 56% in treating refractory status.
Valnoctamide (VCD) and Sec-butylpropylacetamide (SPD) are
a chiral isomer of valpromide, a central nervous system-active
amide derivative of valproic acid. VCD and SPD are considered
as new treatment medication for SE due to their more potent
anticonvulsant activity and the reproductive safety.
Ketamine (KET) different studies suggest that, when used at
infusion rates greater than 0.9 mg/kg/h may be a useful
adjunctive or potentially earlier treatment for RSE.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 19:3
Allopregnanolone, a metabolite of progesterone, has recently
emerged as a compound with broad-spectrum anticonvulsant
activity in animal model. It is currently tested in phase III, ran-
domized, double-blind, placebo-controlled trial for treatment of
SRSE.
Supplementary/alternative therapies have been investigated
and reported in small numbers, but there are no sufficient data to
guide treatment. These therapies include deep brain stimulation
of thalamic nuclei, surgery in highly selected medically refractory
cases, electroconvulsive therapy, trans cranial magnetic stimu-
lation, ketogenic diet and vagal nerve stimulation. A
FURTHER READING
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report of the guideline Committee of the American Epilepsy Soci-
ety. Epilepsy Curr 2016; 16: 48e61.
Niquet J, Suchomelova L, Thompson K, et al. Acute and long-term
effects of brivaracetam and brivaracetam-diazepam combinations
in an experimental model of status epilepticus. Epilepsia 2017; 58:
1199e207.
€ llner JP. Lacosamide in status epilepticus: systematic
Strzelczyk A, Zo
review of current evidence. Epilepsia 2017; 58: 933e50.
86 Crown Copyright Ó 2018 Published by Elsevier Ltd. All rights reserved.