REFERAT

STATUS EPILEPTICUS

Complied by:

Laura Rahardini
1102014147

Advised by:

dr. Donny H. Hamid Sp.S

Clinical Rotation in Neurology Department of Pasar Rebo

Public Hospital Period of May 21st – June 30th 2018
YARSI UNIVERSITY
Definition

Status epilepticus (SE) is defined as a condition resulting either from the failure of
mechanisms responsible for seizure termination or from the initiation of mechanisms which lead
to abnormally prolonged seizures (after time point T1), and a condition that can have long-term
consequences (after time point T2), including neuronal death, neuronal injury, and alteration of
neuronal networks, depending on the type and duration of seizures, etc. In the case of convulsive
(tonic-clonic) SE, both time points (T1 at 5 min and T2 at 30 min) (Au, Branco, & Tasker, 2017)

The consensus of the International League Against Epilepsy (ILAE) task force on the
classification of SE is that treatment of convulsive seizures should therefore be initiated at around
5 min (Au, Branco, & Tasker, 2017).

In this new definition, there are two time points for SE, T1, and T2. T1, which is when
treatment should be initiated, is 5 min for convulsive SE based on studies that showed a seizure
lasting 5 min is likely to be prolonged. In contrast, T2, which is defined as the time point at which
long-term consequences may occur, continues to be 30 min (Seinfeld, Goodkin, & Shinnar, 2016)

Table 1. Operational dimensions with t1 indicating the time that emergency treatment of SE should be started and t2
indicating the time at which long-term consequences may be expected
Operational dimension 2 Time (t2),
Operational dimension 1 when a seizure may cause long term
Time (t1), when a seizure is consequences (including neuronal
likely to be prolonged leading injury, neuronal death, alteration of neuronal

Type of SE to continuous seizure activity networks and functional deficits)

Tonic–clonic SE 5 min 30 min

Focal SE with impaired 10 min >60 min
consciousness
Absence status epilepticus 10–15 mina Unknown
a
Evidence for the time frame is currently limited and future data may lead to modifications.

(Trinka, Cock, Hesdorffer, & al, 2015)

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Epidemiology

With an incidence of 6 to 41 per 100,000 for convulsive SE, between 108 and 738 cases
would be expected to occur in Northern Ireland each year. Incidence is bimodal, with peaks in
infancy and in the elderly (>60). The overall case fatality rate is between 7.6 and 39%13. The
mortality rate is higher in the elderly at 38% compared to 14% for younger adults (Kinney & Craig,
2015).
Over half of SE patients present with de novo seizures and approximately 10% will have
recurrent episodes of SE. Patients presenting with SE also have a higher likelihood of developing
chronic epilepsy when compared to those who present with a first seizure, that does not fulfill the
criteria for SE (Kinney & Craig, 2015).
SE has been the subject of many large epidemiologic studies. A value of up to 200,000
episodes per year was derived from a prospective, population-based study performed in Richmond,
VA, in which the estimated incidence was 41 per 100,000 population (Seinfeld, Goodkin, &
Shinnar, 2016).
This lower value is in keeping with rates obtained from studies performed in Switzerland,
Germany, and Italy. SE occurs at all ages but is most common at the extremes of life. In the
Richmond study, the incidence was nearly 150 per 100,000 persons in children less than 1 year of
age. The incidence dropped to >25 per 100,000 persons by 5 years of age until it increased again
to >50 per 100,000 persons after 40 years of age. In the Rochester study, the cumulative incidence
was four per 1000 to age 75 and showed greater increase after age 60. Further, SE of longer
duration (more than 2 h) occurred more frequently among infants and the elderly compared with
persons aged 1 to 65 years in that study. In another study, the incidence rate for children, 5 years
was 7.5 per 100,000 and that in the elderly population was 22.3 per 100,000 (Seinfeld, Goodkin,
& Shinnar, 2016).

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Etiology and Patophysiology

In 50% of cases of SE, no cause is identified. Most episodes of SE are secondary to old
structural lesions (e.g. a past stroke), with acute cerebral insults including acute stroke, anoxia,
toxic and metabolic causes and alcohol and drug withdrawal, accounting for a significant
proportion of the remaining cases. Patients with epilepsy can develop SE for various reasons
including reduced serum drug levels from poor adherence with treatment regimens, or the effects
of intercurrent illness and fever (Kinney & Craig, 2015).

Identified aetiology of status epilepticus across major studies (Kinney & Craig, 2015).

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 ACUTE PATHOPHYSIOLOGY - MECHANISMS OF STATUS EPILEPTICUS

The pathophysiology of status epilepticus

SE is an evolving state with changes in neuronal and synaptic chemistry and systemic
physiology resulting in progressive pharmacological refractoriness. For the first 30 minutes
physiological compensation occurs to meet the increased metabolic demands. Heart rate, blood
pressure and serum glucose level are all elevated to minimize the risk of cerebral damage After
30 minutes, decompensation occurs with hypotension, hypoxia, metabolic acidosis, cardiac
arrhythmias and cerebral auto-regulatory failure ensuing, all of which can lead to neuronal
damage. Later complications include rhabdomyolysis, renal failure, pulmonary edema,

increased intracranial pressure, and electrolyte disturbance.

Within seconds of the development of SE alterations occur in protein phosphorylation at

various synapses, ion channel function and neurotransmitter release. Within minutes, receptor
expression changes in favour of excitation as a result of progressive reduction in GABA (γ-
aminobutyric acid) receptors and an increase in AMPA (α-Amino-3- hydroxy-5-methyl-4-
isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors. (Figure 2). By one
hour there is an increase in excitatory neuropeptides. The excess in excitotoxic transmission is

a suggested mechanism for neuronal cell death (Kinney & Craig, 2015).

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Classification

For classification of SE in four axes:

1. Semiology

2. Etiology

3. EEG correlates

4. Age

Axis 1: Semiology

This axis refers to the clinical presentation of SE and is therefore the backbone of this
classification. The two main taxonomic criteria are:
1. The presence or absence of prominent motor symptoms
2. The degree (qualitative or quantitative) of impaired consciousness

Those forms with prominent motor symptoms and impairment of consciousness may be
summarized as convulsive SE as opposed to the nonconvulsive forms of SE (NCSE).

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 Table 2. Axis 1: Classification of status epilepticus (SE)
(A) With prominent motor symptoms
A.1 Convulsive SE (CSE, synonym: tonic–clonic SE)
A.1.a. Generalized convulsive
A.1.b. Focal onset evolving into bilateral convulsive SE
A.1.c. Unknown whether focal or generalized
A.2 Myoclonic SE (prominent epileptic myoclonic jerks)
A.2.a. With coma
A.2.b. Without coma
A.3 Focal motor
A.3.a. Repeated focal motor seizures (Jacksonian)
A.3.b. Epilepsia partialis continua (EPC)
A.3.c. Adversive status
A.3.d. Oculoclonic status
A.3.e. Ictal paresis (i.e., focal inhibitory SE)
A.4 Tonic status
A.5 Hyperkinetic SE
(B) Without prominent motor symptoms (i.e., nonconvulsive SE, NCSE)
B.1 NCSE with coma (including so-called “subtle” SE)
B.2 NCSE without coma
B.2.a. Generalized
B.2.a.a Typical absence status
B.2.a.b Atypical absence status
B.2.a.c Myoclonic absence status
B.2.b. Focal
B.2.b.a Without impairment of consciousness (aura continua, with
autonomic, sensory, visual, olfactory, gustatory, emotional/
psychic/experiential, or auditory symptoms)
B.2.b.b Aphasic status
B.2.b.c With impaired consciousness
B.2.c Unknown whether focal or generalized
B.2.c.a Autonomic SE

(Trinka, Cock, Hesdorffer, & al, 2015)

Axis 2: Etiology

The term “idiopathic” or “genetic” is not applicable to the underlying etiology of SE. In
idiopathic or genetic epilepsy syndromes, the cause of status is not the same as for the disease, but
some metabolic, toxic, or intrinsic factors (like sleep seizures) may trigger SE in these syndromes.
Therefore, the term “idiopathic” or “genetic” is not used. SE in a patient with juvenile myoclonic
epilepsy (which itself is “idiopathic” or “genetic”) can be symptomatic, due to inappropriate
antiepileptic drug (AED) treatment, abrupt drug withdrawal, or drug intoxication.

The term “unknown” or “cryptogenic” is used in its strict original meaning: unknown cause.
The assumption that it is “presumably” symptomatic or genetic is inappropriate (Trinka, Cock,
Hesdorffer, & al, 2015).

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Axis 3: Electroencephalographic correlates

In any type of SE, the ictal EEG patterns is not specific. Epileptiform discharges are
presumed as the sign, but with increasing duration of SE, the EEG changes and rhythmic non-
epileptiform patterns may appear. Similar EEG patterns, such as triphasic waves, can be recorded
in various pathologic conditions, leading to substantial confusion in the literature. Although the
EEG is overloaded with movement and muscle artifact in the convulsive forms of SE and thus of
limited clinical value, it is necessary in the diagnosis of NCSE, as the clinical signs (if any) are
often subtle and nonspecific.

Currently there are no evidence-based EEG criteria for SE. Based on large descriptive series and
consensus panels, this following terminology to describe EEG patterns in SE:

1 Location: generalized (including bilateral synchronous patterns), lateralized, bilateral

independent, multifocal.

2 Name of the pattern: Periodic discharges, rhythmic delta activity or spike-and-wave/sharp-

and-wave plus subtypes.

3 Morphology: sharpness, number of phases (e.g., triphasic morphology), absolute and relative
amplitude, polarity.

4 Time-related features: prevalence, frequency, duration, daily pattern duration and index, onset
(sudden vs. gradual), and dynamics (evolving, fluctuating, or static).

5 Modulation: stimulus-induced vs. spontaneous.

6 Effect of intervention (medication) on EEG.

(Trinka, Cock, Hesdorffer, & al, 2015)

Axis 4: Age

1. Neonatal (0 to 30 days).

2. Infancy (1 month to 2 years).

3. Childhood (> 2 to 12 years).

4. Adolescence and adulthood (> 12 to 59 years).

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 5. Elderly (≥ 60 years).

SE in neonates may difficult to recognize. Some forms of SE are seen as an integral part of the
electroclinical syndrome; others can occur in patients within a certain electroclinical syndrome, or
when trigger factors or precipitating causes are present, such as sleep deprivation, intoxication, or
inappropriate medication. Examples are phenytoin in some forms of progressive myoclonic
epilepsies, carbamazepine in juvenile myoclonic epilepsy, or absence epilepsies (Trinka, Cock,
Hesdorffer, & al, 2015).

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Clinical Diagnosis and Differential Diagnosis

Distinguishing seizure from psychogenic non-epileptic attack

Clinical feature Suggestive of Epileptic Suggestive of Psychogenic non-epileptic attacks.
Seizures (Status Epilepticus) (pseudostatus)
Onset Sudden onset. May have focal Gradual onset potentially lasting minutes, can have
seizure activity at onset. a lead in of panic symptoms (which may not be
recalled by the patient). At times can start with
sudden onset.
Motor state Tonic, then evolving into Whole body stiffening, with some voluntary
clonic synchronous movements at times, can be flaccid largely during
movements. the ictus (ictal atonia), back arching, side to side
head movements, undulating pelvic thrusting.
Evolution A definite tonic phase, then Varying, tonic/clonic movements. Not following
clonic phase. As progresses the specific sequence, with pauses during the ictus.
clonic movements become less Movements usually asynchronous. Subtle eye
pronounced, with perhaps movements may occur.
nystagmus or subtle twitching
as the only manifestation.
Vocalisation At onset, may have loud May occur in the middle of a seizure, crying and
guttural cry as air is forced out shouting are possible.
past a tonic larynx.
Eyes Eye closure is not typical. Eyes are commonly forcibly closed. (This is not
Eyes maybe deviated. Pupils always the case). Typically could be deviated away
tend to be unresponsive. from the observer. Pupils are normal.
Tongue Can have deep lateral tongue Typically superficial frontal tip of the tongue
biting. location.
Cyanosis Present Absent
Responsive? None. No withdrawal from Variable withdrawal from painful stimulus. Limb
painful stimulus. movements may change with mild restraint.
Consistency Usually stereotyped seizure Variable nature to events.
episodes.
Recovery Delayed recovery after event, Prompt recovery. Non-organic amnesia observed.
with amnesia.

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 Nocturnal Can happen. Not recognised. Events can occur from apparent
seizures sleep. The only way to be sure is to have EEG
confirmed sleep pattern preceding the event.
Ictal Not a distinguishing factor Not a distinguishing factor
incontinence
Injuries Common Common (fractures, head injuries, burns all
reported)

Pseudostatus epilepticus (prolonged non-epileptic attacks) should be considered in all

patients presenting with apparent SE. Differentiating between the two on clinical grounds alone
can be difficult, even for experienced practitioners. Given the limited access to EEG, when the
clinical diagnosis is not established beyond reasonable doubt, it is best to err on the side of caution
and treat as SE. The importance of making an accurate diagnosis is all too obvious, to prevent
medicalising a psychological condition, to prevent iatrogenic morbidity from anticonvulsant
medications, and to reduce morbidity and mortality associated with intubation and ICU stay
(Kinney & Craig, 2015).

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Treatment and Management

The management of any patient presenting with an episode of SE begins with the ABCs
(airway breathing and circulation). If available, the patient is often placed on a cardiac monitor
and pulse oximeter with the application of supplemental oxygen if indicated. (Seinfeld, Goodkin,
& Shinnar, 2016)

Drug Administration route

Rectal Buccal (B)/Intranasal(N) Intraosseous Intravenous

(IO)/Intramuscular (IM)

Diazepam Bolus Bolus Bolus

0.2---0.5 IO: 0.25 mg/kg × 2 0.15---0.2 mg/kg × 2
mg/kg/dose15,17
doses6 doses15,17
0.5 mg/kg/dose5,6 0.2---0.3 mg/kg × 2
doses12

0.5 mg/kg × 2 doses7 0.25 mg/kg × 2 doses6

0.3 mg/kg × 2 dose7

0.5 mg/kg10
Maximum dose Maximum dose
10 mg6; 20 mg15,17 <5 year, 5 mg7; ≥5 year,
10 mg7; 10 mg10,12,15,17

Lorazepam Bolus Bolus Bolus

0.1 mg/kg × 2 doses7 B: 0.1 mg/kg × 2 0.1 mg/kg × 2

doses7,10 doses5,7,10,12,15,17
Maximum dose Maximum dose Maximum dose
4 mg7 B: 2.5 mg10; 4 mg7 4 mg5,7,10,12,15,17

Midazolam Bolus Bolus Bolus

B: 5---10 mg17 IO: 0.15 mg/kg × 2 0.15 mg/kg × 2 doses6
doses6
IN: 0.2 mg/kg7 IM: 0.15 mg/kg × 2 0.15 to 0.2 mg/kg × 2
doses6 doses12

IM: 0.2 mg/kg × 2 0.2 mg/kg × 2 doses10

doses7,10
Maximum dose Maximum dose
IN: 5 mg/nostril7 IM: 5 mg10; 13---40 kg,
5 mg15; >40 kg, 10 mg15;

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 10 mg17

Fosphenytoin Bolus Bolus

(PE, phenytoin
equivalents)
IM: 20 mg PE/kg7 20 mg PE/kg7,12,15
Maximum dose Maximum dose
IM: 1000 mg PE7 1000 mg PE7; 1500 mg
PE15

Phenytoin Bolus Bolus

IO: 20 mg/kg6 15---20 mg/kg16,17
18 mg/kg5
18---20 mg/kg10
20 mg/kg6,7,12
Maximum dose Maximum dose
IO: 1000 mg7 1000 mg11,16

Phenobarbital Bolus
10---20 mg/kg16
15 mg/kg/dose15,17
15---20 mg/kg10
20 mg/kg6,12
Maximum dose
1000 mg10

Drug Administration route

Rectal Buccal (B)/Intranasal (N)Intraosseous Intravenous (IO)/Intramuscular (IM)

Valproic acid Bolus

20 mg/kg12
25---45 mg/kg16
30---45 mg/kg10 40
mg/kg15,17
Maximum dose 1500
mg10; 3000 mg15,17

Levetiracetam Bolus
20 mg/kg16
20---30 mg/kg12 60
mg/kg15,17 Maximum
dose 4500 mg15,17

(Au, Branco, & Tasker, 2017)

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 In order to minimise these and to reduce variability in practice, SE should be managed with
a protocol which provides details on appropriate doses of medications to be given in a timely
manner.

* Pay attention to prehospital doses of benzodiazepines. If maximum dose of diazepam (20mg IV/PR)
already given then go directly to phenytoin. If they have receive10mg diazepam, it is reasonable to give 4mg
lorazepam but to omit the second bolus at T15 minutes, but otherwise advance through the protocol as normal.

A suggested protocol for management of first and second stage of SE.

(Kinney & Craig, 2015)

They show that early use of benzodiazepines is important for controlling SE. They work by
enhancing the inhibitory GABAergic system, and at higher concentrations limit sustained
repetitive neuronal firing. Lorazepam, diazepam and midazolam are the most frequently used
(Kinney & Craig, 2015).

Diazepam achieves early high brain concentrations and therefore has a very fast onset of
action. While diazepam and lorazepam are equivalent at achieving seizure control, lorazepam is
the drug of choice in early status due to its favorable pharmacokinetic profile, with a half- life of

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12-24 hours. Intravenous benzodiazepines have significant side effects including respiratory
depression (3-10%), hypotension (<2%), and impaired consciousness (20-60%) (Kinney & Craig,
2015).
Second line therapies include phenytoin/fos-phenytoin, phenobarbital, valproate,
levetiracetam and lacosamide. Phenytoin is the most commonly used second line drug in the
United Kingdom. It should be given at a dose of 20mg/kg infused at a rate of 50mg/kg. Slower
infusion rates are used if cardiac arrhythmia or hypotension occurs. A loading dose can also be
given if the patient is taking phenytoin.

Second line management of status epilepticus.

Drug Mean Dose ADRs Mode of action
Efficacy
(%)
Phenobarbitone 73.6% 20mg/kg IV up to Respiratory depression, GABA potentiation
60mg/ min hypotension, severe
sedation, tolerance and
the potential for drug
interactions
Phenytoin 50.2% 20mg/kg at 50mg/ cardio-respiratory risks Sodium channel
minute (25mg/minute if (cardiac arrhythmia, modulation
cardiovascular hypotension, reduced
instability or elderly) cardiac output, the
‘purple-glove’
syndrome
Valproate 75.7% 30-60mg/kg IV up to Hyperammonaemia. Multiple. Sodium
3mg/kg/min. Probably There is a risk of hepatic channel modulation,
safe at 6 mg/kg/min. and pancreatic toxicity, GABA
and valproate potentiation,
encephalopathy. bleeding glutamate/NMDA
tendency due inhibition.
to its effects on platelets
and platelet function
Levetiracetam 68.5% 1000 and 3000 mg in Free of significant Synaptic vesicle
young adults, or 20 mg/ adverse-effect protein 2A
kg (Infuse at 500mg/

15
 minute)

Lacosamide not 200-400mg bolus over Bradycardia, PR interval Sodium channel

available 5 minutes prolongation modulation

(Kinney & Craig, 2015)

Third line agents for status epilepticus

Loading Maintenance ADRs Mode of T1/2 after
Drug dose dose action prolonged
administration
Midazolam 0.1- 0.05-0.4mg/kg/hr Hypotension, GABAa 6-50h
(midazolam 0.3mg/kg at tachyphylaxis agonist
paper in 4mg/ minute , increasing
neurology) bolus does needed
with time.
Propofol 2mg/kg 5-10mg/kg/hr Propofol GABAa 1-2h
bolus infusion agonist
syndrome
(PRIS)

Hypotension.
Pentobarbital 10-20mg/kg 0.5-1mg/kg/hr Accumulation, GABAa 15-22h
bolus at increasing to 1- hypotension, agonist
25mg/min 3mg/kg/hr if and
required immunosuppre
Thiopenone 100-250mg Infusion of 2- ssion. GABAa 14-36h
bolus over 5mg/kg/hr agonist
20 secs. 5-
mg boluses
every 2-3
minutes
until seizure
control.
(Kinney & Craig, 2015)

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 Third line agents use anaesthetic agents; propofol, midazolam, thiopental or phenobarbital.
This line used for refractory SE state, when first and second line therapies have failed, usually 30
minutes into the SE episode and usually used in intensive care unit. Decisions such as treatment
duration and target of treatment (either clinical seizure suppression or EEG guided, such as
suppression-burst suppression) are thus on an individual patient basis. Usually the patient will be
anesthetized for 12- 24 hours and then the agents weaned slowly over a period of hours. If after
the first wean there are further clinical or electrographic seizures they will require further
anesthesia. This situation is then termed super refractory SE (Kinney & Craig, 2015).

The first steps in the management of a patient in Generalized Convulsive Status Epilepticus
(GCSE) are to attend to any acute cardiorespiratory problems or hyperthermia, perform a brief
medical and neurologic examination, establish venous access, and send samples for laboratory
studies to identify metabolic abnormalities. Anticonvulsant therapy should then begin without
delay. The treatment of nonconvulsive status epilepticus is thought to be less urgent than GCSE,
since the ongoing seizures are not accompanied by the severe metabolic disturbances seen with
GCSE. However, evidence suggests that nonconvulsive status epilepticus, especially that caused
by ongoing, focal seizure activity, is associated with cellular injury in the region of the seizure
focus; therefore this condition should be treated as promptly as possible using the general approach
described for GCSE (Lowenstein, 2013).

The treatment of nonconvulsive status epilepticus is thought to be less urgent than GCSE,
since the ongoing seizures are not accompanied by the severe metabolic disturbances seen with
GCSE. However, evidence suggests that nonconvulsive status epilepticus, especially that caused
by ongoing, focal seizure activity, is associated with cellular injury in the region of the seizure
focus; therefore this condition should be treated as promptly as possible using the general approach
described for GCSE (Lowenstein, 2013).

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 (Lowenstein, 2013)

An electroencephalogram (EEG) is not immediately required for treatment, and the urgency
of this test depends on the patient’s clinical presentation and response to treatment. If a patient has
continued abnormal movements or is not returning to baseline after emergent treatment then an
EEG must be performed to evaluate for persistence of the SE (Seinfeld, Goodkin, & Shinnar,
2016).
Other indications for emergent EEG in patients prone to or being treated for SE includes
the use of neuromuscular blockade and high-dose suppressive therapy for the treatment of
refractory SE (Seinfeld, Goodkin, & Shinnar, 2016).

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 References

Au, C. C., Branco, R. G., & Tasker, R. C. (2017). Management Protocols for Status Epilepticus
in The Pediatric Emergency Room: Systematic Review Article. Journal de Pediatria, 84-
94.
Kinney, M., & Craig, J. (2015). Grand Rounds: An Update on Convulsive Status Epilepticus.
Ulser Medical Journal, 88-93.
Lowenstein, D. H. (2013). Status Epilepticus. In S. L. Hauser, Harrison's Neurology in Clinical
Medicine (pp. 251-253). New York: McGraw-Hill Education .
Seinfeld, S., Goodkin, H. P., & Shinnar, S. (2016). Status Epilepticus. Cold Spring Harb Med.
Trinka, E., Cock, H., Hesdorffer, D., & al, e. (2015). A Definition and Classification of Status
Epilepticus - Report of the ILAE Task Force on Classification of Status Epilepticus. Cold
Spring Harb Perspective Medicine.

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