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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. 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 epilepticusand 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 2867% 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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Page 1: Status Epilepticus - WordPress.com · REVIEW ARTICLE – STATUS EPILEPTICUS CMI 13:2 26 April 2015 Status epilepticus is defined as “a continuous, generalized, convulsive seizure

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 period1. 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 seizures23

.

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

follows5.

Impending status epilepticus

“Impending status epilepticus”, is defined as

continuous or intermittent seizures lasting more than

5 minutes without full recovery of consciousness

between seizures5.

Established status epilepticus

“Established status epilepticus” is defined clinical or

electrographic seizures lasting more than 30 minutes

without full recovery of consciousness between

seizures5.

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 cases9.

Classification Status epilepticus can be

classified based on the presence

or absence of convulsions, into

Status Epilepticus

Page 2: Status Epilepticus - WordPress.com · REVIEW ARTICLE – STATUS EPILEPTICUS CMI 13:2 26 April 2015 Status epilepticus is defined as “a continuous, generalized, convulsive seizure

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

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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

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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.

Abbreviations: IV, Intravenous; ECG, Electrocardiogram; SpO2, Pulse oximeter oxygen saturation; CSF, Cerebrospinal

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

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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

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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,

50,

51,

52

.

*********************************************************************************

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Laughter - The Best Medicine What Doctors Say, and What They're Really Thinking Well, well!...., what have we here...? He has no idea and is hoping you'll give him a clue. Let's see how it develops. Maybe in a few days I can pick up something curable. If it doesn't clear up in a week, give me a call. I don't know what it is. Maybe it will go away by itself. Well, we're not feeling so well today, are we...?" I'm stalling for time. I have no idea what you have. There is a lot of that going around." This is the third one this week. I'd better read up about it. I'd like to run some more tests." I can't figure out what's wrong. Maybe the kid in the lab can solve this one.