ORIGINAL CONTRIBUTION

A Malignant Variant of Status Epilepticus

Martin Holtkamp, MD; Jalal Othman, MD; Katharina Buchheim, MD; Florian Masuhr,
MD; Eva Schielke, MD; Hartmut Meierkord, MD

Background: Status epilepticus (SE) frequently does not

respond to common first-line anticonvulsants. In a substantial portion of patients, administration of anticonvulsant anesthetics is inevitable. Even this aggressive approach fails to terminate SE in an undefined number of
cases. We have coined the term malignant SE for this
most severe variant of SE.

SE and persistent epileptic activity after failure of firstline anticonvulsants.

Results: Status epilepticus that could not be controlled

versity hospital.

by first-line anticonvulsants resulted in malignant SE in

20% of cases. Patients with malignant SE were significantly younger than patients with refractory SE (P = .
03). Encephalitis was identified as an independent risk
fac- tor for malignant SE (P = .008). Outcome in
malignant SE was poor, with significantly longer
duration of sei- zure activity (P .001), longer stay in
the neurologic in- tensive care unit (P .001) and in the
hospital (P = .007), and more patients with functional
dependency at dis- charge from the hospital (P = .04).

Patients: Sample of 35 episodes of SE not responding

Conclusions: Malignant SE is not rare after failure of

Objective: To assess frequency, risk factors, and in-

hospital outcome of malignant SE.

Design: Retrospective cohort study.

Setting: Neurologic intensive care unit of a large uni-

to first-line anticonvulsants in 34 patients.

Main Outcome Measures: Predictive and prognos-

tic features of episodes of malignant SE with persistent

epileptic activity after high-dose anesthetics compared
with features of the remainder of cases with refractory

S
Author Affiliations:
Department of Neurology,
CharitUniversittsmedizin
Berlin (Drs Holtkamp, Othman,
Buchheim, Masuhr, and
Meierkord), and Department of
Neurology, Auguste-ViktoriaKrankenhaus Berlin
(Dr Schielke), Berlin, Germany.

first- line anticonvulsants. The patient at risk is typically

young and suffers from encephalitis. Such patients
should be treated aggressively early in the course of SE
to prevent malignant SE.
Arch Neurol . 2005;62:14281431

(SE) MAY
occur with various degrees of
severity. In many cases, the
condition can be terminated
by first-line anticonvulsants, but about 30% to 50% of cases are
refractory.1,2 There are no standardized
treatment guidelines for refractory SE
(RSE). In current practice, anticonvulsant anesthetics are applied after failure of
first-line drugs in almost all patients with
generalized convulsive SE and in most patients with complex partial SE.3 However, even anesthetics may fail to terminate SE, 4-12 a condition for which we
suggest the term malignant SE (MSE). Malignant SE cannot be terminated by any
substance and continues for weeks or
months. In some of the reported cases, the
condition has been suggested to represent a distinct disease entity, but a cause
could not be determined.11
TATUS EPILEPTICUS

(REPRINTED) ARCH NEUROL / VOL 62, SEP 2005

148

While RSE has been characterized as to

frequency, risk factors, and outcome,2
simi- lar data on MSE are lacking. In the
cur- rent study, we compared predictive,
thera- peutic, and prognostic features
of MSE with those of the remainder of
cases of SE not responding to first-line
anticonvul- sants. The identification of
patients at risk may help to prevent the
development of MSE by the use of
aggressive therapeutic interventions
early in the course of SE.
METHODS

DEFINITION AND CLASSIFICATION

Malignant SE was defined as persistent clinical
and/or electrophysiologic epileptic activity immediately recurring within 5 days after tapering of the maximal dose of intravenous anesthetic anticonvulsants required to achieve an
electroencephalographic (EEG) burst suppres-

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2005 American Medical Association. All rights reserved.

sion pattern previously. This time gap was cho-

(REPRINTED) ARCH NEUROL / VOL 62, SEP 2005

149

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2005 American Medical Association. All rights reserved.

sen to ascertain that the suppressive effect of high-dose

anesthet- ics on the EEG, which may last hours to days,13,14
had ceased.
Refractory SE was defined as all forms of continuous clinical and/or electrophysiologic epileptic activity not responding
to first-line anticonvulsants regardless of the delay from seizure onset, and excluding patients with MSE. First-line anticonvulsant drugs had to be applied in adequate form and dose.
A treatment regimen was considered adequate if it included intravenous administration of at least 10 mg of diazepam, 1 mg
of clonazepam, 6 mg of lorazepam, or 5 mg of midazolam hydrochloride followed by phenytoin in a minimum dose of 10
mg/kg.2 Status epilepticus not treated with phenytoin was considered refractory with continuing epileptic activity after a
double dose of benzodiazepines.
In comatose patients with no or only subtle motor phenomena, SE was defined by the presence of repetitive generalized
or focal epileptiform discharges (spikes, sharp waves, and
spike waves) excluding periodic lateralized epileptiform
discharges, generalized periodic epileptiform discharges, and
stimulus- induced rhythmic, periodic, or ictal discharges.
Termination of SE was defined in patients treated with
anesthetics by ces- sation of seizure activity and absence of a
burst suppression pat- tern or flat line on the EEG. Patients
who did not receive an- esthetics were regarded as
successfully treated if seizure activity ceased clinically. Two or
more unprovoked epileptic seizures that had occurred more
than 4 weeks before the onset of SE defined preexisting
epilepsy.
Encephalitis was defined as encephalopathy (depressed or
al- tered level of consciousness lasting 24 hours or longer,
lethargy, or change in personality) and 1 or more of the
following symp- toms: fever, focal neurologic findings,
cerebrospinal fluid (CSF) pleocytosis, and EEG or
neuroimaging findings consistent with encephalitis,15 after
exclusion of systemic infections. Encephali- tis was infectious,
noninfectious, or of unknown etiology.

PATIENT SAMPLE
All episodes of SE not responding to first-line anticonvulsants
in patients aged 18 years or older admitted between January 1,
1993, and December 31, 2002, to the Neurological Intensive
Care Unit, CharitUniversittsmedizin Berlin, Germany, were
analyzed retrospectively. The study had the approval of the institutional review board. In a first step, the computer-assisted
patient files were searched by using the keywords status epilepticus, seizure clustering, and prolonged epileptic seizures. By
these criteria, 138 episodes in 129 patients suitable for a diagnosis of SE were identified. We then excluded all episodes of
SE that responded to adequate application of first-line anticonvulsants. We also excluded all episodes of nonepileptic origin
(psychogenic seizure, prolonged convulsive syncope, transient ischemic attack, etc) that had initially been regarded as
SE. The records of 5 patients with 6 episodes could not be retrieved in the archives. Thus, 35 episodes in 34 patients fulfilled our definition of SE refractory to first-line anticonvulsants and were included in the present analysis.

CLINICAL DATA
We used a structured data collection grid completed by 2 independent reviewers to analyze the clinical variables. For each
episode of SE, patients demographic data (age, sex) and history of epilepsy were documented. Furthermore, data concerning cause, symptoms, and treatment course were evaluated. Finally, duration of SE, treatment duration in the neurologic
intensive care unit, length of in-hospital stay, in-hospital mor-

tality, and functional outcome at hospital

discharge using the Glasgow Outcome Scale16
were analyzed.

STATISTICAL ANALYSIS

Tabl
e.
Cau
ses
of
Mali
gna
nt
and
Refr
acto
ry
Stat
us
Ep
ile
pti
cu
s

Data were collected with the database program Access 2000 (Mi- crosoft,
Redmond, Wash). Statistical calculations were per- formed with SPSS version
11.0 software (SPSS Inc, Chicago, Ill). Frequency distributions of predictive,
therapeutic, and prognos- tic features were compared between patients with
MSE and RSE to identify characteristics of MSE, and were calculated by the 2
test. For analysis of continuous data with normal distribution, the unpaired,
2-tailed t test was used, and for data with nonnor- mal distribution, the MannWhitney test was used. Predictors as- sociated with MSE (P .20) were entered
into a backward step- wise logistic regression analysis to identify independent
risk factors. Differences were considered significant if P .05.
RESULTS

STUDY POPULATION
A total of 35 episodes in 34 patients fulfilled the diag- nostic
criteria for SE not responding to first-line anti- convulsants. The
mean SD age was 52.1 18.4 years (range, 18-88 years). Seven
episodes (20%) were com- patible with our definition of MSE. Six
patients (86%) with MSE were female, but sex distribution was not
sig- nificantly different from that of patients with RSE (16 [57%]
female; P = .17). The mean SD age of patients with MSE (38.7 13
years) was significantly lower than that of patients with RSE (55.4
18.2 years; P = .03).
PREEXISTING EPILEPSY, CAUSE,
AND SYMPTOMS
Only 1 of the 7 patients with MSE had preexisting epi- lepsy,
compared with 8 (29%) of those with RSE. Encepha- litis was the only
single cause significantly more fre- quently seen in MSE (5 [71%])
than RSE (3 [11%]; P = .003). All 8 patients with encephalitis (5 with
MSE, 3 with RSE) had had fever and symptoms of encephalopathy for
at least
24 hours before the onset of seizure activity. In 6 of the pa- tients, CSF
pleocytosis (median white blood cell count, 52/
L; range, 16-256/L) with predominantly mononuclear cells was
found. Oligoclonal bands were found in the CSF of 3 patients, and in 2
of the 8 patients a causative agent was proven (herpes simplex virus
and cytomegalovirus). In a multivariate analysis, only encephalitis was
an inde- pendent risk factor for MSE (odds ratio, 31.5; 95% confidence interval, 2.5-396; P = .008). Further individual causes are listed in
the Table. The most common clinical presen- tation was complex
partial SE in both groups, found in 5 (71%) of MSE episodes and 12
(43%) of RSE episodes. No symptomatology of SE was seen
significantly more often in 1 of the 2 study groups. Focal onset of
seizure activity occurred in 5 (71%) of cases of MSE and thus had an
in- cidence not significantly different from that in RSE (22 [79%]).
TREATMENT
Titration of anesthetic anticonvulsants to a burst suppres- sion pattern
was performed by definition in all cases of MSE. An anesthetic was
administered in 10 cases of RSE (36%)

No. (%)

Cau
se
Infla
mma
tory
CNS
disea
ses

OU
TC
OM
E
ME
AS
UR
ES
Seizure duration
was significantly
longer in MSE
(me- dian, 17
days) than RSE
(median, 2 days;
P
.001). The
median length of
stay
in
the
neurologic
intensive care unit
R
was
significantly
S
longer in MSE (53
E
days) than RSE (10
days; P
.001).
(
Median
in-hospital
n
stay was also signifiCOMMENT
=
cantly longer in
MSE (100 days)
2
than RSE (25 days;
8

)
Encepha
litis
5 (71)
3 (11)
.003
Multiple
sclerosi
s
0
3 (11)
.5
Cerebrovasc
ular CNS
diseases
Acute
stroke
0
3 (11)
.5
Remote
stroke
0
4 (14)
.39
Intracere
bral
hemorr
hage
0
2 (7)
.64
Cerebral
venous
thrombo
sis
1 (14)
1 (4)
.37
Secondary
brain
damage

Inf
ant
ile
0
1
(4)
.8
Hy
po
xic
1
(14
)
2
(7)
.5
Neop
lasia
Pri
ma
ry
brai
n
tu
mo
r
0
1
(4)
.8
Cer
ebr
al
me
tas
tas
is
0
2
(7)
.64

P = .007). In-hospital
mortality was similar in
MSE (1 [14%]) and RSE
(5 [18%]). One patient
with MSE and 2 patients
with RSE died during
persistent seizures. The
other patients died of
medical
complications.
Five of 6 surviving
patients with MSE and 4
of 23 surviving pa- tients
with RSE were discharged
from the hospital with a
reduction of 2 points or
more on the Glasgow
Out- come Scale compared
with admission values,
indicating
marked
functional dependency (P
= .04).

Encephalopathy

In hyperammonemia
Hypertensive
Substance associated
Low levels of
AEDs
0
0
NA Alcohol
associated
0
3
(11)
.5
Drug associated
0
1 (4)
.8
Abbreviations: AEDs,
antiepileptic drugs; CNS,
central nervous system;
MSE, malignant status
epilepticus; NA, not
applicable; RSE, refractory
status epilepticus.

(N = 35)

Application of

Status
Termin
ation
Anesthetics
With
Further
Nonane
sthetizin
g
A
n
t
i
c

0
0

1 (4)
1 (4)

.8
.8

20% of all patients with

SE refractory to first-line
anticonvulsants.
In
a
systematic review including
almost 200 patients, the
efficacy of RSE treatment
with
anesthetic
anticonvulsants
was
assessed.
Epileptic
activity
recurred
between 60 minutes and 6
hours after the initial
loading dose in 8% to 20%
of cases and after 6 hours
of intravenous treatment
in 12% to 51% of cases,
depend- ing on the drug
used.17
However, these
Status figures indicate treatment
Epilepticus
Refracto failure with anesthetics and
First-linedo
not represent the
Anticonvulsants
frequency of malignant or
other difficult-to-treat forms
of SE. Thus, our study
provides the first data, to
our knowledge, about the
frequency of MSE in a large
series of patients with SE
not responding to first-line
anticon- vulsants.
In this study, encephalitis
was identified as an indeonvulsants
(n = 18)

pendent
predictor
of
MSE.
An
infectious agent
was iden- tified
in a quarter of
our
patients,
which is in line

w
i
t
h
s
t
u
S
t
a
t
u
s

(n = 11)

St
at
us
Pe
rsi
sti
ng
fo
r

5
d

T
e
r
m
i
n
a
t
i
o
n
W
i
t
h
A
n
e
s
t
h
e
t
i
c
s

dies on encephalitis
reporting
specific
microbiological
agents only in a
minority of cases.15
Therefore, encephalitis
frequently has to
be diagnosed on
the
basis
of
clinical,
CSF,
EEG,
and
magnetic
resonance imaging
find- ings15; in the
present
study,
symptoms
of
encephalopa- thy
and fever before
seizure onset, as
well as mononuclear
CSF
pleocytosis, were
regarded
as
sufficient.

T
i
t
r
a
t
e
d
t
o
E
E
G
S
e
i
z
u
r
e
S
u
p
p
r
e
s
s
i
o
n
(n = 6)

Stat
us
After Tapering
Anesthetics

(n = 4)

Previous
studies
found
encephalit
is to be a
primary
cause of SE

unknown.4,7-9,11 Van
Lierde et al11 reported
a series of 6

Figure. Flowchart indicating

the treatment response in
35 episodes of status
epilepticus refractory to
first-line anticonvulsants.

(P = .003), and in 4
(40%) of those cases
the anesthetic was
titrated to a burst
suppression pattern
(P = .02) (Figure).
Duration
of
anesthetic
therapy
was
significantly
longer
in
MSE
(median, 15 days)
than RSE (median, 3
days; P = .03).
Anesthetics of first
choice in MSE were
thiopental sodium (n
= 5), midazolam (n =
1), and propofol (n =
1). Anesthet- ics of
first choice in RSE
were propofol (n = 6),
midazolam (n = 2),
and thiopental (n =
2). Propofol was
used signifi- cantly
more often in RSE
than MSE (P = .04).

young
patients
with
refractory multifocal febrile
SE, most of whom required
long-lasting
general
anesthesia. A cause could
not be established in a
single case, and the existence of a distinct RSE
syndrome was discussed.
Interestingly,
mild
mononuclear
CSF
pleocytosis has been described in many patients
but has been attributed to
SE rather than to CNS
infection.4,8,11 Some studies
have fo- cused on SEinduced
pleocytosis,
describing increased white
blood cell counts in the
CSF up to 71/L in 10% to
20% of patients with SE
lacking concomitant infectious diseases.18,19 In a
clinical landmark study by
Ami- noff and Simon,19 a
polymorphonuclear CSF
pleocyto-

sis was reported in the vast majority of SE cases.

However, the typical CSF feature of viral encephalitis
is mono- nuclear pleocytosis, as seen in the current
patients and in most previously described patients with
malignant or otherwise-termed forms of long-lasting
SE.4,8,11 Thus, at least some of the reported cases of SE
refractory to an- esthetics with unknown cause may
have been caused by encephalitis. The present findings
indicate that a malig- nant course of SE depends on the
underlying cause. This argues against the hypothesis
that MSE or similar forms of difficult-to-treat SE
display a distinct clinical entity.
In the present study, some cases were regarded to be
refractory to first-line anticonvulsants after administration of a double dose of benzodiazepines without subsequent phenytoin.20 The rationale of this approach is
based on the preliminary finding that the addition of second- and third-line medications rarely controls seizures.21 Treatment failure with anesthetics did not depend on the drug used, but barbiturates, midazolam, and
propofol share similar mechanisms of action, since all
ex- ert -aminobutyric acid (GABA)ergic properties. In
con- tinuing SE, a progressive erosion of efficacy of
GABAer- gic drugs is well known in patients21 and
animal models,22 and the administration of nonGABAergic drugs such as ketamine hydrochloride has
been encouraged in RSE.23
Although experimental studies on ketamine in prolonged SE have been promising,24 clinical evidence is anecdotal.25 Further studies focusing on alternatives to or
endorsement of GABAergic drugs are urgently needed in
RSE and MSE.
The small number of patients, the retrospective design, and the lack of long-term prognostic data do not
allow firm conclusions about the possible impact of
MSE on clinical outcome. However, it should be noted
that more patients in the MSE group than in the RSE
group were severely disabled at hospital discharge.
Thus, MSE not only prolongs the in-hospital stay but
also is associ- ated with adverse effects on the clinical
outcome.
In summary, the present study indicates that the typical patient at risk to develop a malignant course of SE is
young and has encephalitis. Early aggressive treatment
strategies seem to be reasonable in these patients. To further investigate predictors, clinical features, and outcome of patients with MSE, the establishment of a prospective multicenter database appears to be appropriate.
Accepted for Publication: December 7, 2004.
Correspondence: Martin Holtkamp, MD, Department of
Neurology, CharitUniversittsmedizin Berlin,
Schumannstr 20/21, 10117 Berlin, Germany (martin
.holtkamp@charite.de).
Author Contributions: Study concept and design:
Holtkamp, Othman, Buchheim, and Meierkord. Acquisition of data: Holtkamp, Othman, Buchheim, and
Schielke. Analysis and interpretation of data: Holtkamp,
Othman, Buchheim, Masuhr, and Schielke. Drafting of
the manu- script: Holtkamp, Othman, Buchheim,
Masuhr, and Meierkord. Critical revision of the
manuscript for impor- tant intellectual content:
Holtkamp, Othman,
Buchheim, Schielke, and

Meierkord. Statistical analysis: Holtkamp,

Othman, and Buchheim. Administrative,
technical, and ma-

terial support: Holtkamp and Meierkord. Study supervi- sion: Masuhr

and Meierkord.
Acknowledgment: We thank Brigitte Wegner, MD, In- stitute of
Medical Biometry, CharitUniversittsmedi- zin Berlin, for
statistical advice.

REFERENCES
1. Treiman DM, Meyers PD, Walton NY, et al; Veterans Affairs Status Epilepticus Cooperative Study
Group. A comparison of four treatments for generalized con- vulsive status epilepticus. N Engl J
Med. 1998;339:792-798.
2. Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF.
Refractory status epilepticus: frequency, risk factors, and impact on outcome.
Arch Neurol. 2002;59:205-210.
3. Holtkamp M, Masuhr F, Harms L, Einhaupl KM, Meierkord H, Buchheim K.
The management of refractory generalised convulsive and complex partial sta- tus epilepticus in
three European countries: a survey among epileptologists and critical care neurologists. J Neurol
Neurosurg Psychiatry. 2003;74:1095-1099.
4. Pohlmann-Eden B, Gass A, Peters CN, Wennberg R, Bluemcke I. Evolution of MRI changes and
development of bilateral hippocampal sclerosis during long lasting generalised status epilepticus.
J Neurol Neurosurg Psychiatry. 2004;
75:898-900.
5. Skaff PT, Labiner DM. Status epilepticus due to human parvovirus B19 encepha- litis in an
immunocompetent adult. Neurology. 2001;57:1336-1337.
6. Lousa M, Sanchez-Alonso S, Rodriguez-Diaz R, Dalmau J. Status epilepticus with neuron-reactive
serum antibodies: response to plasma exchange. Neurology. 2000;
54:2163-2165.
7. Nixon J, Bateman D, Moss T. An MRI and neuropathological study of a case of fatal status
epilepticus. Seizure. 2001;10:588-591.
8. Chee MW, Lo NK. Asymmetric hippocampal atrophy and extra-hippocampal epi- lepsy following
refractory status epilepticus in an adult. J Neurol Sci. 1997;
147:203-204.
9. Yamashita M, Yamamoto T. Amygdalo-subicular degeneration in a young adult with status
epilepticus and choreoathetoid movements of acute onset. Clin Neuropathol. 1999;18:45-50.
10. Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol and midazolam in the treat- ment of refractory
status epilepticus. Epilepsia. 2001;42:380-386.
11. Van Lierde I, Van Paesschen W, Dupont P, Maes A, Sciot R. De novo crypto- genic refractory
multifocal febrile status epilepticus in the young adult: a review of six cases. Acta Neurol Belg.
2003;103:88-94.
12. Yaffe K, Lowenstein DH. Prognostic factors of pentobarbital therapy for refrac- tory generalized
status epilepticus. Neurology. 1993;43:895-900.
13. Parviainen I, Uusaro A, Kalviainen R, Kaukanen E, Mervaala E, Ruokonen E.
High-dose thiopental in the treatment of refractory status epilepticus in inten- sive care unit.
Neurology. 2002;59:1249-1251.
14. Stover JF, Lenzlinger PM, Stocker R, et al. Thiopental in CSF and serum corre- lates with
prolonged loss of cortical activity. Eur Neurol. 1998;39:223-228.
15. Glaser CA, Gilliam S, Schnurr D, et al. In search of encephalitis etiologies: diag- nostic challenges
in the California Encephalitis Project, 1998-2000. Clin Infect Dis. 2003;36:731-742.
16. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet.
1975;1:480-484.
17. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with
pentobarbital, propofol, or midazolam: a systematic review. Epilepsia. 2002;43:146-153.
18. Barry E, Hauser WA. Pleocytosis after status epilepticus. Arch Neurol. 1994;51:
190-193.
19. Aminoff MJ, Simon RP. Status epilepticus: causes, clinical features and conse- quences in 98
patients. Am J Med. 1980;69:657-666.
20. Manno EM. New management strategies in the treatment of status epilepticus.
Mayo Clin Proc. 2003;78:508-518.
21. Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s.
Neurology. 1993;43:483-488.
22. Kapur J, Macdonald RL. Rapid seizure-induced reduction of benzodiazepine and
Zn2 sensitivity of hippocampal dentate granule cell GABAA receptors. J Neurosci.
1997;17:7532-7540.
23. Bleck TP. Refractory status epilepticus in 2001. Arch Neurol. 2002;59:188-189.
24. Borris DJ, Bertram EH, Kapur J. Ketamine controls prolonged status epilepticus.
Epilepsy Res. 2000;42:117-122.
25. Sheth RD, Gidal BE. Refractory status epilepticus: response to ketamine. Neurology.
1998;51:1765-1766.