REVIEW ARTICLE – STATUS EPILEPTICUS CMI 13:2 26 April 2015 Status epilepticus is defined as “a continuous, generalized, convulsive seizure lasting more than 5 minutes, or two or more seizures during which the patient does not return to baseline consciousness A.T. Prabhakar, MBBS, MD, DM. Dept. of Neurological sciences, Christian Medical College, Vellore Abstract Status epilepticus is defined as a continuous, generalized, convulsive seizure lasting more than 5 minutes, or two or more seizures during which the patient does not return to baseline consciousness. It is a neurological emergency and early initiation of intravenous anticonvulsants is key to a successful outcome. Lorazepam and diazepam are the drugs of choice for initial administration. Priority must be given to secure the airway and maintain blood pressure. If seizures continue despite the initial therapy, Intensive care unit admission may be required for monitoring and therapy. Corresponding Author: Dr. A.T.Prabhakar Email: [email protected]Introduction Status epilepticus is a common neurological emergency characterised by continuous seizure activity or recurrent seizures without recovery between attacks. It is associated with high mortality and morbidity and it requires emergent, targeted therapy. Definition Status epilepticus was defined by the International League Against Epilepsy (ILAE) more than 20 years ago as a single epileptic seizure of >30 minutes duration or a series of epileptic seizures during which function is not regained between ictal events in a 30 minute period 1 . Since it has been established that generalized tonic-clonic seizures do not last longer than 2 minutes except when it evolves into status epilepticus, and irreversible neuronal injury may start after 20 to 30 minutes of generalized convulsive status epilepticus, it has been suggested that aggressive therapy for status epilepticus be initiated after 5 minutes of generalized tonic-clonic seizures 23 . The new proposed operational definition for status epilepticus is defined as “a continuous, generalized, convulsive seizure lasting more than 5 minutes, or two or more seizures during which the patient does not return to baseline consciousness” 4 . The terms “impending status epilepticus” and “established status epilepticus” are useful to guide management and can be defined as follows 5 . Impending status epilepticus “Impending status epilepticus”, is defined as continuous or intermittent seizures lasting more than 5 minutes without full recovery of consciousness between seizures 5 . Established status epilepticus “Established status epilepticus” is defined clinical or electrographic seizures lasting more than 30 minutes without full recovery of consciousness between seizures 5 . Etiology The main causes of status epilepticus are low blood concentrations of antiepileptic drugs in patients with chronic epilepsy (34%), metabolic causes (including hypoxia, electrolyte imbalance and alcohol and drug withdrawal ) (30%) remote symptomatic causes (24%), cerebrovascular accidents (22%) 6 . Additionally in studies from India central nervous system infections contribute to 28–67% of the aetiologies 7,8 . No clear aetiology can be identified in 20% of cases 9 . Classification Status epilepticus can be classified based on the presence or absence of convulsions, into Status Epilepticus
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REVIEW ARTICLE – STATUS EPILEPTICUS
CMI 13:2 26 April 2015
Status epilepticus is defined as
“a continuous, generalized,
convulsive seizure lasting more
than 5 minutes, or two or more
seizures during which the
patient does not return to
baseline consciousness
A.T. Prabhakar, MBBS, MD, DM. Dept. of Neurological sciences, Christian Medical College, Vellore
Abstract Status epilepticus is defined as a continuous, generalized, convulsive seizure lasting more than 5
minutes, or two or more seizures during which the patient does not return to baseline consciousness. It
is a neurological emergency and early initiation of intravenous anticonvulsants is key to a successful
outcome. Lorazepam and diazepam are the drugs of choice for initial administration. Priority must be
given to secure the airway and maintain blood pressure. If seizures continue despite the initial therapy,
Intensive care unit admission may be required for monitoring and therapy.
hypoxia, electrolyte imbalance and alcohol and drug
withdrawal ) (30%) remote symptomatic causes
(24%), cerebrovascular accidents (22%) 6.
Additionally in studies from India central nervous
system infections contribute to 28–67% of the
aetiologies 7,8
. No clear
aetiology can be identified in
20% of cases9.
Classification Status epilepticus can be
classified based on the presence
or absence of convulsions, into
Status Epilepticus
REVIEW ARTICLE – STATUS EPILEPTICUS
CMI 13:2 27 April 2015
convulsive SE (CSE) and nonconvulsive SE (NCSE).
Nonconvulsive status epilepticus is defined as a
mental status changes from baseline of at least 30 to
60 minutes duration associated with continuous or
near continuous ictal discharges on EEG10
. Electro-
clinically status epilepticus can be classified as focal
or generalized; and based on the seizure type it can
be further classified (Fig.1).
Treatment In status epilepticus, time is brain, and early
initiation of intravenous anticonvulsants is key to
a successful outcome. Experimental data shows that
there is time dependent loss of synaptic GABAA
receptor followed by movement of N-methyl-D-
aspartate (NMDA) receptors to the synapse5,11
.
Hence, starting therapy early can avoid the time
dependent development of pharmacoresistance to
benzodiazepines and other anticonvulsants. Early
therapy can be initiated at home by the care givers.
In the emergency room, along with IV administration
of anticonvulsants, priority must be given to secure
the airway and maintain blood pressure. If seizures
continue despite the initial therapy Intensive care
unit admission may be required for further
monitoring and therapy. In patients presenting with
status epilepticus it is useful to plan therapy in a
series of progressive stages (Figure: 2).
Out of hospital therapy and emergency room
management
Benzodiazepines are the drug of choice for out-of-
hospital treatment. Since IV access may not be
possible in the home setting, other modes of
administration such as rectal, buccal and nasal are
advised. Rectal diazepam at 0.2 to 0.5 mg per
kilogram of body weight has been shown to be
effective in home initiated therapy in children12
.
Buccal administration of midazolam has been found
to be effective and may be more socially acceptable
than rectal administration in the out of hospital
setting 13
. For administration of buccal midazolam, 2
mL (10 mg) is to be drawn into a 2 mL syringe and
Convulsive status Epilepticus Non-convulsive status Epilepticus
Generalized convulsive status
epilepticus
Primary generalized convulsive
SE
Secondarily generalized
convulsive SE (focal onset)
Focal motor status epilepticus
( epilepsia partialis continua)
Myoclonic
Tonic
Clonic
Atonic
Typical ("classic") absence
status epilepticus
Atypical absence status
epilepticus
Primary generalized NCSE
Focal onset with generalized NCSE
Complex partial status epilepticus
Abbreviations: SE, Status epilepticus; NCSE: non-convulsive status epilepticus
Fig. 1: Classification of Status Epilepticus
Status Epilepticus
REVIEW ARTICLE – STATUS EPILEPTICUS
CMI 13:2 28 April 2015
squirted around the buccal mucosa
after parting the lips, but without
trying to open the jaws13
. Intranasal
midazolam sprays are available
commercially, and can safely and
effectively administered at home14
.
Impending status epilepticus
Benzodiapepines are the first line
therapy in impending status
epilepticus. Lorazepam is the drug
of choice for intravenous (IV) administration.
Diazepam is also effective – it has a quicker onset of
action but shorter duration of effect. Dosages:
Lorazepam- up to 0·1 mg/kg (adults- 4 mg, repeat
2mg after 5-10 mins if necessary). Diazepam - up to
0·25–0·4 mg/kg (5mg, repeat 5mg after 5-10 mins in
adults). Midazolam is the drug of choice for
intramuscular (IM) administration15,16
.
Established Convulsive Status Epilepticus
(30–60 Minutes)
When benzodiazepines fail to terminate the status
epilepticus, IV phenytoin / fosphenytoin,
phenobarbitone or sodium valproate is used. ,17,16,18,5
Fosphenytoin is preferred to phenytoin because of its
water solubility and neutral pH, thereby allowing
more rapid administration with less adverse effects
such as venous irritation18
. Phenytoin is
administered at a dose of 18 to 20 mg/kg intraven-
ously over 20 minutes (with a maximum infusion
rate of 50 mg/min). In children when IV access is
not possible, intraosseous route can be used.19
Maintenance dose: 5-7 mg/kg/day. Phenobarbital is
often considered when seizures still continue even
after loading with hydantoins20,
21
It can be given as a
bolus of 20 mg/kg followed by another 5-10 mg/ kg
if needed20
. Intravenous sodium valproate is as
effective as phenytoin and can be used as a first line
agent when benzodiazepines fail8,22
. Valporate can
be loaded intravenously at a dose of 20 to
40 mg/kg infused a rate of 5 mg/kg per minute
without adverse effects on blood pressure or heart
rate23,24
. Levetiracetam and lacosamide can be used
as adjunctive agents in patients with focal or
nonconvulsive status epilepticus.
Refractory Status Epilepticus
(> 60 Minutes)
Refractory status epilepticus is
defined as the failure of adequate
doses of two intravenous drugs to
stop seizures5. Induction of
pharmacological coma and adding
on AEDs is the strategy that is
followed. Intensive care unit
admission is advised with
endotrachal intubation and
mechanical ventilation when required.
Midazolam: Midazolam when used as an infusion
can be used to treat refractory status epilepticus. It is
initiated with a loading dose of 0.2 mg/kg bolus
given at a rate of 2 mg/min. Additional boluses
should be given every five minutes until seizures stop
(up to a maximum of 2 mg/kg), followed by a
continuous infusion of 0.1 mg/kg/hour, which can be
titrated upwards to as high as 5 mg/kg/hour25,26
. If
seizures are not controlled within 45 to 60 minutes of
optimal dose of midazolam therapy, alternate strategy
for pharmacological coma must be used.
Propofol : Propofol is a highly lipophilic phenol
derivative and GABA-A agonist with anticonvulsant
properties.27,
26,28
. Propofol infusion is initiated with a
1 to 2 mg/kg loading dose, which can be repeated if
the seizures do not stop. The infusion rate can be
titrated over the next 30 to 60 minutes to maintain a
seizure-free state. Continuous EEG monitoring may
be used and the dose of the infusion may be titrated
to achieve burst suppression pattern. Infusion rates
of up to 10 to 12 mg/kg/hour may be required but
should not be maintained for more than 48 hours
because of the risk of the propofol infusion
syndrome27
[82]. The propofol infusion syndrome
consists of rhabdomyolysis, severe metabolic
acidosis, and cardiac and renal dysfunction29
. Acid-
base imbalance, serum creatine phosphokinase, and
serum triglycerides are markers of propofol infusion
syndrome and must be monitored while patient is on
propofol. Treatment with propofol should be
considered unsuccessful if it fails to terminate seizure
activity within 45 to 60 minutes of an adequately
Early initiation of
intravenous
anticonvulsants is key to
a successful outcome.
I.V. Lorazepam is the
drug of choice.
Start Phenytoin if
seizures continue.
Continued on page 30
CMI 13:2 April 2015 29
REVIEW ARTICLE – STATUS EPILEPTICUS
Start anti-convulsant therapy IV Lorazepam up to 0·1 mg/kg (4 mg, repeat 2mg after 5-10 mins in adults) or IV Diazepam up to 0·25–0·4 mg/kg (5mg, repeat 5mg after 5-10 mins in adults)
Seizures continuing?
Intravenous phenytoin 15-18 mg/kg at 50 mg per min or Intravenous valproic acid 20- 40 mg/kg at 5 mg per kg per min
Seizures continuing ?
Additional intravenous Phenytoin 5-10 mg/kg
Admit in ICU, Will need to be treated as refractory status epilepticus (next box) Endotracheal intubation may be required for securing airway.
Seizures continuing?
Pharmacologic Coma Midazolam loading 0·2 mg/kg fol-lowed by infusion @ 0·1–2 mg/kg/h
or Propofol loading 2–5 mg/kg, infusion @ 2–10 mg/kg/h
or Pentobarbital loading up to10 mg/kg followed by infusion @ 0·5–2 mg/kg/h
or Thiopental loading with 3 to 5 mg/kg bolus, followed by infusion @ 3 to 5 mg/kg/hr.
Ketamine bolus 1·5 mg/kg followed by infusion @ 0·01–0·05 mg/kg/h (contraindicated in raised intracranial pressure) Inhalational General Anaesthesia
Pharmacologic Coma Manage-ment - Titrate infusions to either seizure suppression or burst suppression based on continuous EEG monitor-ing. - Continue pharmacologic coma for 24-48 hours. - Add ‘Add-on AEDs’ (Box 1) be-fore weaning off infusions.
Seizures stop
Take focused history and ex-amination Investigations: Random blood glucose, arterial blood gas, elec-trolytes, urea, creatinine, liver function test, cal-cium, magnesium, phosphorous, toxin screening, Neuroimaging (CT/MRI), EEG and CSF if CNS infection is sus-pected.
Seizures stop
Refractory status epilepticus
Out of hospital therapy
Diazepam Rectal 2-5 years 0.5mg/kg, 6-11
years 0.3mg/kg, ≥12 years 0.2g/kg (max 20mg)
Buccal midazolam : midazolam (0.5mg/kg)
upto Max 10 mg squirted around the buccal mu-
cosa after parting the lips, but without trying to
open the jaws
Intranasal Midazolam (0.2mg/kg)
Status Epilepticus
●≥5 minutes of continuous seizures, ●≥2 discrete seizures with incomplete recovery of consciousness between the events
Initial Assessment - Secure airway, - Oxygen supplementation - IV access with 2 large bore canulas – start anti-convulsant immediately - Monitor respiration, blood pressure, monitor SpO2. - Administer Inj. Thiamine 100 mg IV, followed by 50 mL of 50% dextrose if random blood glu-cose testing is not available.
fluid; CNS, Central nervous system; CT, Computed tomography; MRI, Magnetic resonance imaging; EEG, Electroen-
cephalogram; AED, Anti epileptic drug ; IVIG, Intravenous immunoglobulin.
Figure 2: Management of Status Epilepticus– Flowchart
REVIEW ARTICLE – STATUS EPILEPTICUS
CM1 13:2 30 April 2015
Box 1. Add-On AEDs Levetiracetam 20-60 mg/kg IV Valproate Sodium 20-40 mg/kg IV. Phenobarbital 20-40 mg/kg Topiramate 10 mg/kg/d, orally for 2 consecutive days, followed by maintenance doses of 5 mg/kg/d. Lacosamide 200 mg IV
dosed infusion. In this case, switching to barbiturate
infusion or adding a benzodiazepine should be
considered.
Barbiturates (thiopentone, pentobarbital):
Thiopentone can be administered as a 3 to 5 mg/kg
bolus, followed by additional boluses of 1 to 2 mg/kg
every 3 to 5 minutes until seizures are controlled and
there is burst suppression pattern on EEG. The
infusion should be continued at a rate of 3 to 5
mg/kg/h30,31
. Pentobarbital is administered as a 10
mg/kg bolus, followed by a continuous infusion at a
rate of 0.5 to 1.0 mg/kg/h. Prolonged barbiturate
infusions are associated with hypotension, cardiac
depression and possible immune dysfunction32
. If
seizures are terminated with barbiturate infusion, it
must be continued for at least 24- 48 hours before
being tapered and stopped. Continuous EEG
monitoring is useful to detect burst suppression
pattern and electrographic control. Before tapering
the infusion, adding on additional AEDs and
ensuring high therapeutic concentrations of
previously loaded AEDs should be considered.
Inhalational Anaesthetic Agents: Inhalational
anaesthetic agents such as isoflurane and desflurane
can be used for refractory status epilepticus. End
tidal concentrations of 1.2–5% can be used to
achieved seizure control and a burst suppression
pattern on EG33,34,35
. Anaesthesia should be stopped
once a day, and if seizures recur, resume treatment
and continue for another 24 hours.
Newer Antiepileptic Drugs
Newer AEDs have less pharmacokinetic interactions
and have a better safety profile. There is growing
evidence that they can be used as add- on AEDs after
the use of benzodiazepines in status epilepticus.36,37
Levetiracetam: Levetiracetam is a newer AED
that acts via the synaptic vesicular protein 2A
(SV2A). It has less drug interactions and can be
safely used in the elderly and patients with multiple
medical co-morbidities ,37,38,36
. In a study comparing
the efficacy of phenytoin, valproate and
levetiracetam as second-line drugs in status
epilepticus, levetiracetam was found to be less
effective than valproate to control status epilepticus
when used after the administration of
benzodiazepine39
Levetiracetam can be given as an
IV loading dose of 20 – 60 mg/kg bolus and
continued in divided doses as oral or IV38
.
Lacosamide: Lacosamide is a new anticonvulsant
drug that acts by slow inactivation of the voltage-
gated sodium channel, and is available as infusion
and can be used in refractory status epilepticus40,41,42
.
It can be loaded as an IV bolus of 200 mg and
continued at 400 – 600 mg per day.
Topiramate: Topiramate is an AED with multiple
mechanisms of action. It blocks voltage-dependent
sodium channels, enhances the activity of GABA at a
non-benzodiazepine binding site on GABAA
receptors, and antagonizes NMDA–glutamate
receptors. It is also a weak inhibitor carbonic
anhydrase. Topiramate can be used as an adjunctive
therapy in refractory status epilepticus43,44
. Since IV
topiramate is not available the tablets can be crushed
and administered through the nasogastric tube. A
loading dose of 10 mg /kg over 2 days followed by
a maintenance dose of 5 mg per kg can used44
.
Ketamine: Ketamine is an NMDA receptor
antagonist and has been proved to be effective in
proved useful in refractory status epilepticus45,46
. It is
neuroprotective and does not produce cardiac
depression or hypotension. Ketamine can raise
intracranial pressure and hence it is contraindicated
in patients with raised intracranial pressure. Despite
its adverse effects ketamine is a promising drug to
be considered as an agent of last resort5
Tapering off continuous infusions
In patients treated with pharmacological coma,
continuous infusions must be continued for 12 to 24
hours after control of seizures and must be gradually
... Continued from page 28
REVIEW ARTICLE – STATUS EPILEPTICUS
CM1 13:2 31 April 2015
tapered over the next 24 hours. If seizures recur
while tapering, the infusion must be continued for
longer and must be tapered more slowly the next
time. Prior to re-initiating a taper, adding on another
maintenance AED and ensuing high therapeutic
levels of other maintenance AEDs must be
considered.
Maintenance Therapy: Along with emergency
treatment, attention must be given to maintenance
AED therapy to prevent recurrence of seizures. In
patients with known epilepsy, their usual AEDs must
be continued and dose adjustments made by
monitoring AED levels. In patients presenting with
new onset of status epilepticus, the AEDs, phenytoin
or valproic acid, which are given as an initial IV
loading must be continued as oral maintenance
therapy. In refractory status epilepticus controlled
with pharmacological coma, it is advisable to add on
additional AEDs as maintenance therapy prior to
tapering of the infusions31
.
Role of Continuous EEG monitoring
Electrographic seizures may persist after treatment
convulsive status epilepticus and may present
clinically as impaired level of consciousness. Hence
continuous EEG monitoring (cEEG) is useful in
monitoring therapy in patients with convulsive status
epilepticus not awake following treatment and also in
patients with non-convulsive status epilepticus47
.
cEEG monitoring is also useful in the treatment of
refractory status epilepticus with pharmacological
coma. It is used assess if the target of burst
suppression is achieved on induction of
pharmacological coma; and to monitor for relapse of
seizures during the tapering of infusions.
Emerging Therapies Immunomodulation with steroids and IVIG have
been tried in cases thought to have an inflammatory
or autoimmune etiology. The improved
understanding of the role of inflammation in
epileptogenesis and the increasing spectrum of
autoimmune encephalitis is the rationale for the use
of immunomodulation in refractory status
epilepticus48
. Non-pharmacological treatments such
as resective surgery, ketogenic diet, vagal nerve
stimulation, hypothermia and electroconvulsive
therapy and transcranial magnetic stimulation have
been used in cases of refractory status epilepticus48,49,
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