STATUS EPILEPTICUS

Presented by: Vivi Kristiani, MD

February, 2017
 Outline

Preface
Clinical Recognition
Neuroimaging and Laboratory Tests
First Steps in Management
Deterioration: Causes and Management
Outcome
Conclusion
 Preface

Status epilepticus -> neurologic emergency that not

only needs rapid pharmacologic intervention but
also is more properly treated when its cause is
identified.
A critical juncture is the time of successful
administration of antiepileptic agents and duration of
status epilepticus less than 10 hours predicts a better
outcome.
The cause of tonic-clonic status epilepticus is diverse
This presentation mainly concentrates on management
of refractory tonic-clonic status epilepticus.
 Clinical Recognition (1)
continuous seizures of more than 5-minute
duration or two or more discrete seizures without
full recovery of consciousness
A single seizure with initial full recovery of consciousness
Typical tonic-clonic status epilepticus, the fits begin to
overlap one another
Extreme case, some body parts may be in a resolving clonic
stage and others in a new tonic spell as status epilepticus
progresses. The tonic phase seems to become
progressively shorter or may even disappear. Additionally,
the clonic phase may lose its characteristics and become
brief and less intense, even dispersing into multiple
twitches.
 Clinical Recognition (2)

Most of the time, a tonic-clonic seizure starts with a tonic contraction

lasting 15-30 seconds, and continues with several minutes of
repeated muscle contractions, loss of pupil. lary light response and
corneal reflexes, and emergence of bilateral Babinski signs,
Profuse sweating, tachycardia, increased bronchial secretion, and
marked hypertension (as the result of a sympathetic outpouring).
Before the next seizure begins, patients cannot be roused. The
interval is often marked by labored breathing with frothing at the
mouth.
Tonic-clonic status epilepticus can lead to remote effects involving
vital organ and the most pertinent consequence These
manifestations of status epilepticus can be brief and transient, but
also are potentially concerning (e.g., pulmonary edema or
aspiration).
 Neuroimaging and Laboratory
Tests (2)

The most staking abnormalities have been found in the

hippocampus and reflect the clinically observed memory deficits in
some patients. The hipocampus may swell &have complete cell loss
In the CA1 region.
Chest radiography may give: an early indication of gastric
aspiration; neurogenic pulmonary edema ; Fractures of long bones
and vertebral bodies (expected in elderly patients); Bilateral or
unilateral posterior fracture-dislocation of the humeral head
(characteristic fracture), but rib fractures and vertebral body
compression fractures should be considered when pain suggests
those regions.
Radiographs are indicated in patients with localized pain.
Sometimes, MRI of the shoulder is needed to document a major tear
or fracture. Pain in the shoulder should not be attributed simply to
muscle soreness following Seizures.
 Neuroimaging and Laboratory
Tests (3)
Conventional EEG documents status epilepticus (more
important in patients who need second-line drugs for
treatment).
In convulsive status epilepticus a five-phase evolution
has been proposed. The initial stage shows single
epileptic activity followed by high-voltage slow
activity. The EEG shows an episode of silence in the
postictal phase. The next stages are merging of
electrographic seizures accompanied by fluctuating
amplitude and frequency of EEG rhythms, continuous
ictal activity, or continuous ictal activity punctuated
by low-voltage flat periods that finally evolve into a
burst-suppression pattern of periodic epileptiform
 This classification has been criticized because the
progressive temporal evolution observed in animal
experiments does not appear in clinically encountered
cases. A major controversy exists about whether the
periodic epileptic discharges in the final stage represent
continuing seizure activity requiring more aggressive
treatment or reflect postictal recovery. Moreover, the
claim that the response to treatment declines
proportionally with each stage, with a response of
almost 20% remaining in patients with periodic epileptic
discharges, has not been substantiated in series of
adults with status epilepticus.
 Neuroimaging and Laboratory
Tests (4)

Mostly electroencephalographic recordings characteristically show a discrete

seizure with intermittent flattening that may evolve into periodic lateralized
epileptiform discharges (PLEDS). During the course of status epilepticus, EEG
may continue to demonstrate outbursts of epileptic activity without any
clinically observed motor accompaniment. Whether PLEDs represent
potentially reversible continuing epileptic activity or severe cerebral damage
is uncertain, but many experts consider PLEDS (bilaterally independent or
bilaterally synchronous generalized) an inter-ictal phenomenon if no motor
manifestations occur.
A single EEG infrequently captures all elements of status epilepticus. An EEG
should be obtained in a patient with prolonged (about 1 hour) postictal
unresponsiveness, to differentiate coma due to continuing seizures from
postictal sleep but earlier in a patient who has received neuromuscular
blocking agents and sedative agents with a prolonged anesthetic effect.
Generally, to best monitor effect of treatment, video-EEG monitoring is
required in any patient with status epilepticus
 First Steps in Management
(1)

The first measure is airway control.

Endotracheal intubation is necessary because large doses of
benzodiazepines have caused drowsiness and upper airway collapse. Not all
patients in status epilepticus need endotracheal intubation, and a surprising
number tolerate multiple doses of lorazepam. Endotracheal intubation is
needed when a second-line agent rnidazolam or propofol is administered.
Mechanical ventilation is necessary after endotracheal intubation, and
oxygen delivery is substantially improved by intermittent mandatory
ventilation and pressure support. Fiber optic bronchoscopy may be indicated
to investigate possible bronchial obstruction from a foreign body or mucus
plug. In the rare situation of neurogenic pulmonary edema, mechanical
ventilation with high settings of positive end-expiratory pressure is
necessary, but pulmonary edema is short-lived. Aspiration occurred much
more often than pulmonary edema in one series of patients with status
epilepticus.
 First Steps in Management
(2)

Two intravenous peripheral catheters must be placed in large arm veins for
administration of antiepileptic drugs and possibly a peripherally inserted
central catheter for vasopressors.
In patients with multiple seizures, hydration with 0.9% saline (200 mL/hr)
is started immediately to reduce the risk of renal failure from
rhabdomyolysis, particularly if the admission serum creatine kinase is
considerably increased.
Metabolic acidosis is frequently found but should not be corrected with
bicarbonate until the pH has declined to 7.0.
Acute non-oliguric renal failure from rhabdomyolysis (acutely rising serum
creatinine, hyperkalemia, and hyper phosphatemia). Initial treatment is to
change iv fluids from normal saline to D5W with 3 ampules of bicarbonate
at 200 mL/ hr to maintain urinary output of more than 100 mL/ hr.
Phosphate binders (calcium acetate) are needed until laboratory values
normalize.
 First Steps in Management
(3)

Cardiac arrhythmias present in 50% of the patients. Sinus tachycardia is most

prevalent. In other patients, multifocal atrial tachycardia, ventricular
tachycardia, or a brief asystole after bradycardia has been found. Although ST
depressions can be transient in patients with ECG abnormalities suggesting
ventricular strain or myocardial ischemia, selective protective B-blockade (e.g.,
with metoprolol) should be considered.
Benzodiazepines, first line of treatment & virtually immediately followed by iv
phenytoin loading. Diazepam one of the most successful agents but associated
with severe respiratory depression, may lead to unnecessary intubation.
Lorazepam is preferred benzodiazepine, terminating seizures in almost 80%
patients. Effective for approximately 1-3 hours, administered in a dose of 4 mg
at 1-2 mg/ min to a max of 8 mg total. Lorazepam not more effective than
phenobarbital or a combination of diazepam and phenytoin for initial treatment,
but a rct found the highest response rate &fewest side effects in lorazepam-
treated patients. Lorazepam appeared to be more effective than diazepam in a
rct investigating its safety when administered. Lorazepam be considered the
most appropriate first-line agent to terminate status epilepticus.
 First Steps in Management
(4)
Iv loading with phenytoin is standard after patients have been treated with
benzodiazepines. Oral administration of 300 mg of phenytoin after iv loading should begin
6 hours after infusion & produces steady serum levels of phenytoin after 4 days of
treatment. Phenytoin is infused in isotonic saline, the rate must not exceed 50 mg/ min
(half dose in elderly patients). Infusion in a typical patient of 80 kg takes 30 min, but
seizures should stop after approximately 10 min. A rapid infusion has the disadvantage of
increasing the risk of hypotension and cardiac arrhythrnias (more common in elderly
patients) and a direct cardiotoxic effect (in poorly hydrated patients)
Some of the major side effects have been overcome with the introduction of fosphenytoin
(not widely available outside the US). Fosphenytoin (Cerebyx), a water-soluble disodiurn
phosphate ester of phenytoin, does not require the propylene glycol vehicle (often
responsible for hypotension & cardiac arrhythmias). When using fosphenytoin iv for status
epilepticus (the dose is similar to that of phenytoin), its expressed in phenytoin
equivalents (with recommended rate for status epilepticus 100-150 mg of phenytoin
equivalents per min three times, faster than that for phenytoin iv).
lf status epilepticus is not reversed with lorazepam, phenytoin, or fosphenytoin, several
more options are available, but recommendations are not based on comparative studies,
vary considerably, and are guided by personal opinion, and follow trends.
 Deterioration: Causes and
Management (1)

Two major forms of clinical deterioration occur in status epilepticus: First,

recurrence of seizures almost immediately after completion of phenytoin (or
fosphenytoin) infusion; Second, breakthrough seizures every time the anesthetic
agent is tapered. Both forms are considered therapy-refractory status epilepticus.
Failure to control seizures has several causes.
The most common cause is an inadequate dose of phenytoin. A typical but highly
insufficient 1,000 mg infusion of phenytoin has been ordered. This dose, originally from
the landmark paper by Wallis et al., is most likely used because a dose of 1 g easily
remembered however it translates to a body weight of 50 kg.
Other causes of failure to control seizures, besides an acute structural brain lesion, are
persistence of a metabolic derangement (e.g., hyponatremia, recurrent hypoglycemia,
or hyperglycemia), drug toxicity, and cns infection.
In some patients, the reason for the poor initial response remains unknown, and
treatment with lorazepam and phenytoin is simply not sufficient to control seizures.
It is best to have a predetermined idea of which agent to use rather than to
frequently switch agents.
 Deterioration: Causes and
Management (2)

Before a new antiepileptic agent is considered, an additional infusion of fosphenytoin

at one-third or half of the original infusion dose (usually 5-10 mg/ kg) is useful to
maximize fosphenytoin loading. This probably should be given after an additional iv
dose of 4 mg lorazepam.
Many neuro intensivists and epileptologists now directly proceed with midazolam,
propofol, pentobarbital anesthesia.
Midazolam has emerged as a preferred second-line antiepileptic drug for status
epilepticus. The recommended loading dose is 0.2 mg/kg intravenously in a bolus,
and this is followed by an infusion of 0.1-0.6 mg/kg/hr until the EEG is free of seizure
activity. However, midazolam is several times more expensive than barbiturates when
used in an iv infusion. In addition, with increasing doses, blood pressure may decrease
significantly, with a need for long-term vasopressors.
An alternative approach is to use high doses of propofol. Propofol is administered in a
bolus of 2 mg/kg followed by an infusion of 5 mg/kg/hr, later tapered to 1-5 mg/kg/hr.
Propofol acts through enhancement of y-aminobutyric acid (GABA) media ted
transmission, possibly at the chloride ion channel, different from that with
benzodiazepines and barbiturates.
 Deterioration: Causes and
Management (3)

The enthusiasm for propofol has diminished after an early initially unexplained report of
fourfold higher mortality. There have been many reports of a propofol infusion
syndrome (PRIS), an unexplained sudden cardiovascular collapse in patients treated
with high doses (more than 10 mg/kg/hr) and for more than 3 days, although PRIS may
occur hours after infusion of propofol and in much lower doses. Propofol is currently ill-
advised in the treatment of status epilepticus when often high doses or prolonged
treatment is anticipated.
Pentobarbital can be strongly considered if prior drugs fail. Iv Pentobarbital with initial
bolus of 10-15 mg/kg over 1~2 hours followed by infusion of 1-3 mg/ kg/ hr until
seizures stop clinically and on EEG. Pentobarbital has a marked cardio depressant
effect, and many patients need vasopressors for blood pressure support. Aiming f0r an
EEG without seizure activity may considerably reduce the side effects of pentobarbital.
However, in daily practice, the EEG may fluctuate from burst suppression to bilateral
PLEDS without appreciable bursts of seizures. This EEG recording may be a satisfactory
end point.
Major management problem arises when generalized tonic-clonic seizures are not
controlled/continue to recur after discontinuation of barbiturate therapy. Failure to
control seizures with barbiturate anesthesia seems very uncommon, but if it happens,
the chance of effectively controlling seizures is low and morbidity is high in these
 Deterioration: Causes and
Management (4)
lsoflurane is an attractive option and highly effective. In a series of 11 patients with
treatment-refractory status epilepticus, morbidity and mortality remained high despite
seizure control. Isoflurane is used in concentrations of minimum alveolar concentration
(MAC of 1.15%) but progressively higher concentrations are often needed to control
seizures.
Lidocaine has shown efficacy in therapy; refractory status epilepticus. Lidocaine is
injected in a bolus of 1.5-2 mg/ kg in several minutes, fOIlOWed by an infusion of 3
mg/kg/ hr. The infusion should not be continued for more than 12 hours. Its use is limited
in patients with a history of cardiac arrhythmias or ecg evidence of any type of heart
block and poor ejection fraction on echocardiography, Use in patients with liver failure is
also contraindicated due to decreased hepatic clearance, and a high level of lidocaine,
which itself can lead to seizures, may result.
New alternative agents are ketarnine and valproate. Experience is very limited and only
successful cases have been published. Physician must exercise great caution in their use
as a treatment for status epilepticus. A short-acting anticonvulsant, an N-methyl-D-
aspartate receptor antagonist, ketarnine, surprisingly controlled status epilepticus in one
patient refractory to phenytoin, phenobarbital, midazolam, propofol, valproate, and
lidocaine infusion. This unconfirmed experience is valuable. Ketamine was used in a bolus
of 2 mg/kg over 2 min followed by an infusion of 10-50 mg/kg/ min, a dose that does not
cause respiratory depression The infusion dose is then tapered to 7.5 mg/ kg/ hr for 7-14
days.
 Deterioration: Causes and
Management (5)

Valproate iv has been recently introduced, but its efficacy is unknown, control of seizures
is only 30%. Major advantage may be that it does not reduce blood pressure and may be a
good alternative in patients who have become cardiovascularly unstable with midazolam
and propofol. It also has virtually no respiratory depression. Iv loading doses of valproate
can be 25-30 mg/ kg, with infusion rate of 20 mg / min to attain a steady-state serum
concentration of 75 mg/ L. It is highly bound to albumin, and toxicity may rapidly arise in
patients with poor nutritional intake and it has been implicated in abnormal hemostasis.
When all else fails, it makes common sense to try to treat seizures with a radically
different approach. Levetiracetam, Nimodipine, resection of an (identifiable) epileptic
focus, vagus nerve stimulation, high-dose phenobarbital (100-300 mg/mL plasma levels),
or electroconvulsive therapy have all been considered with variable success.
Weaning from intravenous antiepileptic drugs has not been carefully studied. We prefer to
treat patients aggressively (burst-suppression or mostly suppressed EEG pattern) for at
least 24 hours, aiming for a seizure-free period of another 24 hours. Then we reduce the
dose 10% every hour, while monitoring with video EEG for recurrence and then either stop
weaning or increase the dose.
An aggressive approach with prolonged use of anesthetic drugs for several months may be
justified only in young patients with traumatic brain injury, in encephalitis, and in patients
with NIRI findings that do not suggest widespread cortical damage.
 Outcome (1)

The prognosis of status epilepticus depends on several factors. The most

important finding has been the association of the actual time that patients have
remained in tonic-clonic status epilepticus and later morbidity. This finding,
however, probably does not hold for patients in non-convulsive status epilepticus.
Nonconvulsive status epilepticus lasting many days may result in a favorable
outcome, but data are sparse in this category of patients.
Patients with tonic clonic status epilepticus have a considerable risk of permanent
morbidity. A duration of status epilepticus of less than 10 hours seems an
important cutoff point and good outcome is possible within this time period.
Considerable neurologic improvement can be expected in some patients. A
neuropsychologic study in nine patients with previous epilepsy who were tested
before and after status epilepticus found no substantial changes in cognitive
ability.29
In most of our patients-some treated for 3-6 months-=seizures stopped (burned
out) or became stimulus-induced myoclonic twitches, but often leading to long-
term disability. Status epilepticus in young patients with normal MRI warrants long-
term management and a satisfactory outcome is not an unrealistic possibility.
 Outcome (2)

A review of deaths related to status epilepticus found a mortality of 2% in

adult status epilepticus. In a study of 282 consecutive admissions, mortality
from status epilepticus could be linked to an underlying disorder in all but
two patients. Mortality was higher in patients with stroke if status epilepticus
occurred within 7 days of stroke. Anoxic-ischemic insult to the brain and older
age predicted mortality in status epilepticus and could be related to cardiac
resuscitation in the first place.
The risk of subsequent epilepsy in adult patients with de novo status
epilepticus is 12% and includes a small risk of recurrent status epilepticus.
Risks are higher in patients with known structural lesions, onset of seizure
disorder durin adolescence, and neurologic abnormalities. In general,
predictive factors for poor outcome include the lack of response to first
treatment and the underlying cause of status epilepticus, particularly when
these are associated with anoxic-ischemic encephalopathy, acute stroke,
encephalitis, diffuse axonal head injury, or a primary malignant tumor. Status
epilepticus associated with anoxic-ischemic injury and older age significantly
increase the odds of a higher incidence of severe, persistent disability.
 Conclusion

One can expect that a large proportion of patients with status

epilepticus can be controlled with benzodiazepines
(lorazepam 4-8 mg) and an adequate loading dose of
phenytoin (20 mg/ kg, 50 mg/ min).
Recurrence of seizures after adequate phenytoin loading
could be treated with midazolam or propofol infusion.
If all else fails, intravenous administration high-dose
phenobarbital, isoflurane, or electroconvulsive therapy should
be considered.
Outcome of status epilepticus is strongly related to the
response to the first dose of antiepileptic agent and to the
underlying trigger.
Thankyou