Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepticus

nonconvulsive status are controversial, and not all
papers describe the same entity.

Part of the reason for the confusion and controversy
surrounding NCSE is its relative youth as a diagnostic
and clinical entity. Convulsive seizures, and probably
seizures prolonged enough to constitute convulsive
status epilepticus (SE), were known in antiquity, and
convulsive status has been described in the medical
literature for the past few centuries. NCSE, however,
was unknown to early epileptologists. There are
clearly many other causes of altered consciousness
and behavior, and the relationship between spells of
altered consciousness and epilepsy (recognized primarily
by the repetitive stereotyped, involuntary motor
activity of convulsions) was not obvious. The connection
became understandable when briefer episodes
of nonconvulsive seizures such as absence seizures
became recognizable and diagnosable through the development
of EEG technology in the 1930s and 1940s
(1). Only then could it be recognized that epileptic
seizures and these spells of staring, immobility, and
unresponsiveness had a related physiologic basis. This
also made it clear that both conditions could be treated
with antiepileptic medications.

It may have been postictal confusion that first suggested
the connection between epileptic convulsions
and prolonged episodes of altered mental status. A
century ago, Charcot in Paris and Gowers in England
speculated on whether episodes of altered behavior in
patients with epilepsy represented seizures or a postictal
state (2). It was only after the development of the
EEG decades later that this question could be answered.

Lennox's studies of absence seizures and their prolongation
to the state of absence status epilepticus
effectively established the existence of NCSE. Schwab
described SE of a nonconvulsive variety in the 1950s
(3). Niedermeyer and Khalifeh described "spike wave
stupor" in 1965 (4), and it was only in the 1970s that
more case reports and larger series began to make
NCSE known to most neurologists. The history of
nonconvulsive status has been summarized in greater
detail by Kaplan (2).

I. TYPES OF NCSE

NCSE has generally been divided into two types:
absence SE, characterized by generalized spike and
slow wave discharges, and complex partial SE, usually
with focal discharges and considered the equivalent of
prolonged or repetitive complex partial seizures. Indi-

TABLE 1
Absence Status Epilepticus: Clinical Features

vidual
cases may have features of one or the other, or
both; overlap is substantial and is a source of major
confusion. There are other possible types of NCSE that
do not fit neatly into one of these categories.

Absence SE may be considered those cases similar
to "status epilepticus in petit mal" described by
Schwab (3) (Table 1). They have no features of a focal
epilepsy and have rapid, generalized 3-Hz epileptiform
discharges on the EEG (Fig. 1). Pure cases represent
very prolonged absence seizures. Patients often
have a history of absence, myoclonic, or generalized
convulsive seizures. Typical clinical manifestations include
confusion with occasional blinking or myoclonus,
with episodes lasting up to days. They may start
with a generalized convulsion. Medication withdrawal
and other precipitants may prompt an episode
of absence SE. Such patients were described well by
Andermann and Robb (5). More recently, relatively
frequent episodes have been reported in elderly patients
with no prior epilepsy ("de novo SE"), in association
with withdrawal of benzodiazepines, at times
used for anxiety or sleep (6).

Other than absence seizures, there are several types
of generalized seizures that can be so prolonged as to
constitute status epilepticus. These others, including
myoclonic status (7) and tonic, clonic, and generalized
tonic– clonic seizures, all have substantial motor manifestations,
and are not "nonconvulsive."

Complex partial status epilepticus (CPSE) is NCSE
with a presumed focal onset (Table 2). CPSE was
reported less often than absence SE until recently,
perhaps because of some very stringent definitions
(described later). Clinical manifestations include an
"epileptic twilight state" with a lack of responsiveness
or confusion, and bizarre, and particularly fluctuating,
behavior (8 –11). At times there are oral or manual
automatisms. Cases include both prolonged repetitive
complex partial seizures and continuous seizure activity.
Possibly because of the association with vascular

disease and prior focal epilepsy, CPSE appears somewhat
harder to treat than absence SE and is more
likely to recur. Some NCSE studies are restricted to
pure absence SE, some to CPSE, and many include all
varieties of NCSE.

Logically, there are many forms of focal seizures
without convulsions or other dramatic motor presentations,
depending on where in the brain they start
and develop. Prolonged focal seizures from sensory or
association areas of the brain may constitute other
forms of NCSE.

TABLE 2
Complex Partial Status Epilepticus: Clinical Features

Confusion to unresponsiveness
"Epileptic twilight state" with fluctuating mental status
Recurrent or prolonged complex partial seizures
Observed or presumed focal onset, often temporal or frontal; focal
slowing and discharges on EEG
Often prior epilepsy and vascular disease in the elderly
Can last up to months; often recurrent
May produce severe amnesia following

Other forms of focal NCSE are discussed later with
respect to their presentations. One of the most interesting
is a disturbance of language (without confusion
or stupor) termed aphasic status epilepticus. This can
appear quite similar to the new-onset aphasia from a
stroke. The location of epileptiform discharges corresponds
at times very well to the classic location of
vascular lesions causing similar aphasias. For example,
left-frontal-onset focal seizures may produce more
of a Broca aphasia with preserved comprehension
(12), while more posterior and inferior seizures may
produce an aphasia more akin to a Wernicke aphasia
(13, 14). Aphasia is most properly diagnosed when the
seizures remain focal rather than extend to involve an
alteration in consciousness (15), which would be a
complex partial seizure. Speech arrest alone, however,
is not properly considered aphasia, and seizures causing
speech arrest may arise in many different areas of
the brain.

Overlap. The definite overlap of absence SE and
CPSE confuses the classification of NCSE and may
explain why reported cases of absence SE outnumber
those of CPSE while complex partial seizures are far

more common than absence seizures in overall adult
clinical practice. Both exhibit confusion or other mental
status changes along with minimal motor activity
and usually no systemic physiologic disturbances. A
history of primary generalized epilepsy and rapid
rhythmic, generalized EEG discharges argue in favor
of absence SE, while a history of focal seizures or other
focal neurologic disease and a fluctuating course suggest
CPSE. Nevertheless, an individual seizure may
start focally and generalize rapidly. Cases considered
as atypical absence SE may well be complex partial
seizures with generalization and prolongation. This
concept is buttressed by work correlating EEGs with
the clinical presentation. Tomson and colleagues (16)
studied 32 patients with NCSE, 14 with focal EEG
changes (thus labeled CPSE), and 18 with generalized
discharges, 6 of whom had primary generalized epilepsy.
Patients could not be differentiated by clinical
features alone. Similarly, Granner and Lee (17) noted a
predominance of generalized EEG discharges in
NCSE, but many of these patients had focal discharges
on interictal EEGs or after antiepileptic drug (AED)
treatment.

There are additional confused, stuporous, or comatose
patients found to have rapid, rhythmic, continuous
epileptiform discharges on the EEG, with or without
clinically evident seizures, in the setting of severe

medical illnesses or, perhaps most commonly, following
clinically evident convulsions or generalized convulsive
SE. Seldom are the EEG discharges or seizures
the only clinical problems. Many of these patients
have serious cerebrovascular disease or toxic and metabolic
encephalopathies, or both (18, 19). Figure 2
illustrates an example. These patients might be termed
in electrographic status epilepticus (ESE) or as having
epileptic encephalopathies. These cases may be included
as types of NCSE, whatever the response to
AEDs, but this is controversial.

II. EPIDEMIOLOGY

More than 20 years ago, Celesia (20) stated that
NCSE constituted nearly a quarter of SE cases in a
moderate-sized series. Subsequently, Shorvon (21) estimated,
from the prevalence of different types of epilepsy
and the incidence of episodes of SE in each, that
there were approximately 3.5 cases of complex partial
SE and 15 cases of other nonconvulsive SE per 100,000
population per year. Interestingly, DeLorenzo and colleagues
(22) estimated, from ascertainment of actual
cases, an incidence of about 60 cases of SE per 100,000
per year in the United States. Together with Shorvon’s
figures, this would corroborate Celesia’s estimate of

one-quarter of all SE cases. Still, the diagnosis is often
missed, and any ascertainment must be an underestimate.
Tomson and colleagues (16) found 1.5 cases of
NCSE per 100,000 per year in Sweden, about one-tenth
the estimated incidence. Clearly, NCSE is not a rare
condition, but it is often not noticed or misdiagnosed.
There are certainly many more cases waiting to be
diagnosed.

III. PRESENTATION

NCSE presents in protean ways, accounting in part
for its underrecognition and underdiagnosis. Some
patients present with typical absence or complex partial
SE, as described earlier, but many other unusual
alterations in consciousness, behavior, and neurologic
function can be manifestations of NCSE. Focal SE confined
to nonmotor areas of the brain may be particularly
deceptive.

Focal weakness or sensory changes, including visual
field abnormalities, may be the manifestation of
focal NCSE (23). Visual hallucinations and visual loss
similar to those of migraine can be an unusual manifestation
of focal NCSE (24). Catatonia (25) and atonia
(26) have been described as manifestations of NCSE.
Speech difficulties due to dysarthria rather than aphasia
can be caused by SE arising in the opercular regions
(27). Prolonged somasthetic or visceral sensory
disturbances may represent sensory status (28). NCSE
may produce diminished responsiveness following
electroconvulsive therapy (29).

Among the most likely settings for NCSE is following
supposed control of convulsive or other SE, but
with persistent neurologic dysfunction despite apparently
adequate treatment (e.g., Fig. 3). Fagan and Lee
(30) described eight patients who had ongoing NCSE
after treatment for convulsive status. SE was generalized
on the EEG. The patients’ conditions ranged from
confused to comatose, and all improved with treatment.
It was surmised that patients might have fared
poorly had the NCSE not been discovered. DeLorenzo
and colleagues (31) found that nearly half of the patients
with apparent control of convulsive SE demonstrated
persistent electrographic seizures when followed
by EEG and that 14% of the total population
monitored warranted a diagnosis of ongoing NCSE.
Patients were comatose, but with no overt motor signs,
and the diagnosis was made possible by EEG alone.

Confusion in the elderly is also a relatively common
setting for NCSE (32), but there are of course many
other possible causes. Many of the elderly patients

diagnosed with NCSE have not had epilepsy earlier in
life but have had benzodiazepine withdrawal or other
significant effects of medications on the brain (6).

Confusion is a common problem in emergency
rooms. NCSE is a possible explanation and is probably
missed frequently. In one larger series of patients with
NCSE seen in emergency rooms, agitation, lethargy,
disruptive behavior, mutism or other language disturbances,
delirium, staring, oral automatisms, inappropriate
laughter or crying, rigidity, and several other
types of bizarre behavior were presenting signs (33).
Mistaken diagnoses included metabolic encephalopathies,
postictal states, psychiatric disorders, intoxication,
and hyperglycemia. Many of the patients had
some suggestions that NCSE was a possibility through
earlier epilepsy or other neurologic dysfunction, such
as strokes. Renal disease and medication or other intoxication
were common precipitants.

IV. DEFINITIONS

Making a diagnosis of NCSE is clearly dependant
on the definition of the illness or criteria we use for
determining that NCSE is a proper label for the patient’s
illness. Definitions have not been accepted uniformly,
so different studies describe different clinical
entities, leading to some confusion in diagnosis. The
underdiagnosis of NCSE and the difference of opinions
on appropriate definitions of NCSE surely reinforce
one another.

Though there is a lack of universally accepted definitions,
some features are common to most diagnostic
criteria. There are three main features to the diagnostic
criteria for NCSE in clinical studies (Table 3). All patients
will have clinical neurologic deficits, particularly
alterations in alertness and responsiveness. The
associated EEG findings and a rapid response to
AEDs, particularly benzodiazepines, are variable and
are more controversial components of the criteria.

Early definitions were particularly demanding. To
diagnose complex partial SE, Mayeux and Lueders
(34) required prolonged complex partial seizures with
continuous focal or secondarily generalized seizures
on the EEG or repeated complex partial seizures with
a focal EEG. Treiman and Delgado-Escueta (11) required
recurrent or persistent complex partial seizures,
fluctuating neurologic signs, recurrent epileptiform
EEG patterns, and a prompt clinical and EEG
response to AEDs. Few patients in more recent series
would meet these criteria. More recently, Cockerell
and colleagues (35) diagnosed CPSE in patients with

confusion lasting at least 30 minutes, with allowance
for persistent or continuous epileptiform discharges
on the EEG and with no definite requirement of medication
responsiveness. For NCSE, Tomson and colleagues
(16) required impaired consciousness for an
hour and an EEG with continuous seizure activity,
while Kaplan (2) sought impaired consciousness for 30

TABLE 3
Criteria for Diagnosis of NCSE

to 60 minutes with some form of seizure activity on
the EEG. Neither required an immediate response to
AEDs to make the diagnosis.

Several papers demonstrate that a response to AEDs
may be delayed even up to days (30, 33), and a clinical
diagnosis must often be made before there is a clear
response to medications. Many astute clinicians have
also made the diagnosis of NCSE and treated patients
successfully, all without an EEG ever being obtained.

There are certain clinical conditions or situations in
which one should retain a high index of suspicion that
NCSE may explain the patient’s altered neurologic
function (Table 4). By far the most common is following
recognized seizures or convulsive SE when the
patient has not recovered to baseline despite apparently
sufficient treatment. Altered mental status in the

TABLE 4
Clues to the Recognition of NCSE

Following generalized convulsions or GCSE
Subtle signs such as twitching, blinking, and nystagmus in a
stuporous patient
Otherwise unexplained stupor or confusion, especially in the
elderly
Altered mental status in the elderly, particularly after
benzodiazepine withdrawal
History of seizures and a new medical or surgical stress
"Stroke plus"

elderly should always prompt a consideration of medication
toxicity or medication withdrawal. In the case
of benzodiazepine withdrawal (such as after stopping
sleep medications) NCSE is not rare. Certainly, patients
with altered mental status who have "subtle"
signs such as blinking or twitching or spontaneous
nystagmus must be considered for the diagnosis. Patients
with a history of epileptic seizures may have
NCSE precipitated by a new medical illness, trauma,
or surgery. Finally, patients who seem to a neurologist
to be faring worse or recovering less rapidly than
typical from a stroke may have intermittent seizures
or NCSE as a partial explanation of the deterioration
or lack of improvement.

V. THE EEG IN NCSE

Making a diagnosis of NCSE traditionally involves
the clinical picture of an abnormal mental status with
diminished responsiveness, a supportive EEG, and
often a response to anticonvulsant medication. Complexities
and controversies arise in each area. In particular,
a tremendous variety of EEG samples have
been offered as supporting a diagnosis of NCSE in
scores of cases in the medical literature. The EEGs
vary strikingly, and many would probably be rejected
by individual epileptologists as insufficient to diagnose
NCSE in isolation, though they may be acceptable
given the clinical history and course. Some features
seem more reliable than others.

EEG Stages in Status Epilepticus

From experimental animal studies and clinical samples
from patients with generalized convulsive SE
(GCSE), Treiman and colleagues (36) proposed that
the EEG in GCSE typically follows a standard evolution
through five characteristic stages: discrete sei-

zures,
merging seizures, continuous seizures, continuous
seizures with brief "flat" periods on the EEG,
and prolonged flat periods with periodic discharges.
The later stages (4 and 5) are often unaccompanied by
actual convulsions and could be considered a type of
NCSE. Still, whether these later stages of GCSE are
considered actual seizures or SE at the time is quite
controversial, and different clinical examples of these
stages might fit into one diagnosis of NCSE and not
another.

Continuous, rapid generalized epileptiform discharges
with occasional "flat" periods ("stage 4") are
usually associated with a significant clinical deficit
and will be considered NCSE or "subtle" SE by most.
Subsequent longer-interval periodic discharges
("stage 5") are not accepted by all as evidence of
ongoing SE. Still, there is no simple and universally
accepted way to distinguish one of these situations
from the other, and it is clear that neither responds
particularly well to AEDs.

Periodic Lateralized Epileptiform Discharges
(PLEDs)

PLEDs are not considered by most epileptologists to
be a manifestation of clinical seizures or SE, at least at
the time of the EEG recording. Clinical seizures have
occurred in at least 80% of PLED patients before the
EEG (37– 40). Many had prior SE. PLEDs are associated
with stroke (the most common cause in many
reports), tumors, infections, metabolic disturbances,
and earlier epilepsy. Head injury, subdural hematomas,
anoxia, brain abscess, congenital lesions, cysts,
tuberous sclerosis, multiple sclerosis, and Creutzfeld–
Jakob disease have all been reported as causes. There
is usually acute, serious neurologic illness, and the
mortality is high—up to 50% within 2 months (41).

Almost all reports of PLEDs show EEGs with epileptiform
discharges at a frequency of 1 Hz or slower,
often every 1 to 2 seconds, some with intervals of up to
10 seconds. The discharge frequency declines over
days in a given patient, and most PLEDs will resolve
after days to weeks (37).

In the largest study of PLEDs to date, Snodgrass and
colleagues (40) found that almost 90% of patients had
clinical seizures, usually a few days before the EEG
showing PLEDs, and two-thirds had some form of SE
before the PLEDs. PLEDs may not be a manifestation
of seizures at the time, but they are certainly a risk for
more seizures, and half the surviving patients without
prior epilepsy developed subsequent epilepsy.
Snodgrass and colleagues considered PLEDs to be

"the terminal phase of status epilepticus." Most investigators
agree.

More rapid periodic discharges are typically seen in
EEG recordings of actual clinical seizures. The discharge
frequency may distinguish between these clinical
entities. Most recordings of PLEDs, as described
above, would not be considered clinical seizures although
those with more rapid discharges (at least >1
Hz and certainly >1.5 Hz) would be read as seizures
by most electroencephalographers.

No absolute frequency criterion can be used to distinguish
PLEDs from seizures. One report of seven
patients over the age of 60 described recurrent confusional
episodes associated with PLEDs (43). Discharge
intervals were as long as 4 seconds. Clinical deficits
resolved with a slowing of the EEG discharges,
whether spontaneously or prompted by benzodiazepines.
Carbamazepine appeared to prevent recurrences,
but they did occur when the medication was
decreased. The authors considered PLEDs an "unusual
status epilepticus of the elderly." PLEDs are generally
not considered seizures or SE by themselves, but
clinicians must keep an open mind about rules specifying
what is and what is not NCSE.

Continuous versus Intermittent Discharges

Almost all definitions of NCSE include EEGs with
epileptiform spike or sharp wave discharges or slowing
and a rapid, rhythmic appearance. These may be
included within two or more electrographic seizures
with a discrete onset of typical ictal discharges or with
continuous discharges throughout the recording. Recurrent
electrographic seizures without clinical recovery
between them clearly indicate status epilepticus.
Continuous discharges are more controversial. Slower
discharges constitute PLEDs or PEDs (as discussed
above), but faster discharges would be read by most
electroencephalographers as an ongoing seizure.

There was no significant clinical difference between
intermittent electrographic seizures and continuous
discharges (with a discharge frequency of ≥1 Hz) in
the diagnosis of focal SE in one study (23), but this
study included all focal SE and not just NCSE. In the
large series of SE patients from Richmond, Virginia,
intermittent SE (of all types) had a lower mortality
than continuous SE, but this was with convulsive clinical
activity rather than for NCSE alone (43). Another
study found that continuous and intermittent seizures
in all forms of SE (not just NCSE) had no difference in
outcome (44). For purposes of diagnosis, there appears

to be no clear difference between continuous and intermittent
electrographic seizure activity.

Electrographic Status Epilepticus (ESE)

ESE should be considered as "true" status though
treatment is often unsuccessful in effecting a clinical
improvement. Many of these recordings appear similar
to Treiman's "stage 4" and also to EEGs published
in a wide variety of case reports of NCSE.

As always, the clinical outcome is determined primarily
by the etiology. Many cases are caused by
anoxia or sepsis with multiple medical problems, and
the outcome is usually poor. Nevertheless, considering
such cases as not representing SE because of the
inadequate response to medication is analogous to
insisting on a successful outcome with antibiotics before
diagnosing an infection. Several clinical series
have demonstrated that the response to AEDs in
NCSE is often delayed or very slow such that clinical
decisions must be made long before this evidence is
available (30, 33, 45).

ESE should be considered a type of SE for several
reasons. First, the EEG discharge appearance, rhythmicity,
and frequency are characteristic for many clinical
reports of SE and similar to those from the study
of Granner and Lee (17) (below). Second, the very
large majority of patients with ESE have had clinical
seizures recently, and most will have clinical seizures
following the ESE recording (18, 19, 46), indicating
that this is not simply a sign of "burnt out" seizures.
For example, patients with ESE, on emergence from
pentobarbital treatment, will usually go on to have
clinically evident seizures (47). Finally, while many
patients with ESE have catastrophic neurologic and
medical illness and may not respond to AEDs, many
others (especially those without anoxia) will have EEG
and clinical improvement on medication (So). In the
end, it makes most sense to consider ESE as a manifestation
of status epilepticus (usually NCSE) and treat
accordingly (keeping in mind that some of the causative
illnesses are devastating) rather than stating that
something is not an epileptic seizure because we
might fail to fix it.

Clinical Guidance

Finally, rather than debate what should be seen with
NCSE, we can be guided by the EEG patterns actually
found in patients with a secure clinical diagnosis.
Granner and Lee (17) reviewed EEGs from 85 episodes
of NCSE in 78 patients with the clinical diagnosis

TABLE 5
Status Epilepticus: EEG Criteria

confirmed by EEG and response to AEDs. EEG waveform
morphologies were quite variable and included
typical and atypical spike wave discharges, multiple
or polyspike wave discharges, and rhythmic delta activity
with intermixed spikes. Discharge frequency
was always 1 to 3.5 Hz (mean 2.2 Hz), and only 4%
were 3 Hz or faster. Two-thirds were generalized and
13% focal, with another 18% generalized with a focal
emphasis. In summary, EEGs in a wide variety of
cases of NCSE share three typical features, shown in
Table 5.

VI. MORBIDITY: DAMAGE FROM NCSE

Neurologists agree that NCSE should be avoided,
but the exact long-term risk from an episode of NCSE
is far less certain. In trying to discern the longerlasting
risks one must consider both experimental and
clinical information.

Experimental Results

The pathology of GCSE was detailed by Meldrum
and colleagues in the 1970s, just as NCSE was becoming
recognized clinically. Their landmark studies laid
the foundation for our understanding of the neuronal
and neurologic effects of convulsive status. They induced
episodes of GCSE lasting up to 5 hours in
baboons (48). The typical EEG showed brief runs of
10- to 20-Hz spikes followed by 2- to 3-Hz polyspikes.
After hours of seizures it still showed rapid epileptiform
discharges punctuated by flat periods. Subsequent
pathologic studies showed neuronal damage in
the neocortex, cerebellar Purkinje and basket cells, and
hippocampus (49). Much of the damage appeared to
correlate with the associated hyperpyrexia, hypotension,
hypoxia, acidosis, and hypoglycemia.

Paralysis and artificial ventilation in baboons with
similar seizures and EEG activity led to reduced neuronal
damage, indicating that control of systemic factors
provided some protection (50). Nevertheless, even
with maintenance of normal homeostasis, SE led to
hippocampal neuronal loss, suggesting that the elec-

trical
activity of SE damaged these neurons independent
of systemic and metabolic factors. These latter
experiments also provided a model of NCSE, but with
persistent and very rapid epileptiform discharges.

Lothman and colleagues found that kainic acid
(whether applied systemically or locally in the hippocampus)
particularly affected limbic structures,
producing seizures that could be nonconvulsive (51,
52). To overcome concern that the neuronal injury was
a direct toxic effect they also used electrodes implanted
in the rat hippocampus (53, 54). Rapid repetitive
stimulation for 30 to 90 minutes led to seizures
and self-sustaining SE persisting for 12 to 24 hours
after the stimulation ceased. Electrographic seizures
included rapid discharges, often over 10 Hz. Animals
with frequent limbic seizures or SE sustained hippocampal
neuronal loss, but those with briefer and
less frequent seizures did not (55).

Chemical and electrical methods of inducing SE
may damage neurologic tissue independent of the
subsequent seizures, leaving open the question of
whether it is the seizures and SE or the precipitant
itself that damages neurons. To address this, Sloviter
(56) showed that indirect electrical stimulation via the
perforant pathway (the primary afferent excitatory
pathway to the hippocampus) induced damage restricted
to hippocampal neurons in rats.

The typical stimulations used to provoke experimental
SE have been intense, and the intensity of the
resulting epileptiform discharges appears to correlate
with the likelihood of neuronal damage. Lowenstein
and colleagues (57) used flurothyl to induce seizures
in paralyzed ventilated rats and found evidence of
neurologic damage in the amygdala and pyriform
cortex strongly associated with prolonged, "high-frequency"
(ca. 10 Hz) discharges, but there was no
damage following discharges slower than 1 Hz. Damage
was directly related to the duration and intensity
of electrographic seizure activity.

The electrical activity of different types of SE varies
considerably. Many of these experiments used prolonged,
high-frequency stimulation to provoke SE,
and the resultant electrographic seizure discharges
were also of high frequency and often sustained for
hours. Discharges greater than 3 Hz are common in
generalized clinical seizures (58), and many of these
models produced sustained discharges of 6–15 Hz,
possibly more representative of GCSE than of NCSE,
with its usually less dramatic electrographic patterns.

Human NCSE is not simply generalized convulsive
SE without the convulsions. It may be sustained for
hours or days but seldom includes the high-frequency

discharges characteristic of generalized convulsions in
humans or in the experimental paradigms discussed.
Many of the models establish a clear correlation between
the intensity of the electrical seizure activity on
one hand and the extent of neuronal damage on the
other. With less intense seizure activity, neuronal
damage may be minimal or even absent. If the electrical
activity of NCSE is often insufficient to cause lasting
neuronal damage, it becomes unclear exactly how
well these high-intensity stimulation models can be
extrapolated to human NCSE, and we must turn to
clinical studies.

Human pathologic studies of the effects of SE have
been scarce, in part because fatal cases are often associated
with acute, severe brain-injuring illnesses such
as ischemic strokes, hemorrhages, and encephalitis, all
of which may cause damage independently. One case–
control study (59) examined hippocampal cell densities
in patients who died after episodes of GCSE in
comparison to those of matched patients with epilepsy
but no SE and to normal controls. SE patients had
significantly decreased hippocampal densities compared
with normals and somewhat less than in epilepsy
controls, suggesting that the episodes of SE were
responsible for the additional damage.

Episodes of NCSE are seldom fatal unless they occur
in association with GCSE or other acute, severe
neurologic illnesses, in which case it is difficult to sort
out the offending agent. For the most part, pathologic
studies of patients with pure forms of NCSE remain
unavailable.

Clinical Morbidity

Lothman (51) has summarized the many physiologic
changes (such as acidemia and hypotension) that
occur during SE, but most apply to GCSE. Studies of
the long-term effects of SE must assess clinical consequences,
including subsequent seizure frequency and
cognitive–neuropsychologic function following an episode
of SE. Seldom can a baseline be assessed before
the SE to see if there is a change. Most studies are of
GCSE, and it correlates with worsened seizure control,
but this may be due to the underlying illness causing
SE rather than to the episode itself (60). Nevertheless,
there may be a subset of patients with a worsened
clinical course following SE.

Absence SE. Most authors have found little longterm
morbidity from absence SE. Nevertheless, this
conclusion usually rests on clinical impressions in
moderate-sized series rather than on actual measure

ment.
No long-term sequelae were noted in several
prominent series (4–6).

CPSE. Early reports on CPSE included very few
patients. Most returned to normal or "baseline cognitive
function" (10, 34, 61), but not all were studied
thoroughly with subsequent neuropsychologic tests.
In a more recent CPSE series (35), none of 20 patients
had cognitive deterioration, and 5 had meticulous
neuropsychologic assessment.

Krumholz and colleagues (62) reported 10 patients
with CPSE for 36 hours or longer, all of whom had
lasting neurologic deficits. Two patients each had
strokes or encephalitis, and another three had multiple
medical problems that may have contributed to the
deficits. Three patients had refractory epilepsy, and all
sustained prolonged memory deficits, lasting 3 to 24
months, but at least 2 improved. CPSE occurred more
frequently in medically sick patients, raising the question
of synergistic harmful effects of NCSE and medical
illnesses. Other individual reports (9, 11) also
found prolonged memory deficits after NCSE; it is
uncertain whether they are permanent.

NCSE. Reports of NCSE not necessarily specifying
absence SE or CPSE are more numerous (16, 32, 63–
65). They show few long-term sequelae, but most include
limited follow-up. That of Guberman and colleagues
(63) is exceptional by including 5-year follow-
up on 8 patients, showing no intellectual,
memory, or behavioral deterioration. Scholtes and colleagues
(65) evaluated 65 patients and found good
outcomes in all but one.

ESE. Patients with ESE in the setting of serious
medical illness have a terrible prognosis, but it is not
possible to dissect out that portion of the long-term
harm done by epileptiform discharges or NCSE (18,
19, 46, 66).

Most clinical studies of the effects of SE are pediatric
and retrospective. Several have found negative consequences,
but it is very difficult to control for many
variables. Comprehensive neurologic and neuropsychologic
evaluations before and after SE are seldom
available. Also, patients with a progressive illness
worsen, whether or not related to the SE, and many
patients with neurologic deficits fluctuate with time.
Finally, it is difficult to control for the influence of
AEDs. Medications, doses, serum levels, and drug
interactions may change frequently in patients with
refractory epilepsy, including at the time of testing.

Dodrill and Wilensky (67) obtained neuropsychologic
testing on 143 adults with epilepsy. Nine had
episodes of SE over a 5-year interval, and these patients
worsened neuropsychologically while some

control patients improved, but SE patients had an
average 14-point lower IQ score before the SE and
were taking an average of 2.8 AEDs versus 1.7 AEDs
for controls. Maytal and colleagues (68) studied 193
children with SE, almost all convulsive. Seventeen had
cognitive and other deficits after the SE, usually attributed
to an acute illness such as a stroke. They concluded
that "the major neurologic sequelae are usually
due to the underlying insult rather than to the prolonged
seizure itself."

VII. TREATMENT

Although clinical studies show little evidence of
permanent neurologic injury from episodes of NCSE it
would be unwise to ignore the prolonged memory
dysfunction in several well-reported cases, and NCSE
has some similarities to convulsive SE (69). It is possible
that a minority of episodes of NCSE might lead
to significant deficits. From case reports and by analogy
to GCSE, the more prolonged cases may be worse
(70), and NCSE may last for days without proper
diagnosis. Concomitant systemic factors such as infection,
metabolic disturbances, hypotension, and medications
might increase the likelihood of damage in a
synergistic fashion (62). Episodes associated with focal
lesions such as strokes may involve two processes,
with a greater chance of lasting harm (71). Finally, by
extrapolation from experimental studies (57) episodes
of NCSE with more rapid (and presumably excitatory)
epileptiform discharges may be more worrisome.

Patients with NCSE should be treated quickly with
AEDs for several reasons. They are clearly ill with
ongoing seizures and have impaired consciousness
and other neurologic deficits that are potentially reversible
and certainly treatable. Also, NCSE, like other
forms of SE, entails the attendant morbidity of incidental
trauma, aspiration pneumonia, etc. Additionally,
many episodes of NCSE begin with and may end
with generalized convulsions, in turn potentially
harmful. Finally, we must remain alert to the possibility
that some prolonged episodes might cause lasting
damage. NCSE remains an underdiagnosed, treatable
condition and one well worth both diagnosing and
treating.

Treatment of NCSE is often easier than diagnosis,
but when the initial treatment is unsuccessful subsequent
treatment can become far more complicated and
difficult. Straightforward absence SE may be terminated
by benzodiazepines relatively quickly. Other
treatments such as carbon dioxide inhalation, oral bar-

biturates,
benzodiazepines, and ethosuximide can be
effective (5). Intravenous phenytoin can also help (3).
Absence SE due to benzodiazepine withdrawal (e.g.,
de novo absence status in the elderly) usually responds
to brief courses of benzodiazepines, although barbiturates
may also be helpful (6). With such an acute
precipitant, long-term treatment may be unnecessary.
When longer treatment is necessary, valproate has
been effective in preventing recurrences (72), but this
does not mean that other medications would be ineffective,
especially given the overlap syndromes and
the possibility that many episodes of absence SE are
actually focal-onset, secondarily generalized seizures.
Infrequently, AEDs, including vigabatrin and tiagabine,
have been reported to precipitate or worsen generalized
NCSE (73, 74).

Complex partial SE may be interrupted and controlled
by traditional intravenous medications, phenytoin
and phenobarbital (9) or oral carbamazepine
(10). More frequently, intravenous benzodiazepines
are used to interrupt the NCSE once it is recognized
(75). Nevertheless, CPSE is often recurrent (35), and
patients are much less likely to remain off medication.

In occasional cases of NCSE, patients recover spontaneously
(16). Benzodiazepines are used nearly uniformly
in the attempt to interrupt NCSE in the rest of
patients, and they are often successful (16, 63). Lorazepam
may be the preferable drug (33). Nevertheless,
there are clearly many cases in which the NCSE
proves resistant (35, 76). In a recent series of patients
with NCSE where the foci were found to be primarily
in frontal areas (45) there was often a delay of 2 days
before diagnosis. In most of these refractory patients,
intravenous benzodiazepines were unsuccessful in
breaking the SE. Most responded to intravenous phenytoin,
but one required pentobarbital.

Electrographic status or the NCSE discovered after
known convulsions or GCSE can be even more refractory
(46). In one large series, only 60% of patients with
NCSE had an initial response to benzodiazepines (17).
Benzodiazepines often improve the EEG without leading
to clinical improvement. Higher doses of longacting
intravenous medication such as phenytoin and
phenobarbital (30, 77) or increasing levels of already
used AEDs (33) may be helpful. In the end, even
patients with periodic discharges or PEDs (whether
considered SE or not) actually did reasonably well, as
long as anoxia was not the cause (78), and most returned
to baseline.

In the idealized case, any form of NCSE is diagnosed
readily and responds immediately to intravenous
benzodiazepines. This is not a rare scenario, but

it is unlikely to cover most patients. Fortunately, given
the relatively minimal evidence of ongoing damage
and rapid establishment of lasting neurologic deficits
due to NCSE, treatment probably need not be as aggressive
as for continuing convulsive SE. Many of the
treatments cited above occurred over days though this
is not the recommended plan. It is relatively rare that
patients will need such aggressive treatment as pentobarbital-
induced coma or treatment with such substitutes
as propofol, ketamine, and much higher doses
of benzodiazepines such as lorazepam and midazolam.
Still, there are many reasons for treating NCSE
expeditiously. Treatment should be individualized
and judicious (2) but should not be delayed.

NCSE presents in remarkably varied ways but often
in typical situations such as following other seizures
or in the setting of acute stroke. Because there are no
motor manifestations, the diagnosis is missed frequently,
but it is also made frequently by astute neurologists
and other clinicians. The diagnosis is well
worth making because NCSE impairs the patient’s
health significantly, and it is often a treatable and
completely reversible condition.

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