Acta Neurol Scand 2007: 115 (Suppl.

186): 715 2007 Blackwell Munksgaard

No claim to original US government works
ACTA NEUROLOGICA
SCANDINAVICA

Advances in the pathophysiology of status

epilepticus
Chen JWY, Naylor DE, Wasterlain CG. Advances in the
pathophysiology of status epilepticus.
Acta Neurol Scand 2007: 115 (Suppl. 186): 715.
2007 Blackwell Munksgaard. No claim to original US government
works.
J. W. Y. Chen, D. E. Naylor,
C. G. Wasterlain
Department of Neurology and Brain Research Institute,
Geffen School of Medicine at UCLA, and VA Greater Los
Angeles Health Care System, Los Angeles, CA, USA

Status epilepticus (SE) describes an enduring epileptic state during All authors declare no conflict of interests
which seizures are unremitting and tend to be self-perpetuating. We
describe the clinical phases of generalized convulsive SE, impending
SE, established SE, and subtle SE. We discuss the physiological and
biochemical cascades which characterize self-sustaining SE (SSSE) in
animal models. At the transition from single seizures to SSSE, GABAA
(gamma-aminobutyric acid) receptors move from the synaptic
membrane to the cytoplasm, where they are functionally inactive. This
reduces the number of GABAA receptors available for binding GABA
or GABAergic drugs, and may in part explain the development of time-
dependent pharmacoresistance to benzodiazepines and the tendency of
seizures to become self-sustaining. At the same time, spare subunits of
AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
and NMDA (N-methyl-D-aspartic acid) receptors move from Claude G. Wasterlain, Department of Neurology, Geffen
subsynaptic sites to the synaptic membrane, causing further School of Medicine at UCLA, and VA Greater Los
Angeles Health Care System, West L.A. VA Medical
hyperexcitability and possibly explaining the preserved sensitivity to Center (127), 11301 Wilshire Boulevard, West Los
NMDA blockers late in the course of SE. Maladaptive changes in Angeles, CA 90073, USA
neuropeptide expression occur on a slower time course, with depletion Tel.: +1 310 268 3595
of the inhibitory peptides dynorphin, galanin, somatostatin and Fax: +1 310 268 4611
neuropeptide Y, and with an increased expression of the proconvulsant e-mail: wasterla@ucla.edu
tachykinins, substance P and neurokinin B. Finally, SE-induced
neuronal injury and epileptogenesis are briey discussed. Accepted for publication 11 December, 2006

the natural course of SE in 38 patients and

Introduction
Status epilepticus (SE) describes a unique patho-
logical state, an enduring epileptic condition
during which seizures tend to become self-perpet-
uating. It is distinct from a series of severe seizures,
and this was already recognized by Trousseau (1):
in the status epilepticus, something happens (in the
brain) which requires an explanation. Powerful
inhibitory mechanisms quickly terminate even
severe seizures, but fail during SE. As a result,
SE rarely terminates spontaneously before exhaus-
tion and brain damage sets in.
Status epilepticus was rst described in the
XXVXXVI tablets of the Sakikku cuneiform
written during the 7th or 8th century bc (2), but
it was not until 1876 that SE was clinically dened
by Bourneville (3), as more or less incessant
seizures. In 1903, Clark and Prout (4) described
recognized three distinct phases in its clinical
evolution: an early phase of pseudo-status, fol-
lowed by two succeeding phases of convulsive and
stuporous status. Recent experimental and clinical
evidence (58) supports that subdivision.
Unfortunately, we have seen only limited pro-
gress in our understanding and treatment of
SE. Recent population-based statistics in Virginia
show that mortality rate is still 14% in young
adults and 38% in the elderly (9). The VA
Cooperative Study actually found a mortality
rate of 55% in adults (6). In children, mortality
rate was found to be only 3% in the Richmond
study (9), and both mortality and sequellae may
have been reduced during the last 30 years
(10, 11), but reports of SE-associated neuronal
injury (12) or of brain atrophy following SE are
still frequent (1320).

7
Chen et al.
Very few placebo-controlled trials of the treat-
ment of SE have been carried out (6, 21, 22). Most
new antiepileptic drugs are not available in intra-
venous form for treating SE, and no drug has ever
been accepted for the treatment of SE based on
type I evidence of efcacy and safety. This deplor-
able state of affairs makes it all the more imper-
ative that we try to understand SE and its
consequences, in order to develop more effective
treatments. In this review, we try to dene SE and
to summarize recent progress in the pathophysio-
logical mechanisms that initiate and maintain it.
The definition of SE
Earlier clinical descriptions were restricted to gen-
eralized tonicclonic SE. In the rst international
meeting on SE, the Xth Marseilles Colloquium in
1962, Gastaut (23) stated that there are as many
types of status as there are types of epileptic
seizures and dened SE as a term used whenever a
seizure persists for a sufcient length of time or is
repeated frequently enough to produce a xed or
enduring epileptic condition (24). He suggested
that the diagnosis of SE requires 3060 min of
enduring epileptic condition, but did not formally
include time parameters in his denition. In spite of
its qualities, the difculty of applying Gastauts
denition in clinical settings and clinical trials
quickly became evident. To solve this dilemma,
time-dependent denitions of SE became widely
accepted. The duration of what is accepted as SE
shortened from 30 min in the guidelines of the
Epilepsy Foundation of Americas Working Group
on Status Epilepticus (25) to 20 min (26) to 10 min
in the VA Cooperative Trial (6), and recently in the
operational denition of SE to 5 min (2729). This
trend reects the need to nd a denition of SE that
does not delay therapeutic intervention, even if not
all such patients are in a true enduring epileptic
condition. Early therapeutic intervention mitigates
the risk of SE-induced neuronal injury (5, 30, 31)
and of the time-dependent development of phar-
macoresistance (32, 33).
The sequential phases of SE: impending SE, established SE, and
subtle SE
Our current understanding of the basic mechanisms
of SE in animal models and in clinical situations ts
the Clark and Prout description of three sequential
phases of SE (4), which we call impending SE,
established SE, and subtle SE (7, 34).
Impending status epilepticus is dened as con-
tinuous seizures or intermittent seizures without full
recovery of consciousness between seizures lasting
8
more than 5 min. Previous authors have used a
similar concept, e.g. early heralds of status (4) or
early SE (35). Established status epilepticus is
dened as clinical or electrographic seizures lasting
more than 30 min without full recovery of con-
sciousness between seizures. The transformation
from impending SE to established SE is probably a
continuum, and at best could only be approximated
by time parameters. But there is good support in
the clinical and experimental literature for a cut-off
at 30 min: this is the time constant of transformation
from prolonged seizure to SE in the Richmond data
(7, 8), and the time when SE has become self-
sustaining in experimental animals (5), when
SE-induced damage becomes evident (31), and
when pharmacoresistance to anticonvulsant has
developed (6, 33, 36). The term subtle status
epilepticus was coined by Treiman (6) to describe
the late, burned-out stage of SE during which both
the motor and electroencephalographic (EEG)
expression of seizures becomes less orid. This
stage is similar to the stuporous stage described
by Clark and Prout (4).
Basic mechanisms: current concepts
Self-sustaining SE
One of the distinguishing feature of SE is the self-
sustaining, or in Gastauts words, enduring epi-
leptic condition. Models of self-sustaining SE
(SSSE) were developed by a number of investiga-
tors (5, 3745). In most electrical and chemical
models of SE initiated in conscious, unanesthetized
animals, seizures rapidly become self-sustaining
despite the withdrawal of the epileptogenic stimu-
lus. Human data are far less clear, but show that
seizures which last more than 30 min rarely stop
spontaneously (8). Fig. 1 demonstrates that, after
30 min of intermittent stimulation of an excitatory
glutamatergic pathway (gray bar) in the rat,
stopping the stimulation no longer stops electro-
graphic (Fig. 1A,C) or behavioral (Fig. 1B) sei-
zures, which self-perpetuate for many hours and
eventually become subtle (Fig. 1C; 12 h). Vice-
domini and Nadler showed that these properties
are shared by many excitatory pathways (46).
Time-dependent pharmacoresistance
Another unique feature of SSSE is the progressive,
time-dependent development of pharmacoresis-
tance: the potency of benzodiazepines may
decrease 20-fold in 30 min of SSSE (32); phenytoin
also loses potency, but more slowly (32). By
contrast, even late in its course, NMDA blockers
 Pathophysiology of status epilepticus

Figure 1. Features of SSSE induced by 30 min perforant path stimulation (PPS). (A) Representative course of spikes. (B) 24 h
distribution of seizures (black bars). PPS is indicated by the gray bar on top. Each line represents 2 h of monitoring. (C) Electro-
graphic activity in the dentate gyrus during SSSE [modied from Mazarati et al. (5)]. (DF) The effects of an NMDA receptor
blocker (F) and an AMPA/kainate antagonist (E), administered 10 min after the end of PPS, on SSSE induced by 30 min PPS. Each
graph shows the number of spikes per 30 min epoch, plotted against time during the course of SSSE. PPS is indicated by gray bars.
Notice that ketamine (10 mg/kg i.p.) irreversibly aborted SSSE. CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione) (10 nmol into the
hilus) induced only transient suppression of seizures, which reappeared within 24 h [modied from Mazarati and Wasterlain (47)].
(G) Time-dependent development of pharmacoresistance in SSSE induced by 60 min PPS. Bar graphs on the left: When administered
before PPS, both diazepam (DZP) and phenytoin (PHT) very eectively blocked the development of SSSE. On the right: When
injected 10 min after the end of PPS, neither drug aborted SSSE, although they slightly shortened its duration. *P < 0.05 vs control
(CON). #P < 0.05 vs DZP and PHT pretreatment. Open bars show cumulative seizure time (in minutes), and black bars show the
duration of SSSE (in minutes) (time of occurrence of the last seizure during SSSE) [modied from Mazarati et al. (32)].

continue to be effective in stopping SSSE (47). This
phenomenon is not present during the rst
1015 min of seizures. Pharmacological studies in
animals suggest two distinct phases of SSSE: the
initiation phase and the maintenance phase, which
later can become subtle. The initiation of SSSE
can be easily blocked by many pharmacological
agents which enhance inhibition or reduce excita-
tion (47, 48). However, once SSSE is established, it
is maintained by underlying changes which do not
depend on continuous seizure activity (47) and it is
effectively terminated by only a few agents, most of
which inhibit glutamatergic neurotransmission (47,
49). Fig. 1E shows that, after SSSE is established,
injection of a blocker of AMPA/kainate synapses
into the stimulated hippocampus blocks spikes
(and seizures) for hours, but when the drug is
eliminated, the underlying increase in excitability
expresses itself and seizures recur. The same dose
of benzodiazepine which easily blocks SE when
given early is far less effective when given late
(Fig. 1G). However, ketamine easily terminates
established SE (Fig. 1F).
Pathophysiological and biochemical cascades of SSSE
Repeated seizures produce broad and complex
cascades of pathophysiological and biochemical

9
Chen et al.

Figure 2. Intracellular distribution of GABAA subunits in hippocampal neurons from SE and control rats. Top row: Double-label
immunocytochemistry in dentate and CA3c of control and SE animals using antibodies to GABAA b2/b3 subunits (red) and
synaptophysin (green). Note the co-localization (yellow) of receptor subunits with presynaptic sites in controls (left) and greater
internalization of receptor subunits during SE (right). Second row: Similar confocal image of granule cells using antibodies to
GABAA c2 subunits (red) and synaptophysin (green). Internalization is seen in soma and proximal dendrites of animal in SE. Third
row: EEGs recorded from dorsal hippocampus 1 h after PPS or sham stimulation. Fourth row: mIPSC mean traces from a typical
granule cell from a control and an SE animal, demonstrating smaller amplitude and prolonged decay in the latter [modied from
Naylor et al. (75)].

changes in the brain. The rst milliseconds to
seconds are dominated by the release of neuro-
transmitters and modulators, the activation and
inactivation of ion channels, and receptor phos-
phorylation and desensitization. In a framework of
seconds to minutes, receptor tracking, mainly of
the GABA and glutamate receptors, is responsible
for the key adaptations. The existing receptors can
move from the synaptic membrane into endo-
somes, or be mobilized from storage sites to the
synaptic membrane (Fig. 2). This process drastic-
ally enhances excitability by decreasing the number
of inhibitory receptors and increasing the number
of excitatory receptors in the synaptic cleft (Fig. 3)
(49, 50). In the minutes to hours time range,
neuropeptide modulators often increase the expres-
sion of proconvulsive neuropeptides and decrease
the availability of inhibitory neuropeptides
(5055), and this maintains enhanced excitability.
Finally, in the hours to perhaps days to weeks

10
 Pathophysiology of status epilepticus

Figure 3. Model of the role of receptor trafcking in the transition from single seizures to SE. After repeated seizures, the synaptic
membrane of GABAA receptors forms clathrin-coated pits (Cl), which internalize. This inactivates the receptors, which are no longer
within the reach of the neurotransmitter. These vesicles evolve into endosomes (E), and reach a phosphorylation-dependent decision
point where they are transported toward the soma to lysosomes (L) where the receptors are destroyed, or to the Golgi apparatus (G)
from where they are recycled to the membrane. By contrast, in NMDA synapses, subunits are mobilized to the synaptic membrane
and assemble into additional receptors. As a result of this trafcking, the number of functional NMDA receptors per synapse
increases while the number of functional GABAA receptors decreases [reproduced from Chen and Wasterlain (7) and Wasterlain and
Treiman (76)].

following seizures, long-term changes in gene
expression occur. The changes in gene expression
are the combined effects of repeated seizures, of
seizure-induced neuronal death, and of the subse-
quent neuronal reorganization. Some of the gene
expression represents plastic adaptation to seizure
activity. Many of the early changes in gene
expression (during active SE) are not consolidated
at the translational level because SE profoundly
inhibits brain protein synthesis (56).
Mechanisms involved in the transformation from isolated
seizures to SE
Trafficking of GABA and glutamate receptors
There are several lines of evidence suggesting that
endocytosis of hippocampal GABAA receptors
takes place during the transition from single
seizures to self-sustaining SE. Miniature inhibitory
post-synaptic currents (mIPSCs), which reect the
post-synaptic response to a packet of GABA
released into the synaptic cleft, show a 27%
decrease (Fig. 2). This may underestimate the
change that takes place during SE, as some
recovery might occur during the 90 min that it
takes to prepare the slice in vitro. Based on a seven-
state model of the GABAA receptor, we can
calculate the change in the number of receptors
per synapse for the cell population studied. The
number of GABAA receptors per dentate granule
cell synapse is 18  4 in rats in lithium-pilocarpine
SE for 1 h, compared with 36  11 in controls
(Fig. 3) (49). Immunocytochemical/confocal micr-
oscopy studies of the c2 and b2)3 subunits on the
GABAA receptors show a decrease in the number
of subunits on the synaptic membrane, and an
increased number of subunits in the interior of the
cell (49, 57). Endocytosis and the decrease of
functional GABAA receptors in the synaptic cleft
may in part explain the failure of GABAA inhibi-
tion and the progressive, time-dependent pharma-
coresistance to benzodiazepines (32, 33), which

11
Chen et al.

develop during SE. Interestingly, extrasynaptic
GABAA receptors do not endocytose, raising the
possibility that stimulation of those extrasynaptic
receptors with neurosteroids might be useful in the
treatment of SE.
At the same time, AMPA and NMDA receptor
subunits are recruited to the synaptic membrane
where they form additional excitatory receptors
(Fig. 3) (58). This change is also maladaptive and
proconvulsant, because it further enhances excita-
bility in the midst of uninhibited seizures. Immun-
ocytochemical studies show that the NR1 subunits
of NMDA receptors move from subsynaptic sites
to the synaptic surface, and physiological investi-
gations show an increase in the number of func-
tional NMDA receptors per dentate granule cell
synapse from 52  12 receptors per synapse in
controls to 7.8  1.2 after 1 h of SE (Fig. 3).
Changes in function of synaptic enzymes may
also enhance excitability. The autophosphorylation
of calmodulin kinase II, for example, makes the
enzyme calcium-independent and may increase

Figure 4. Role of neuropeptides in status epilepticus. Galanin-like immunoreactivity in the hippocampus of a control rat (A) and of
an animal killed 3 h after the end of 30 min PPS, during SSSE (B). Notice a dense, ne network of galanin-immunoreactive bers in
the control rat, and their disappearance in the animal in SSSE. Scale bar 200 lm. (CE) Eects of galanin receptor ligands on
SSSE. Galanin is a non-selective GALR1 and GALR2 receptor agonist. 2-Ala-galanin is a selective GALR2 receptor agonist. M15
and M40 are peptides that preferentially block GALR2, and M35 is a preferential blocker of GALR1. (C) Eects of peptides injected
prior to 30 min PPS. (D) Eects of peptides injected after the end of PPS. Galanin, but not 2-Ala-galanin, stopped established SSSE.
These eects were abolished by all three galanin receptor antagonists. (E) Eects of galanin receptor antagonists injected prior to
7 min PPS. M35, but not the two other galanin receptor antagonists, facilitated the establishment of SSSE when given prior to 7 min
PPS. Bars indicate mean  SD of the ratio of SSSE durations in the peptide-treated to control animals. SSSE duration in controls is
indicated by the dashed line. Absolute values (mean  SD, in min) of SSSE duration in control rats are indicated above the dashed
line. *P < 0.05 vs control [modied from Mazarati et al. (54)]. (F) Galanin transgenic mice show altered ability to establish SSSE.
Left: EEG in the dentate gyrus 30 min after the end of PPS. Right: Time in seizures after PPS (mean  SEM). PPS for 30 min was
insucient to induce SSSE in wild-type mice (WT), but induced SSSE in galanin knockouts (GalKO). PPS for 60 min induced SSSE
in WT controls, but had no eect in galanin-overexpressing animals (GalOE). *P < 0.05 vs respective WT control [reproduced from
Mazarati et al. (77)]. (G, H) In situ hybridization of preprotachykinin mRNA in a control animal (G) and an animal killed during
SSSE, 6 h after 30 min PPS (H). (J) The SP antagonist Spantide II (50 nmol into the hilus 10 min after the end of 30 min PPS)
aborted SSSE. Substance P (SP, 10 pmol) injected into the hilus prior to 7 min PPS facilitated the establishment of SSSE. Asterisks
indicate a signicant dierence compared with control (P < 0.05) [reproduced from Liu et al. (50)].

12

glutamate release (59). Other changes are adaptive,
and try to restore homeostasis. For example, traf-
cking of tachykinin receptors decreases the number
of receptors, which would be expected to maintain
homeostasis and decrease hyperexcitability (60).
Maladaptive changes in neuropeptide expression
Self-sustaining SE is associated with a depletion of
the predominantly inhibitory hippocampal
peptides dynorphin (55), galanin (54), somatostatin
(52, 53) and neuropeptide Y (53), and with
increased expression of the proconvulsant tachy-
kinins, substance P and neurokinin B (50). These
changes abate as SSSE subsides, and may play a
role in maintaining self-sustaining seizures over
many hours. The rich network of galanin-IR
hippocampal bers is depleted within 3 h of SE
(Fig. 4A,B). Galanin and its agonists are remark-
ably effective blockers of SSSE (Fig. 4C), acting
through the GalR1 and GalR2 receptors (Fig. 4D),
and galanin antagonists favor the development of
SSSE (Fig. 4E). Galanin-overexpressing mice are
quite resistant to the development of SSSE while
galanin KO mice are very susceptible to it
(Fig. 4F). By contrast, substance P injected into
hippocampus triggers SSSE in response to subcon-
vulsant stimulation, and SSSE is blocked by
substance P antagonists (Fig. 4J). Preprotachyki-
nin mRNA, which codes for substance P, is
expressed during SSSE in dentate granule cells,
where its expression is undetectable in controls
(Fig. 4G,H). These maladaptive changes in peptide
networks are slower to develop than the receptor-
trafcking changes described earlier, but they tilt
the balance between hippocampal excitation and
inhibition in favor of excitation, and may partici-
pate in the maintenance phase of SE.
SE-induced neuronal injury and death
Meldrum et al. (62, 63) showed that seizures per se
cause neuronal loss, and Sloviter (61) demonstra-
ted that this loss results from excessive neuronal
ring. SSSE induces widespread neuronal death,
which may take the form of programmed necrosis
(64, 65) mediated through mitochondrial release of
death proteins which activate caspases (66, 67).
Apoptosis can also occur, particularly in the
immature brain. In humans, evidence that seizures
induce neuronal injury is limited and often anec-
dotal. Patients who die from SE show brain lesions
and decreased neuronal density in the hippocam-
pus (68). Neuron-specic enolase, a marker of
neuronal death, is increased in the serum of
patients after SE (69, 70). Many MRI studies
Pathophysiology of status epilepticus
found cerebral edema acutely and atrophy chron-
ically after SE (15, 16, 71, 72), although there are
exceptions (73). The presence of focal atrophy in
areas of intensive seizure activity (14, 17, 18)
supports a causal link between seizures and cell
loss. Patients who had a normal brain MRI before
SE, showed atrophy by MRI after SE and neur-
onal loss at autopsy (19). SE induced by domoic
acid poisoning showed neuronal loss at autopsy
(74).
SE-induced epileptogenesis
Status epilepticus-induced epileptogenesis is a
widespread phenomenon across many types of
SE, many animal species and many ages. Human
evidence is remarkably sparse, and subject to
diverging interpretations. Although it may be one
of the most important problems associated with
SE, a discussion of its pathophysiology is beyond
the scope of this review.
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