Convulsive Status Epilepticus

David M. Treiman, MD
Address
Department of Neurology, University of Medicine and Dentistry
of New JerseyRobert Wood Johnson Medical School,
97 Paterson Street, New Brunswick, NJ 08901, USA.
Current Treatment Options in Neurology 1999, 1:359369
Current Science Inc. ISSN 1092-8480
Copyright 1999 by Current Science Inc.

Opinion statement
Generalized convulsive status epilepticus (GCSE) is a medical emergency that must be
treated rapidly and aggressively to prevent neuronal damage. Treatment should be
initiated with intravenous lorazepam, 0.1 mg/kg, given at a rate of no more than
2 mg/min. If convulsions persist for more than 10 minutes or recur more than 20
minutes after lorazepam therapy is started, then fosphenytoin (20 mg of phenytoin
equivalents per kilogram) should be infused at a rate of no more than 150 mg/min.
If convulsions still continue, intravenous general anesthesia with pentobarbital,
benzodiazepine drip, or propofol should be initiated after respiratory support has
been established. All patients with GCSE who do not recover consciousness should
be monitored with electroencephalography (EEG), and any residual epileptiform activity
on EEG, including periodic epileptiform discharges (PEDs), should be considered
evidence of continuing GCSE and treated aggressively.

Introduction
Generalized convulsive status epilepticus has been
recognized since Babylonian times [1] but was first fully
described by Calmeil in 1825 [2]. Early in this century,
Clark and Prout [3,4] provided descriptions of both
overt and subtle GCSE and of what we now think of as
nonconvulsive status epilepticus. It was not until the
Marseilles conference [5], however, that detailed
descriptions of different types of status epilepticus (SE),
including GCSE, were recorded.
Status epilepticus is defined as 1) two or more
epileptic seizures without full recovery of neurologic
function between the seizures or 2) more-or-less contin-
uous seizure activity for more than 30 minutes. The
term GCSE is used for SE that manifests as recurrent
convulsive seizures that may be overt or subtle, symmet-
ric or asymmetric, and are associated with profound
coma and bilateral (although often asymmetric) ictal
discharges on EEG [6, Class III]. It is now recognized
that if GCSE is untreated or inadequately treated, it
progresses from overt convulsions to increasingly subtle
motor activity, even though ictal discharges persist on
EEG. Just as there is a progression from overt to subtle
motor activity, there is also a predictable sequence of
progressive EEG changes during GCSE (Figs. 1 to 5).
Initially, discrete electrographic seizures occur; these
usually coincide with overt generalized convulsions. If
GCSE is allowed to continue, the discrete seizures merge
to produce a waxing-and-waning pattern of ictal
discharges, which subsequently become continuous
and monomorphic. The continuous activity eventually
begins to be punctuated by periods of relative flatten-
ing, which lengthen as the ictal discharges shorten, until
all that remains are PEDs on a flat background [7].
Response to pharmacologic agents also changes over
time. The longer GCSE persists [8] or the later the EEG
stage [9], the harder GCSE is to treat.
Between 65,000 [10] and 150,000 [11] cases of SE,
most of which are cases of GCSE, occur in the United
States each year. Hauser [10] has suggested that about
one third of cases of SE are complications of chronic
epilepsy or febrile seizures, one third occur as the initial
presentation of epilepsy, and one third are complica-
tions of encephalopathic insult to the brain. In a recent
Veterans Affairs Cooperative study of the treatment of
GCSE in 384 patients with overt GCSE [12, Class I],
69.5% of patients had a remote neurologic insult,
27.3% had an acute neurologic insult, 32.0% had a life-
threatening medical condition, 6.3% had had cardio-
pulmonary arrest, 6.3% had drug toxicity, and 6.5% had
undergone alcohol withdrawal. In some patients, there
was more than one cause of GCSE. Data from a commu-
nity-based study in Richmond, Virginia [11], are simi-
360 Epilepsy
lar. The mortality rate associated with GCSE is high,
ranging from 5% to 50% in old series [13]. In the Veter-
ans Affairs study [12, Class I], 27% of patients with
overt GCSE and 65% of those with subtle GCSE died
within 30 days of the episode of GCSE.
Drugs used to treat SE have included phenobarbital,
phenytoin, and benzodiazepines, but a direct compari-
son of the efficacy of the standard first-line drugs in the
treatment of GCSE was not published until recently.
Treiman et al. [12, Class I] conducted a nationwide
double-blind comparison of lorazepam, phenobarbital,
diazepam followed by phenytoin, and phenytoin alone
in the initial treatment of GCSE. Success rates are shown
in Figure 6. Lorazepam was effective significantly more
often than phenytoin; results of the other pairwise com-
parisons were not statistically significant. No statistically
significant differences in adverse reactions were seen.
The low success rate of the best drug, lorazepam (only
65% in patients with overt GCSE) was probably due to
the use of electrical as well as clinical criteria to deter-
mine cessation of GCSE. Twenty percent of patients with
overt GCSE had continuing ictal discharges on EEG even
though all convulsive activity had stopped [14]. In these
patients, treatment was considered a failure because of
the electrical evidence of continuing GCSE.
Aggressive intravenous therapy should be initiated if
patients present with recurrent epileptic seizures with-
out full and complete recovery of neurologic function
between seizures or if continuous behavioral or electri-
cal seizure activity persists for more than 10 minutes.
Figure 1. Discrete generalized tonic-
clonic seizures with interictal slowing,
recorded before treatment in a 39-year-old
man. The end of the clonic phase of the
seizure and the appearance of postictal
slowing is shown. (From Treiman et al. [7];
with permission.)
Figure 2. Merging of discrete seizures
recorded before treatment in a 64-year-old
man. Ictal discharges are continuous, but
there is waxing and waning of frequency
and amplitude. An increase in frequency
and amplitude can be seen beginning on
the right side of the recording. (From
Treiman et al. [7]; with permission.)
Convulsive Status Epilepticus Treiman 361

Figure 3. Continuous ictal discharges

recorded before treatment in a 68-year-old
man. Examples are 16 minutes apart.
Continuous ictal activity persisted for
101 minutes and stopped after completion
of phenytoin infusion (and 4 minutes
after completion of lorazepam infusion).
(From Treiman et al. [7]; with permission.)

Figure 4. Continuous ictal discharges

with flat periods recorded before treatment
in a 68-year-old man. The seizure focus is
clearly in the left hemisphere, but spread
of ictal activity to the right hemisphere can
also be seen. (From Treiman et al. [7];
with permission.)

Figure 5. Periodic epileptiform discharges

on a flat background recorded before
treatment in a 64-year-old man. (From
Treiman et al. [7]; with permission.)
362 Epilepsy

Figure 6. Rate of success with each of four first-drug regimens.

In patients with overt generalized convulsive status epilepticus
(GCSE), differences in rate of success were statistically signifi-
cant (P = 0.02), and lorazepam was effective more often than
phenytoin in pairwise comparisons (P = 0.002). Differences in
rate of success were not statistically significant in patients with
subtle GCSE. Darker bars represent patients with overt GCSE;
lighter bars represent patients with subtle GCSE. The percentage
success rates for each treatment are shown for each bar. DZM +
PHTdiazepam followed by phenytoin; LORlorazepam; PB
phenobarbital; PHTphenytoin. (Adapted from Treiman et al.
[12, Class I].)

Treatment
Status epilepticus is a medical emergency. It must be treated as quickly,
vigorously, and effectively as possible.
The goals of treatment are to 1) stop seizure activity as quickly as possible,
2) protect neurons from seizure-induced damage, and 3) allow full recovery
from the episode of GCSE.
Neuronal damage during SE is caused primarily by continuing seizure
discharges. Ongoing seizure activity results in the bombardment of N-methyl-
D-aspartate (NMDA) excitatory neuronal receptors by glutamate and, thus, leads
to the opening of cation channels to calcium. The influx of calcium sets up a
cascade of intracellular neurochemical events that damages or kills the neuron
[1518]. Thus, if complete contro7l of seizures cannot be determined clinically
by observation of progressive recovery of consciousness, it is essential to moni-
tor electroencephalographic activity to ensure that all seizure activity has ceased.
Neuronal damage caused by seizure activity is exacerbated by systemic factors,
especially hyperpyrexia. Therefore, blood pressure, cardiograms, temperature,
and blood glucose levels must be monitored and normalized if necessary.
The longer SE continues, the more likely it is that clinical manifestations
will be subtle. Some patients in coma may have subtle GCSE. Therefore,
in comatose patients, electroencephalograms should be assessed whenever
SE might explain the coma.
The later the EEG stage, the longer the duration, and the more subtle the
behavior, the harder it is to stop SE. Therefore, SE must be treated as early,
as rapidly, and as vigorously as possible.
Periodic epileptiform discharges are electrical manifestations of SE.
Thus, patients in coma who have PEDs on EEG should be treated as
aggressively as patients with GCSE manifested by overt convulsions.
Diminution of the intensity of motor convulsive activity is often a sign
that the patient is getting worse, not better.
Drug efficacy in SE is highly correlated with serum and brain concen-
trations of the drug, at least in experimental animals. It is therefore
essential to use drugs with prolonged brain retention and to initiate
treatment with a dose high enough to achieve and maintain serum
(and therefore brain) concentrations adequate to stop SE.
A predetermined treatment protocol is more effective than random
selection of drugs and doses. Thus, a treatment protocol with adequate
doses and rates of administration should be established. One widely
used treatment protocol is presented in Table 1.
 Convulsive Status Epilepticus Treiman 363

Table 1. Treatment protocol for generalized

convulsive status epilepticus
Time, min Activity

0 Make the diagnosis by 1) observing one additional seizure

in a patient with a history of recent seizures or impaired
consciousness or 2) observing continuous behavioral or
electrical seizure activity for more than 10 minutes.
Call EEG technician and start EEG as soon as possible, but
do not delay treatment while waiting for EEG unless EEG
results are necessary to verify the diagnosis.
5 Establish intravenous catheter with normal saline if phenytoin
will be used (dextrose solutions may precipitate phenytoin)
or with either dextrose or saline if fosphenytoin will be used.
Draw blood for serum chemistry analysis, hematologic studies,
and measurement of AED concentrations. If hypoglycemia is
suspected, confirm by finger-stick testing. Then administer
100 mg of thiamine (if indicated) followed by 50 mL of 50%
glucose by direct push into the intravenous line.
10 Administer lorazepam (0.1 mg/kg) by intravenous push (<2 mg/min).
25 If status does not stop, start phenytoin (20 mg/kg) by slow
intravenous push (<50 mg/min) directly into intravenous port
closest to patient. (An intravenous push of fosphenytoin
can be given at a rate of 150 mg phenytoin equivalents/min.)
Monitor blood pressure and electrocardiogram closely
during infusion.
If status does not stop after phenytoin, 20 mg/kg (or fosphenytoin, 20
mg phenytoin equivalent/kg), administer an additional
5 mg/kg and, if necessary, another 5 mg/kg, to a maximum
dose of 30 mg/kg.
60 If status persists, give phenobarbital (20 mg/kg) by intravenous
push (<100 mg/min) or start barbiturate coma. Support
respiration with endotracheal intubation. Give pentobarbital
(5 to 15 mg/kg) slowly as an initial intravenous dose to suppress
all epileptiform activity. Continue infusing 0.5 to 5 mg/kg/h
to maintain suppression of all epileptiform discharges. Slow
rate of infusion periodically to see whether seizure has stopped.
Monitor blood pressure, electrocardiogram, and respiratory
function closely. If all epileptiform activity is not suppressed,
change to a continuous infusion of propofol or midazolam.
AEDantiepileptic drug; EEGelectroencephalography. (Adapted from Treiman [19].)

Acute treatment of GCSE should always consist of intravenous administra-

tion of antistatus drugs. Intramuscular or rectal administration is too slow
for emergency treatment but may be considered 1) if gaining intravenous
access is likely to take more than 10 to 15 minutes or 2) in home manage-
ment, to prevent seizure flurries from progressing to SE.

General medical therapy

Stabilize airway, maintain breathing and blood pressure, and gain access
to circulation.
Obtain blood samples for complete blood count, serum chemistry studies,
and measurement of antiepileptic drug levels.
Start an intravenous line with normal saline.
364 Epilepsy

If hypoglycemia is suspected, confirm the plasma glucose level by

finger-stick testing. If significant hypoglycemia is present, administer a
glucose bolus by intravenous push (50 mL of 50% glucose in adults;
2 mL/kg of 25% glucose in children). Do not give a bolus of glucose
without confirming the presence of hypoglycemia; hyperglycemia may
exacerbate neuronal damage caused by GCSE [2022]. If thiamine
deficiency is a concern (eg, in chronic substance abusers), give 100 mg
of thiamine intravenously before or simultaneously with the glucose to
avoid precipitating or exacerbating Wernickes encephalopathy.
Do not give bicarbonate unless the serum pH is so low that it is an immedi-
ate threat to life. There is little evidence that GCSE-induced acidosis results
in permanent injury. Administration of large amounts of bicarbonate may
result in metabolic alkalosis once GCSE has been controlled, however.
The value of supplemental oxygen, of steroids to reduce cerebral edema,
and of monitoring for increased cerebral pressure in the management of
GCSE has not been proven.
Muscle paralysis is never indicated in the management of GCSE (except in
certain postoperative situations), and the clinician should never use it
without first establishing continuous electroencephalographic monitoring
to ensure the continuing absence of cerebral seizure activity.
Once SE is controlled, the clinician should evaluate and treat the under-
lying cause of the episode of GCSE.

Pharmacologic treatment
Benzodiazepines
Intravenous lorazepam is widely considered the drug of choice for the acute
management of GCSE, although some physicians start treatment with diazepam
or phenobarbital. In the only controlled clinical trial that has directly compared
the efficacy of standard intravenous drugs for the treatment of GCSE [12,
Class I], lorazepam, 0.1 mg/kg, was effective as initial therapy in 65% of patients;
phenobarbital, 15 mg/kg, was effective in 58%; diazepam, 0.15 mg/kg, followed
by phenytoin, 18 mg/kg, was effective in 56%; and phenytoin, 18 mg/kg, was
effective in 44%. The difference in efficacy between lorazepam and phenytoin
was statistically significant; results of the other paired comparisons were not.
Lorazepam, diazepam, and midazolam have all been used as continuous intrave-
nous drips in the management of refractory GCSE.
Standard dosage Lorazepam, 0.05 to 0.1 mg/kg, infused at a rate of no more than 2 mg/min;
diazepam, 0.15 to 0.25 mg/kg, infused at a rate of no more than 5 mg/min.
Lorazepam has a prolonged effective duration of action against GCSE. Recurrence
rates during a 12-hour protocol were not statistically different with lorazepam,
phenobarbital, diazepam followed by phenytoin, or phenytoin alone [12,
Class I]. Diazepam has a very short effective duration of action against GCSE
because of rapid redistribution to body-fat stores [23]. Therefore, it must
be followed by a long-acting drug, such as phenytoin, within 20 minutes of
administration to avoid recurrence of GCSE. When diazepam is used for refractory
GCSE, it is usually administered as a continuous intravenous infusion. Delgado-
Escueta et al. [24, Class III] recommend administration at a rate of 8 mg/h to
achieve serum concentrations of 200 to 800 ng/mL. When midazolam is used for
refractory SE, the patient should receive 0.2 mg/kg as a bolus injection followed by
an infusion of 0.05 to 0.5 mg/kg/h as needed to eliminate all epileptiform
discharges on EEG.
Contraindications Respiratory distress or previous administration of a benzodiazepine or barbiturate.
(Consider endotracheal intubation.)
Main drug interactions Pharmacodynamic interaction with other benzodiazepines and barbiturates may
decrease respiratory drive and increase sedation.
 Convulsive Status Epilepticus Treiman 365

Main side effects Sedation (lorazepam may delay recovery of consciousness after GCSE is stopped)
and respiratory depression.
Cost effectiveness Enough lorazepam to treat one episode of GCSE costs about $15. Diazepam
is even less expensive but requires intravenous administration of phenytoin or
fosphenytoin. Midazolam is expensive; it costs several hundred dollars to maintain
a continuous infusion of midazolam for 24 hours.

Hydantoins
If lorazepam administration fails to stop continuous seizure activity within 10
minutes or if intermittent seizures persist for more than 20 minutes, another drug
must be added to stop the episode of GCSE. Most physicians now use phenytoin, 20
mg/kg, or fosphenytoin, 20 mg of phenytoin equivalents per kilogram, as the second
drug in the treatment of GCSE that does not respond to lorazepam. Fosphenytoin
is a phenytoin prodrug that is a water-soluble phosphate ester of phenytoin. It is
enzymatically converted to phenytoin by serum phosphatases.
Standard dosage Phenytoin, 20 mg/kg, infused at a rate of no more than 50 mg/min; fosphenytoin,
20 mg of phenytoin equivalents per kilogram, infused at a rate of no more than
150 mg/min. The labeling for fosphenytoin is potentially confusing. Seventy-five
milligrams of fosphenytoin results in 50 mg of phenytoin in the serum after enzy-
matic conversion; thus, 75 mg of fosphenytoin is labeled 50 mg phenytoin equiva-
lents. If phenytoin, 20 mg/kg, or fosphenytoin, 20 mg of phenytoin equivalents
per kilogram, fails to control GCSE, an additional 5 to 10 mg/kg should be given
before a third drug is used. Twenty-five to 30 mg/kg will result in phenytoin serum
concentrations of 30 to 40 mg/mL, which may be necessary to control initially
pharmacoresistant GCSE.
Contraindications Hydantoin allergy and significant hypotension. Hydantoins should be used with
caution in the presence of myocardial damage or cardiac arrhythmias.
Main drug interactions None relevant to acute intravenous administration.
Main side effects Hypotension; cardiac arrhythmia; phlebitis or skin sloughing after extravasation
during intravenous administration or purple-glove syndrome (with phenytoin, not
with fosphenytoin); and rash. Because of the potential for phenytoin-induced
hypotension and cardiac arrhythmia, blood pressure and electrocardiograms should
be monitored during the administration of either phenytoin or fosphenytoin. If
hypotension develops (this is more likely with phenytoin than with fosphenytoin),
the rate of infusion can be slowed. If the QT interval on the electrocardiogram wid-
ens or if arrhythmia develops, phenytoin administration should be stopped. Both
phenytoin and fosphenytoin may result in an allergic reaction and the development
of a drug rash after GCSE. Cutaneous complications after intravenous phenytoin
administration are so common that many nurses no longer file incident reports to
report venous cording or mild skin sloughing after drug administration. The purple-
glove syndrome is a devastating soft-tissue reaction to intravenous phenytoin
administration distal to the antecubital fossa and is characterized by profound
swelling of the hand. This swelling is sometimes severe enough to cause arterial
occlusion and tissue necrosis and necessitate amputation of the hand. The inci-
dence of this complication is surprisingly high. A recent report from the Mayo
Clinic [25, Class II] found a 5.9% incidence of purple-glove syndrome in a consec-
utive series of 152 patients who received intravenous phenytoin during a 3-month
period. Cutaneous complications, including purple-glove syndrome, can be avoided
by using fosphenytoin rather than phenytoin for intravenous administration. This
significant advantage of fosphenytoin far outweighs the drug's higher cost.
Special points When phenytoin or fosphenytoin is used to protect against recurrence of GCSE,
it may be necessary to readminister a partial loading dose to increase the
steady-state concentration of the drug. The appropriate dose for such a
mini-load can be easily calculated with the following formula:

D = Vd x (C1 C0)

where D = dose, Vd = volume of distribution, C1 = desired concentration,

and C0 = starting concentration.
366 Epilepsy

For a drug with a Vd of 1 L/kg, it is evident that a loading dose in mg/kg is equal
to the desired increase in serum concentration in mg/L. Because most antiepileptic
drugs have a Vd of about 1 L/kg or slightly less, the result will be close enough for
clinical purposes if the clinician gives a mini-loading dose of 1 mg/kg for each mg/L
(mg/mL) increase in serum concentration that is desired. Thus, if a patient has a
phenytoin serum concentration of 13 mg/mL and the physician wants to maintain
the phenytoin concentration at 18 mg/mL, the mini-loading dose should be 5 mg/kg.
Of course, the calculation can be made even more accurate by using a precise Vd for
phenytoin of 0.8 L/kg, in which case the mini-loading dose is 4 mg/kg (5 mg/L x 0.8
L/kg = 4 mg/kg). In either case, the calculations are the same for fosphenytoin, so
long as phenytoin equivalent units are used.
Cost effectiveness Generic phenytoin for intravenous administration is very inexpensive. Fosphenytoin
(which is only available as Cerebyx [Parke-Davis, Morris Plains, NJ]) to treat one epi-
sode of GCSE in an adult costs approximately $100. The expense must be considered
in light of the risk of development of serious cutaneous complications with intrave-
nous phenytoin, such as significant skin sloughing or purple-glove syndrome. A
recent pharmacoeconomic study [26] compared the overall cost of phenytoin and
fosphenytoin in the treatment of acute seizures or SE in an emergency department.
Although the cost of fosphenytoin far exceeded that of phenytoin, the overall cost of
fosphenytoin was less than the overall cost of phenytoin when the costs of complica-
tions and increased nursing time were considered.

Barbiturates
Intravenous phenobarbital is the drug of choice of some adult neurologists
and many pediatric neurologists for the initial treatment of GCSE. Because the
high doses of phenobarbital necessary to treat GCSE induce prolonged sedation,
however, many neurologists relegate phenobarbital to the treatment of refractory
GCSE. Pentobarbital has a role only in the management of refractory GCSE when
other drugs have failed and intravenous general anesthesia is required.
Standard dosage Phenobarbital, 15 to 20 mg/kg, infused at a rate of no more than 100 mg/min.
Pentobarbital: loading dose, 5 to 15 mg/kg; maintenance dose, 0.5 to 5 mg/kg/h.
Contraindications Respiratory distress or previous administration of another barbiturate or
benzodiazepine. (Consider endotracheal intubation.)
Main drug interactions Pharmacodynamic interaction with other barbiturates and benzodiazepines that
may decrease respiratory drive and increase sedation.
Main side effects Sedation (phenobarbital delays recovery of consciousness after GCSE is stopped)
and respiratory depression. Phenobarbital for intravenous injection is now prepared
in 68% or 73% propylene glycol, which may cause hypotension, particularly in
children. High-dose pentobarbital drip can cause cardiotoxicity and hypotension.
Cost effectiveness Barbiturates are very inexpensive; however, the low cost must be balanced against
the prolonged sedation and delay in recovery to full consciousness that large doses
of phenobarbital may produce.

Propofol
Propofol, an intravenous general anesthetic that has barbiturate- and
benzodiazepine-like effects on gamma-aminobutyric acid, has been reported
to be effective in the management of refractory GCSE [27, Class III; 28].
Standard dosage An initial intravenous bolus dose of 1 mg/kg is given over 5 minutes. If seizure
activity is not completely suppressed, this dose should be repeated once. Then,
maintenance infusion at 2 to 4 mg/kg/h should be started. The rate of infusion
should be adjusted to 1 to 15 mg/kg/h until the lowest rate of infusion necessary
to suppress completely all epileptiform activity on EEG is reached.
Contraindications Respiratory distress or previous administration of benzodiazepines or barbiturates
should inspire caution and careful attention to respiratory support.
Main drug interactions Pharmacodynamic interaction with benzodiazepines and barbiturates may decrease
respiratory drive and increase sedation.
Main side effects Central nervous system depression, respiratory suppression, metabolic acidosis,
hyperlipidemia, hypotension, and occasional bradycardia or asystole.
 Convulsive Status Epilepticus Treiman 367

Cost effectiveness Propofol is expensive; it costs several hundred dollars to maintain a continuous
infusion of propofol for 24 hours.

Refractory status epilepticus

Most patients who present with overt GCSE and are treated aggressively
with the first three drugs listed in the protocol attain complete cessation
of all behavioral and electrical seizure activity. Some patients require
intravenous general anesthesia to suppress all clinical and electrical seizure
activity, however.
No randomized comparative studies of treatments for refractory GCSE
have been done. In retrospective reviews of clinical experience, however,
continuous infusions of pentobarbital [27,2934, Class III], propofol
[27, Class III], midazolam [3537, Class III], diazepam [24,38,39, Class III]
and lorazepam [40, Class III] have been reported to have efficacy.
Management of refractory GCSE requires continuous electroencephalo-
graphic monitoring. The rate of administration of whatever drug is
used must be increased until all epileptiform activity ceases. This usually
requires that the EEG waveforms become nearly flat. Increasing evidence
suggests that achievement of a burst-suppression pattern is not sufficient.
Often, what are interpreted as bursts are actually epileptiform discharges,
which must be suppressed completely if SE is to be controlled.
Clinical experience suggests that after all epileptiform activity on EEG has
been eliminated, the patient should be maintained in this state for 24 to 96
hours before the clinician attempts to slow the infusion rate and allow
the anesthesia level to decrease. No data are available regarding how long
the epileptiform discharges must be suppressed, however.
Dont give up. Patients with refractory GCSE who have persistent epilepti-
form activity on EEG do not recover. Some patients in whom all epilepti-
form activity is suppressed, however, remain free of epileptiform discharges
as the level of anesthesia is decreased, even after being maintained under
anesthesia for 4 to 6 weeks.

Emerging therapies
A preparation for the intravenous administration of valproic acid recently
became available. Although animal data suggest that very high serum
concentrations of valproate are necessary to stop GCSE [41], a recent report
[42, Class III] suggests the efficacy of intravenous valproate in the manage-
ment of SE. Controlled clinical trials have yet to be done.
Animal data also suggest a possible role for polypharmacy in the manage-
ment of GCSE. When subtherapeutic doses of diazepam and phenytoin
were used in a rat model of GCSE [43], the order of drug administration
influenced the efficacy of the combination. A subtherapeutic dose of
diazepam followed after 10 minutes by a subtherapeutic dose of phenytoin
was not nearly as effective at stopping GCSE as were identical doses of
phenytoin and diazepam given in the opposite order. This order effect
has yet to be tested in human GCSE but suggests new ways to use old
drugs more effectively.
368 Epilepsy
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as:
Of special interest
Of outstanding interest
1. Kinnier-Wilson JV, Reynolds EH: Translation and
analysis of a cuneiform text forming part of a Babylo-
nian treatise on epilepsy. Med Hist 1990, 34:185198.
2. Calmeil J: De l'pilepsie, tudie sous le rapport de son sige
et de son influence sur la production de l'alination mentale
[thesis]. Paris: Universit de Paris; 1824.
3. Clark LP, Prout TP: Status epilepticus: a clinical
and pathological study in epilepsy. Am J Insanity
1904, 60:645699.
4. Clark LP, Prout TP: Status epilepticus: a clinical
and pathological study in epilepsy. Am J Insanity
1904, 61:81108.
5. Gastaut H, Roger J, Lob H, et al.: Les tats de mal
pileptiques. Paris: Masson; 1967.
6. Treiman DM: Generalized convulsive status epilepti-
cus in the adult. Epilepsia 1993, 34(suppl 1):S2S11.
7. Treiman DM, Walton NY, Kendrick C: A progressive
sequence of electroencephalographic changes during
generalized convulsive status epilepticus. Epilepsy
Res 1990, 5:4960.
This is the first report of a predictable sequence of changes
on electroencephalography in generalized convulsive status
epilepticus (GCSE). Identification of this sequence has been
important in increasing understanding of the dynamic nature
of GCSE in both experimental and clinical studies.
8. Treiman DM, Meyers PD, Walton NY, et al.: Duration of
generalized convulsive status epilepticus: relationship
to clinical symptomatology and response to treatment
[abstract]. Epilepsia 1992, 33(suppl 3):66.
9. Treiman DM, Meyers PD, DVA Status Epilepticus
Cooperative Study Group: Utility of the EEG pattern as
a predictor of success in the treatment of generalized
convulsive status epilepticus [abstract]. Epilepsia
1991, 32(suppl 3):93.
10. Hauser WA: Status epilepticus: epidemiologic
considerations. Neurology 1990, 40(suppl 2):913.
This study of the epidemiology of status epilepticus, done in
Rochester, Minnesota, provides much-needed information
about the causes and consequences of the disorder.
11. DeLorenzo RJ, Hauser WA, Towne AR, et al.:
A prospective, population-based epidemiologic study
of status epilepticus in Richmond, Virginia. Neurology
1996, 46:10291035.
This study of the epidemiology of status epilepticus, done in
Richmond, Virginia, provides much-needed information
about the causes and consequences of the disorder.
12. Treiman DM, Meyers PD, Walton NY, et al.: A comparison
of four treatments for generalized convulsive status
epilepticus. N Engl J Med 1998, 339:792798.
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