Drugs (2021) 81:749–770

https://doi.org/10.1007/s40265-021-01502-4

REVIEW ARTICLE

Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive

Status Epilepticus
Pablo Bravo1 · Aparna Vaddiparti1 · Lawrence J. Hirsch1

Accepted: 13 March 2021 / Published online: 8 April 2021

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021

Abstract
Most seizures in critically ill patients are nonconvulsive. A significant number of neurological and medical conditions can be
complicated by nonconvulsive seizures (NCSs) and nonconvulsive status epilepticus (NCSE), with brain infections, hemor-
rhages, global hypoxia, sepsis, and recent neurosurgery being the most prominent etiologies. Prolonged NCSs and NCSE
can lead to adverse neurological outcomes. Early recognition requires a high degree of suspicion and rapid and appropriate
duration of continuous electroencephalogram (cEEG) monitoring. Although high quality research evaluating treatment with
antiseizure medications and long-term outcome is still lacking, it is probable that expeditious pharmacological management
of NCSs and NCSE may prevent refractoriness and further neurological injury. There is limited evidence on pharmaco-
therapy for NCSs and NCSE, although a few clinical trials encompassing both convulsive and NCSE have demonstrated
similar efficacy of different intravenous (IV) antiseizure medications (ASMs), including levetiracetam, valproate, lacosamide
and fosphenytoin. The choice of specific ASMs lies on tolerability and safety since critically ill patients frequently have
impaired renal and/or hepatic function as well as hematological/hemodynamic lability. Treatment frequently requires more
than one ASM and occasionally escalation to IV anesthetic drugs. When multiple ASMs are required, combining different
mechanisms of action should be considered. There are several enteral ASMs that could be used when IV ASM options have
been exhausted. Refractory NCSE is not uncommon, and its treatment requires a very judicious selection of ASMs aiming
at reducing seizure burden along with management of the underlying condition.

1 Introduction
Status epilepticus (SE), as defined by the International
League Against Epilepsy (ILAE), is “a condition result-
ing either from the failure of the mechanisms responsible
for seizure termination or from the initiation of mecha-
nisms which lead to abnormally prolonged seizures (after
time point t1). It is a condition that can have long-term
consequences (after time point t2), including neuronal
death, neuronal injury, and alteration of neuronal net-
works, depending on the type and duration of seizures”
[1]. Further details in the classification of SE in regard to
semiology, etiology, EEG correlates, and age can be found
in the Report of the ILAE Task Force on Classification of
Status Epilepticus [1].
Key Points
Nonconvulsive seizures and nonconvulsive status epilep-
ticus are common complications of acute neurological
brain injury and are associated with worse neurological
outcomes, including later epilepsy, functional status, and
cognition.
Early clinical suspicion, rapid diagnosis, and appropriate
length of monitoring with continuous EEG is funda-
mental in the diagnosis and treatment of nonconvulsive
seizures and nonconvulsive status epilepticus.
Seizure burden reduction while avoiding iatrogenicity is
the mainstay of treatment of nonconvulsive seizures and
nonconvulsive status epilepticus.

* Lawrence J. Hirsch
lawrence.hirsch@yale.edu
1
Comprehensive Epilepsy Center, Department of Neurology,
Yale University School of Medicine, New Haven, CT, USA

Vol.:(0123456789)
750
T1 and t2 have been clearly defined by the ILAE for
generalized convulsive SE as well as for focal SE with
impairment of consciousness (5 and 30 min for the former,
10 and 60 min for the latter), in part as a result of evidence
in animal experiments [2–6] and clinical research [7–10].
There is still limited evidence for the exact time threshold
for long-term consequences in any type of SE other than
convulsive. This threshold is even less clear for frequent
nonconvulsive seizures (NCSs) not qualifying as SE. It
is also likely that t2 is variable, being shorter in patients
with acute brain injury compared to patients with chronic
epilepsy [11].
Since nonconvulsive status epilepticus (NCSE) is, by
definition, simply SE without prominent motor symptoms
[1], the signs and symptoms of NCSE (and NCSs) are
broad and often subtle, including, although not limited
to, inattention, disorientation, confusion, abulia, abnormal
eye movements (e.g. gaze deviation or nystagmus), subtle
repetitive facial or distal movements of extremities, and
in more severe cases, stupor and coma [12–14]. Electro-
graphically, NCSs may range from focal to generalized,
brief and single, to frequent and multiple, including cyclic,
as well as prolonged and continuous [15, 16].
NCSs and NCSE may occur in virtually any condition
that may affect, directly or indirectly, the homeostasis of
the supratentorial brain. This includes cerebral anoxia,
infarcts, intracranial hemorrhage (intraparenchymal/sub-
dural/subarachnoid), neoplasm, infection, traumatic brain
injury, sepsis, prior history of epilepsy, metabolic abnor-
malities, medication overdose/toxicity (e.g., cefepime),
and neurodegenerative disorders, among others [1].
Previous studies have attempted to define the incidence,
prevalence, and mortality of SE and NCSE [11, 16–22].
However, given the evolution in the classification of SE in
the last few decades (from > 30 min to > 5 min threshold
for t1 for convulsive SE), previous estimates of its epide-
miology may not accurately reflect the current understand-
ing [23]. In a recent prospective population-based study
evaluating the incidence of SE based on the latest ILAE
classification, although applying a pragmatic > 10-min
time period for SE for all seizure types, NCSE comprised
18% of all cases, and 30-day mortality for SE of all seizure
types was 4.6% [24].
Regardless of the differences in reported epidemiology of
SE over the past several decades, the substantial morbidity
and mortality of SE, as well as its direct economic burden in
the healthcare system are undeniable [25, 26]. Therefore, a
clear understanding on the diagnosis and treatment of NCSs
and NCSE is vital.
In this review, we discuss the current knowledge on
treatment for NCSs and NCSE, concentrating on acutely ill
patients including available evidence on secondary neuro-
logical injury due to NCSs and NCSE, rationale for early and
P. Bravo et al.
appropriate monitoring with continuous electroencephalo-
gram (cEEG), as well as limited pharmacotherapy evidence
specific to the treatment of NCSs and NCSE. We also pro-
pose a stepwise description of our approach to treating NCSs
and NCSE that clinicians may find practical, even if based
on limited evidence. Finally, we highlight areas that need
further research.
2 The Quest to Define t2 in NCSs and NCSE
Several animal models have demonstrated that repeated
NCSs and NCSE can cause behavioral deficits [27, 28], epi-
lepsy [29, 30], and neuronal death [3, 31]. In a rodent model
of NCSs elicited by irreversible occlusion of the middle cere-
bral artery, not only did NCSs correlate with increased infarct
size and mortality but also their treatment with antiseizure
medications reduced mortality [32]. In another rodent model
of temporal onset complex partial NCSE [33], brain pathol-
ogy 1-week post-NCSE showed active inflammation with
fewer synaptic proteins and excessive microglial and astro-
cytic activation; moreover, 4-week post-NCSE brain pathol-
ogy showed continued immune response with neuronal loss.
Understandably, the search for evidence of neuronal
injury and adverse outcomes in humans with NCSs and
NCSE in acute brain injury is a very complex problem given
the significant heterogeneity in the multiple underlying eti-
ologies that on their own pose a significant risk for detri-
mental neurological outcome. Whether NCSs and NCSE
can cause neuronal injury and/or increase mortality versus
being just a surrogate of increased severity of the underlying
acute brain injury has long been a topic of significant debate
[34, 35]. Many studies on different etiologies of acute brain
injury in all ages have demonstrated an independent and
“dose-related” (proportional to seizure burden) association
of worse outcome with NCSs/NCSE [36–49].
Some studies have more clearly demonstrated a correla-
tion between length of NCSs/NCSE and worse outcome after
controlling for other risk factors. A retrospective study on
49 critically ill patients with NCSs and NCSE, demonstrated
that patients with NCSs/NCSE had an increased mortality
with multivariate logistic regression showing that of all fac-
tors studied, only seizure duration and delay to diagnosis
were associated with increased mortality [36]. A prospec-
tive observational study evaluating 259 infants and children
admitted to the intensive care unit (ICU), adjusting for diag-
nosis and illness severity, concluded that a seizure burden
threshold > 20% per hour (12 min) was independently asso-
ciated with a greater probability and magnitude of neurolog-
ical decline across all diagnostic categories, although seizure
burden was not associated with mortality [43].
Another prospective observational study evaluating
outcome on 60 critically ill children (median of 2.7 years
Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus
follow-up) demonstrated that patients with NCSE, but not
NCSs, were associated with an increased risk of unfavorable
global outcome, lower health-related quality of life scores,
and an increased risk of subsequently diagnosed epilepsy
even after adjusting for neurologic disorder category, EEG
background category, and age [44].
Similarly, in a prospective study on 402 consecutive adult
patients with subarachnoid hemorrhage (SAH), after adjust-
ing for established predictors, patients with seizures (12%
of all patients, median seizure burden 6 h) had more than
3 times higher odds of disability or death. Seizure burden
was associated with worse functional outcome: the higher
the seizure burden, the worse the outcome with every hour
of seizure on cEEG associated with 10% higher odds of dis-
ability and mortality at 3 months [45].
Finally, delay in treatment can lead to further refractori-
ness [50–52]. A prospective study on encephalopathic criti-
cally ill children investigated treatment efficacy before and
after implementing a pathway to expedite EEG monitoring
and seizure management. Data were collected on 41 patients
before and 21 patients after pathway implementation. The
median duration from seizure onset to antiseizure medica-
tion administration was shorter for patients treated with the
pathway compared to the baseline group (64 min vs 139 min,
p = 0.0006). Importantly, seizure termination was much
more likely to occur following initial antiseizure medica-
tion administration after implementing the pathway than in
the baseline group (67% vs 27%, p = 0.002) [53] . Also, a
retrospective observational study on 625 neonates and pedi-
atric patients, in whom NCSs occurred in 28.2% and SE in
11.4%, after controlling for gender and age, showed that both
SE and time from ICU admission to cEEG initiation were
independent predictors of mortality in both neonates and
pediatric patients [54].
Based on the available evidence to date, it is reasonable
to conclude that the longer NCSs and NCSE last, the worse
the outcome. While we cannot conclusively define a t2 at
this time, it is prudent to take a > 12 min per hour seizure
burden [43] as a measure of concern for potential neuronal
injury and that every extra hour of seizure burden might
worsen neurological outcome [45]. Prospective randomized
clinical trials evaluating long-term outcomes after treatment
of NCSs/NCSE with antiseizure medications have not been
performed; thus, aggressive treatment methods remain
unclear.
3 Early Recognition of NCSs and NCSE
Since most seizures in critically ill patients are nonconvul-
sive [19, 55], the diagnosis of NCSs and NCSE requires
a high degree of suspicion given their heterogenous and
usually subtle or undetectable semiology [56, 57]. It is also
751
important to remember that after convulsive SE is con-
trolled, nearly half of the patients may develop NCSs in the
following 24 h [16]. Therefore, appropriate identification
of the population at risk [58], recognition of possible sub-
tle symptoms and signs [1], early and appropriate length of
EEG monitoring [55, 59–61] are all paramount in the diag-
nosis and ultimate treatment of NCSs and NCSE. Moreover,
accurate determination of electrographic patterns and cri-
teria for NCSs and NCSE is fundamental [58, 62–65]. The
most widely accepted criteria for the diagnosis of NCSE
are the Salzburg criteria [66, 67]; a modified version of the
Salzburg criteria and all other related EEG patterns has been
incorporated into the American Clinical Neurophysiology
Society (ACNS)’s Standardized Critical Care EEG Termi-
nology, 2021 version [68].
In a study evaluating 4772 hospitalized patients under-
going cEEG with a subsequent validation study of 1407
patients from a different population compared to the foun-
dational study, it was determined that when different elec-
trographic patterns of interictal activity as well as history
of recent or remote seizures were taken into account, the
length of EEG monitoring necessary to identify subsequent
seizures could be predicted with accuracy after one hour of
EEG monitoring [59, 61, 65]. This risk stratification was fur-
ther validated in a recent study on acute brain injury patients
[69]. These risk factors and the length of EEG monitoring
necessary to decrease the risk of missing NCSs are depicted
in Fig. 1.
It is worth noting that while coma (and other risk factors
evaluated in the studies mentioned above, including acute
structural brain injury) did not have a statistically signifi-
cant association with subsequent seizures, cardiac arrest
patients were not included in the validation study. There-
fore, such criteria cannot be used to determine length of
monitoring when evaluating cardiac arrest patients. This is
evident in a retrospective study on 570 critically ill patients
[55] also evaluating the required length of cEEG to detect
seizures, where cardiac arrest patients were not excluded
and where coma did play a significant role in determining
the length required to capture the first seizure. Patients with
coma required greater than 48 h of cEEG without seizures to
reach a > 93% certainty of not having seizures with further
monitoring.
A comparison of routine EEG and continuous EEG moni-
toring to identify seizures in the ICU was investigated in a
recent meta-analysis involving 16,707 patients. The preva-
lence of either NCSs or NCSE was significantly higher with
continuous EEG (15.6%; odds ratio [OR] = 2.57) than with
routine EEG (6.3%) [70]. This was also evident in a recent
multicenter randomized “pragmatic” clinical trial in Europe
comparing serial routine EEGs to continuous EEG in 364
patients who had never had a clinical seizure, including
those with hypoxic-ischemic encephalopathy, with Glasgow
752
Fig. 1  Duration of cEEG without seizures required to avoid miss-
ing seizures with a certainty of 95 and 98% based on history of any
previous seizures and electrographic patterns (2HELPS2B score:
see box on right side) [59, 61]. BIPD bilateral independent peri-
odic discharges, BIRDS brief potentially ictal rhythmic discharges,
Coma Scale < 11 and follow-up of 6 months [71]. While
there were more seizures detected in the cEEG arm than
the routine EEG arm, there was no significant difference
in mortality, despite potential modifications in pharmaco-
therapy for seizures based on the cEEG results. However,
there were many methodological limitations in this study,
including a marked delay from admission to initial cEEG
hookup (mean 60 h) and no EEG review overnight, leading
to marked delay in treatment of detected seizures (timing of
treatment not provided). Furthermore, only 21% of patients
undergoing cEEG had any change in treatment (vs 11% in
those with routine EEG), leading to a markedly underpow-
ered study; thus, it is not surprising that no effect was found
on mortality. Lastly, treating NCSE early is done mainly to
preserve neurons to improve overall neurological function,
cognition and to prevent later epilepsy; these were not part
of the primary or secondary outcome measures in that trial,
although there was no effect of cEEG on 6-month functional
outcome in a tertiary outcome measure. It remains unclear
whether a larger study, where post-cardiac arrest patients can
be separately studied or excluded, would have demonstrated
different results, or if more rapid cEEG, more timely inter-
pretation, and earlier treatment would lead to better cogni-
tive and functional outcomes, and lower rates of epilepsy.
A retrospective study surveying over 7 million US adult
ventilated ICU patients (excluding cardiac arrest), of whom
22,728 received cEEG, showed that the use of cEEG was
associated with reduced in-hospital mortality after adjust-
ment for patient and hospital characteristics [72]. In a similar
P. Bravo et al.
cEEG continuous electroencephalogram, LPD lateralized periodic
discharges, LRDA lateralized rhythmic delta activity. Plus features:
R superimposed rhythmic, S superimposed sharp waves or spikes, F
superimposed fast activity
large database study including > 40,000 patients, use of con-
tinuous EEG rather than routine EEG was associated with
lower mortality and no difference in cost [73].
4 Treatment of NCSs and NCSE
4.1 Evidence on Pharmacotherapy for NCSs
and NCSE
To date, there has only been one prospective, randomized,
blinded, controlled trial evaluating the efficacy and safety of
antiseizure medications (ASMs) in the treatment of NCSs.
The TRENdS trial (Treatment of Recurrent Electrographic
Nonconvulsive Seizures) was a noninferiority, prospective,
multicenter, randomized treatment trial of patients diag-
nosed with NCSs by cEEG [74]. Inclusion criteria included
patients with electrographic seizures with or without clini-
cal correlate lasting > 10 s and < 30 min, and refractory to
at least 2 ASMs. Treatment was randomized to intravenous
(IV) lacosamide 400 mg or IV fosphenytoin 20 mg/kg. The
primary endpoint was absence of seizures for 24 h deter-
mined by a blinded EEG reviewer. Seizures were controlled
in 19 of 30 (63.3%) patients in the lacosamide arm and 16
of 32 (50%) subjects in the fosphenytoin arm. This trial
demonstrated noninferiority of lacosamide to fosphenytoin
(p = 0.02 for noninferiority) with similar treatment-related
adverse events (AEs).
Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus
The most pivotal randomized clinical trial for treatment
of convulsive SE conducted in 16 Veterans Affairs medical
centers [8] also shed some light on the efficacy of different
ASMs for subtle SE, a prior term that is now considered a
type of NCSE [1]. In this trial, 384 patients with overt con-
vulsive SE and 134 patients with subtle convulsive SE were
included. Subtle generalized convulsive SE was considered
present when the patient had coma and ictal discharges on
the EEG with or without subtle convulsive movements. Four
IV regimens were used: diazepam (0.15 mg/kg) followed by
phenytoin (18 mg/kg), lorazepam (0.1 mg/kg), phenobarbi-
tal (15 mg/kg) and phenytoin (18 mg/kg). Treatment was
considered successful if all clinical and electrical evidence
of seizure activity stopped within 20 min after the start of
the infusion and did not recur during the period from 20 to
60 min after the start of treatment. While lorazepam was
more effective than phenytoin in patients with overt convul-
sive SE, among the 134 patients with a verified diagnosis
of subtle SE, no statistically significant differences among
the treatments were detected; response rates were consist-
ently low in this subgroup (phenytoin 7.7%, diazepam +
phenytoin 8.3%, lorazepam 17.9%, phenobarbital 24.2%).
The rates of success with different ASMs for patients with
subtle SE were much lower than those for patients treated
for overt convulsive SE (range 43.6% to 64.9%). Recurrence
of SE during the 12-hour study period was also higher in
the subtle SE group than in the overt convulsive SE group
(20% vs 11%). Mortality within 30 days after SE was much
higher in patients with subtle SE (65%) compared to overt
convulsive SE (27%). An explanation for the difference in
success rate as well as mortality rate could be drawn from
the dramatically different baseline characteristics in these
two types of SE (i.e. cardiopulmonary arrest: subtle SE 38%
vs overt convulsive SE 6%; life-threatening medical condi-
tion: subtle SE 56% vs overt convulsive SE 32%) as well as
the median duration of SE at enrollment (subtle SE: 5.8 h vs
overt convulsive SE 2.8 h).
The more recent Established Status Epilepticus Treat-
ment Trial (ESETT), was a multicenter, randomized,
double-blind, adaptive clinical trial evaluating the efficacy
and safety of levetiracetam (60 mg/kg, maximum 4500),
phenytoin (20 mg/kg, maximum 1500) and valproate (40
mg/kg, maximum 3000) in patients with benzodiazepine-
refractory convulsive SE [75]. While NCSs and NCSE were
not specifically included in this trial, it is, nevertheless, fun-
damental to discuss these results since these three ASMs
are widely used in the treatment of NCSs and NCSE. A
total of 384 patients, including children aged > 2 years and
adults, were enrolled. While inclusion criteria required a
clinically apparent seizure, it is worth noting that besides the
more obvious focal or generalized tonic-clonic movements,
and generalized or segmental myoclonus, the trial also
included patients who had evolved to having more subtle
753
signs including nystagmoid or rhythmic eye movements
(i.e., had transitioned to nonconvulsive SE). The primary
outcome was cessation of status epilepticus and improve-
ment in the level of consciousness at 60 min. The primary
safety outcome was life-threatening hypotension or cardiac
arrhythmia within 60 min after the start of trial drug dura-
tion. There was no statistically significant difference in the
success rate or AEs with nearly identical rates of success
(levetiracetam 47%, phenytoin 45%, valproate 46%). After
extending enrollment in children, for a total of 478 patients,
the authors then described similar results when comparing
three populations of patients (< 18 years vs 18–65 years vs
> 65 years) [76].
Two recent multicenter, randomized, intention-to-treat,
clinical trials of pediatric benzodiazepine-refractory con-
vulsive status epilepticus, ConSEPT and EcLiPSE, assessed
efficacy of levetiracetam versus phenytoin. In ConSEPT
[77], 233 children aged 3 months to 16 years were ran-
domly assigned to phenytoin (20 mg/kg, maximum 1000)
or levetiracetam (40 mg/kg, maximum 3000); 14 patients
(12%) in each arm had focal onset status epilepticus. Clinical
seizure cessation measured 5 min after completion of infu-
sion of the trial drug occurred in 68 (60%) patients in the
phenytoin group and 60 (50%) patients in the levetiracetam
group (p = 0·16). In this trial, levetiracetam was not superior
to phenytoin and no major ASM-related AEs occurred in
either group. In EcLiPSE [78], 404 children aged 6 months
to < 18 years were randomly assigned to phenytoin (20 mg/
kg, maximum 2000) or levetiracetam (40 mg/kg, maximum
2500); 22 patients (16%) in the phenytoin group and 33
patients (22%) in the levetiracetam group had focal clonic
seizures as initial presentation. Cessation of all visible signs
of convulsive activity was observed in 106 (70%) children
within 35 min of randomization in the levetiracetam group
and in 86 (64%) within 45 min of randomization in the phe-
nytoin group (p = 0.20). In this trial, levetiracetam was not
superior to phenytoin; one patient in the phenytoin group
had serious AEs.
Apart from the three landmark randomized clinical tri-
als in adults and the two recent clinical trials in children
mentioned above, of which only one was restricted to non-
convulsive seizures, there is only low level of evidence for
treatment with ASMs for NCS and NCSE, mostly derived
from subgroup analyses from larger studies of SE. A few
recent and pertinent studies for each of the more commonly
used ASMs are summarized in Table 1: only studies with at
least 10 patients (or 10 episodes) with NCSE were included
[79–88].
In analyzing efficacy and tolerability data for individ-
ual ASMs in NCS and NCSE, lacosamide remains one of
the better-studied drugs. In addition to the TRENdS trial
discussed above providing class I data, an observational
study [80] demonstrated similar efficacy of lacosamide in
754 P. Bravo et al.

NCSE relative to convulsive SE both in terms of seizure
termination and improvement in EEG epileptiform burden.
In an efficacy and tolerability observational study [81] of
lacosamide for the treatment of NCSs and NCSE in an
elderly population (median age 77 years) with post-stroke
epilepsy, 50% responder rate (n = 7/14) was noted with no
side effects even with an initial loading dose of 400 mg.
Cardiac side effects with lacosamide include dose-depend-
ent prolongation of PR interval to 1.4 ms (LCM 200 mg/
day), 4.4 ms (LCM 400 mg/day), and 6.6 ms (LCM 600
mg/day) as well as first-degree AV block [89].
For brivaracetam, based on a subgroup analysis of
NCSE (n = 19/43) patients in a retrospective multicenter
study [79], overall responder rate of 53% was noted with
response within 6 h of a loading dose (median 100 mg).
In a systematic review of brivaracetam in SE, there was
a 50% responder rate correlating with higher mean dose
3.3 mg/kg versus 1.5 mg/kg. No response was seen below
1.9 mg/kg and no correlation was seen with plasma level
[90]. Another retrospective study showed similar results
with higher response rate with doses > 1.82 mg/kg [79].

Table 1  Summary of retrospective case series of ASMs in NCSs and NCSE

ASM Study Total n with Initial dose, Median time Median ASM Response rate Adverse effects (n
n NCS/ median from SE onset trials prior to or%)
NCSE to oral ASM oral ASM
initiation

Brivaracetam Santamarina 43 19 IV 100 mg N/A N/A 53% Somnolence (n = 5)

2019 [79] (25–400 mg) Worsening seizure
(n = 1)
Lacosamide Moreno 53 30 IV 390.6 mg N/A N/A 90% No major AE
Morales
2015 [80]
Belcastro 14 14 IV 400 mg N/A N/A 50% No major AE
2013 [81]
Perampanel Strzelczyk 52 13 PO 6 mg/day 10 days 5 (0–13) 36% Dizziness @ 12 mg/
2019 [82] (2–10 mg/day) day (n = 1) Somno-
lence @ 8 mg/day
(n = 1)
Rohrachter 30 21 Two arms: 2.3 days 4 (2–8) 17% No major AE (ele-
2018 [83] standard dose: (0.5–18.3) 3/16 standard vated liver enzymes
4 mg (2–12) dose without clinical
n 16 2/14 high dose symptoms in 7/30,
High dose: 32 6/7 were also on
mg (16–32) phenytoin)
n 14
Topiramate Fechner 106 17 PO 100 mg 12 days 5 27% Hyperammonemia
2019 [84] (25–400 mg) (35% but most on
concurrent VPA/
PB)
Pancreatitis (0.9%)
Hyperchloremic
acidosis (0.9%)
Madzar 17 12 PO 100 mg (in 29 days (15–66) 11 (7–14) 100% DNP
2016 [85] 6/17, 400 mg)
Pregabalin Swisher 21 21 PO 342 mg/ 1–3 days DNP 52% Dizziness, sedation
2013 [86] day* (n = 2)
Clobazam Madzar 2016 24 16 PO 20 mg/day+ 2 (3–6) days 3 (2–5) 25% DNP
[87]
Sivakumar 17 15 PO 10 mg/day 4 (1–61) days 3 (2–6) 76% Sedation (33%)
2015 [88] PO 20 mg/day+

ASMs antiseizure medications, DNP data not provided, IV intravenous, N/A not applicable, NCSs nonconvulsive seizures, NCSE nonconvulsive
status epilepticus, PO oral
*Average daily dose; + maintenance dose
Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus
Head-to-head comparison of ASMs for treatment of
NCSs and NCSE is limited. In a five-year observational
study [91] comparing IV levetiracetam, lacosamide, val-
proate and phenytoin, no significant difference was seen
in overall resolution rate of SE; however, in the subgroup
of NCSE episodes (74%, n = 207/277), valproate was
significantly more effective than levetiracetam (86% vs
62%, p < 0.002). Of three recent metanalyses compar-
ing levetiracetam and phenytoin for status epilepticus, two
[92, 93] showed no difference in efficacy while one [94]
showed a higher rate of clinical seizure cessation with lev-
etiracetam (75.2% vs 67.8%, p = 0.003). In a retrospec-
tive single-center observational study [95] for treatment of
refractory SE episodes, in the subgroup of episodes with
NCSE without coma, no difference was noted between lev-
etiracetam (34%), valproate (34%) and lacosamide (33%)
for cessation of SE. Phenytoin was ineffective; however,
it was used at significantly lower doses than proven effec-
tive in other trials. Overall, in terms of efficacy among IV
ASMs, newer ASMs such as levetiracetam, brivaracetam
and lacosamide are similar to traditional ASMs such as
phenytoin and valproate.
For enteral ASMs, all data are retrospective with no
head-to-head studies. Pregabalin is the only ASM studied
specifically for NCSs/NCSE [86]. Data for other enteral
ASMs such as perampanel, topiramate and clobazam have
derived from subgroup analyses of NCSs and NCSE from
retrospective studies on SE. In a retrospective single-
center study of NCSs and NCSE [86], 21 critically ill
patients received pregabalin at an average initial dose of
342 mg/day to assess for termination of seizures within
24 h without addition of other ASMs. In this study, over-
all response rate was 52% (11 patients), with higher effi-
cacy in terminating NCSs (9 patients, 82%) than NCSE (2
patients, 18%). It must be noted that most studies evaluat-
ing oral ASMs may not reflect true efficacy and are limited
by many factors including smaller studies with electroclin-
ical heterogeneity, concurrent use of other ASMs and IV
anesthetic drugs, publication bias, and most importantly,
long median times to initiation of therapy from onset of
SE.
4.2 Primum non nocere
There are several reviews available on the treatment of the
broader spectrum of SE [96–105]. Very detailed descrip-
tions of mechanisms of action, efficacy, safety and dosing
for multiple ASMs are available in some of these reviews
[100–106]. Few specifically explore the treatment of NCSE
[14, 57] and NCSs [56, 106]. It is widely accepted in the
medical community that treatment of convulsive SE should
include rapid and aggressive escalation of pharmacotherapy
[107]. However, much less is known regarding the approach
755
to pharmacotherapy of NCSs and NCSE, as exemplified by
the limited number of high-quality clinical trials that address
this topic. In the last decade, a few guidelines in the treat-
ment of SE have become available [108–110]. Although
these guidelines primarily focus on management of con-
vulsive SE, two of them did address a general approach on
the management of NCSE. The European guidelines from
2010 considered NCSE as > 10 min and the Neurocritical
Care Society guidelines from 2012 as > 5 min. Despite these
guidelines, how aggressively NCSs and NCSE should be
treated and which ASMs should be used are still topics of
significant controversy [111, 112]. As clinicians embark on
the treatment of NCSs/NCSE with the well imprinted man-
tra of primum non nocere (first do no harm) as their com-
pass, their journey often encounters seemingly unnavigable
waters with patients suffering from very complex acute and
chronic neurological and medical conditions; clinicians are
left with the decision to treat potentially harmful seizures
with yet potentially toxic pharmacological options in very
sick patients. There is, therefore, a need for a rigorous phar-
macotherapy workflow in which both benefits and risks are
always to be balanced.
Considering the limited evidence in the specific phar-
macotherapy for NCSs/NCSE, and supported by available
guidelines, it is reasonable to differentiate the treatment of
NCSs and NCSE based on three distinct forms:
1. NCSE that follows convulsive SE.
2. NCSE with coma or stupor.
3. NCSE without coma or stupor.
NCSE after convulsive SE usually warrants rapid and
aggressive escalation to IV anesthetic drugs if second-line
pharmacotherapy options fail to control seizures. In this
case, a convulsive SE protocol can be followed. NCSE with
coma (not preceded by convulsive SE), likely requires a judi-
cious and rapid stepwise pharmacotherapy approach with
first- and second-line ASMs using full IV loads and rapid
assessment of response; anesthetic levels of medications
should only be attempted after multiple ASM trials have
failed to control seizures and the patient does not demon-
strate any improvement in the level of consciousness. NCSE
without coma also requires a rapid and stepwise approach
with ASMs; however, it is unclear if or when use of anes-
thetic levels of medications outweigh the risks in this health-
ier population of patients.
4.3 Seizure Burden Reduction as the Mainstay
Target of Pharmacotherapy
With the premise that every hour matters, parenteral ASMs
should always be attempted first. A list of parenteral ASMs
with suggested boluses and maintenance doses can be found
756
in Table 2. While some authors advocate for benzodiaz-
epines as first-line therapy even for NCSs and NCSE [57],
it is unclear at this point if benzodiazepines are superior
to non-benzodiazepine ASMs in NCSs/NCSE as partially
demonstrated in the Veterans Affairs trial for the subgroup
without overt convulsive SE [8]. After exhausting several
parenteral options without improvement in the seizure bur-
den, enteral ASMs and/or general anesthetic drips (in select
cases only) should be considered (Tables 3, 4).
In the first several hours, as long as there is no deterio-
ration in neurological status or development of overt con-
vulsive SE, a judicious trial of parenteral ASMs should be
implemented. After one ASM has been administered at an
appropriate loading dose, and possibly a second bolus, with-
out any objective seizure burden reduction on cEEG, this
ASM should be discontinued, followed by initiation of the
next best option, based on side effect profile, underlying eti-
ology when known, such as primary generalized versus focal
epilepsy, as well as active comorbidities (i.e. liver failure,
renal failure, hypotension, PR prolongation, thrombocyto-
penia, etc.). If an ASM lowers seizure burden but some sei-
zure activity persists, the next ASM can be added on while
continuing the first. This process can be repeated for a few
ASMs over a few hours (not days). When choosing different
ASMs, different mechanisms of action [100–106, 113–116]
should be considered as depicted in Fig. 2.
An often neglected, yet important, factor to consider is
previously effective ASMs. It is not uncommon for NCSs
and NCSE to recur, especially if the underlying etiology
remains active or decompensation of chronic conditions
occurs. An exhaustive review of the patient’s chart may
demonstrate that multiple ASMs have been tried in the past
and that certain ones were more effective than others. This
would save hours, if not days, of unnecessary trial and error.
A medical history review as well as gathering collateral
information with the patient’s family or even previous treat-
ing clinicians may also demonstrate that some patients may
develop NCSs/NCSE after recurrence of specific conditions
such as systemic infections, electrolyte imbalances, acute on
chronic renal failure, hypertensive encephalopathy, hyper-
ammonemia from decompensated cirrhosis, hypoglycemia
in insulin-dependent diabetic patients, among others. Such
conditions should be treated promptly, and early recogni-
tion is key.
Accurate reporting of the seizure burden during the
pharmacotherapy of NCSs and NCSE is crucial. Given that
patients with NCSs and NCSE are usually cared for by a
multidisciplinary team of providers, it is paramount for all
involved to maintain a very close and effective venue of
communication. The seizure burden should be expressed in
an approximate percentage per epoch, i.e. seizure burden %
in past 12 h. More importantly, this seizure burden should be
contrasted with the previous epoch so that treating clinicians
P. Bravo et al.
can modify the treatment accordingly. A seizure burden of
30% in 12 h may sound significant, and indeed it is, but if
contrasted with a previous seizure burden of 80% in the prior
12-h epoch, the management may be to continue the current
treatment, especially if the patient’s overall status is stable, if
there are limitations due to liver/renal failure, and more so if
there has been neurological improvement. On the other hand,
a burden of 30% when the prior burden was < 10% would
suggest an urgent need for a change in treatment.
Counting seizures can also be misleading. In one 12-h
epoch, one could encounter 10 seizures, and in the next
epoch only 5, but if the length of seizures is longer on the
second epoch, the seizure burden is unchanged. Therefore,
the clinician and neurophysiologist should make every effort
to clarify this burden. A patient with 30 seizures in 12 h, but
each lasting 20 s, has a seizure burden of < 2% (10 min out
of 720 min = 0.014) whereas a patient with 10 seizures in
12 h but each lasting 10 min will have a seizure burden of
14% (100 min out of 720 = 0.14). It is understandable that
an on-call provider that is not well aware of an improvement
in the overall seizure burden, especially when cross-covering
multiple patients, may interpret 30 seizures in the last 12 h
as a patient that most certainly requires an anesthetic drip,
whereas the same provider with the appropriate information
will unlikely proceed with such an aggressive escalation of
treatment.
The choice of a specific first ASM is not as important
as is the appropriate dosing and rapid administration. A
stepwise approach on the selection of different ASMs and
IV anesthetic drugs can be found in Fig. 3. All attempts
should be made at loading a patient with a full dose of an
ASM. Subsequent dosing can be tailored based on renal or
hepatic clearance, ASM blood levels, and development of
side effects or AEs. It is important to remember that renal
and hepatic failure are irrelevant when loading a medication;
those only affect elimination rates, not how much is needed
to reach a therapeutic amount to start. It is unclear how long
to wait after loading a medication and what the right rate of
reduction of seizure burden is considered acceptable. It is up
to the clinician’s discretion to take the totality of the clinical
circumstances into consideration to decide which such rate
should be targeted on each individual case. Examples of this
include patients whose seizures are slowly improving and
have multiple acute medical issues but are not intubated.
Waiting several hours or even days for seizures to gradually
reduce in frequency may be less problematic than loading
more medications. Another example is a patient with NCSE
with partially retained consciousness with severe obstruc-
tive sleep apnea or advanced age with risk for aspiration
pneumonia. If the seizure burden is already improving in
those cases, and more so if the neurological status is improv-
ing—even if slowly—it may be preferable to observe further
Table 2  Parenteral antiseizure medications used for NCSs and NCSE [128]
IV (non-drip) Dosing
antiseizure medi- LD = loading dose
cations MD = maintenance dose
Brivaracetam LD: 100–400 mg IV
MD: 50–600 mg/day
divided q12h or q8h
Fosphenytoin LD: 15–20 mg PE/kg IV
(up to 150 mg/min); max
2000 mg. If still seizing,
give additional 5 mg/kg
IV (max 500 mg)
MD: Use phenytoin
Lacosamide LD: 5–10 mg/kg IV over
5–10 min (max 400 mg).
If still seizing, give an
additional 5 mg/kg over 5
min (max 200 mg IV)
MD: 200–600 mg/day
divided q12h–q6h
Levetiracetam LD: 40–60 mg/kg IV over
15 min (max 4500 mg).
Max IV push dose of 1500
mg administered at a rate
of 500 mg/min
MD: 1500–4500 mg/day
divided q12h–q6h
Clinically relevant pharma-
cokinetic interactions with
other antiseizure medica-
tions
↑ Concentrations of carba-
mazepine and phenytoin.
See phenytoin. Conversion half-life to phenytoin ~15 to 30 min.
Note: fosphenytoin is dosed in phenytoin equivalents (PE).
Approx. half-life Dose adjustment in renal Dose adjustment in hepatic Comments
(h) in non-critically impairment (maintenance impairment (maintenance
ill doses) doses)
HD = hemodialysis
9 None Consider dose reduction May obtain brivaracetam
drug level
May be administered IM if
no IV access (up to 99%
absorption after IM admin-
istration).
Compatible in saline, dex-
trose, and lactated Ringers
solution. Non-toxic diluent;
↓cutaneous reactions with
extravasation.
May cause hypotension,
arrhythmias.
Obtain peak phenytoin level
(free and total) 2–3 h post
IV dose or 4 h post IM
dose.
13 Reduce dose in severe renal Consider dose reduction May prolong PR interval or
Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus
impairment (CrCl < 30 induce tachyarrhythmias,
mL/min); max 300 mg/ including atrial fibrillation.
day. HD: 50% removed; Max IV push dose is 400 mg
lower dose based on CrCl, administered at a rate of 80
divide Q12h and add 50% mg/min.
of am dose to pm dose May obtain lacosamide drug
post HD. CRRT​: lower level.
dose based on CrCl, then
increase total daily dose
by 50% and divide Q8h.
6 Reduce dose based on May cause behavioral distur-
CrCl. HD: 50% removed; bances.
lower dose based on CrCl, May obtain levetiracetam
divide Q12h and add 50% STAT drug level.
of AM dose to PM dose No added therapeutic benefit
post HD. CRRT​: lower when co-administered with
dose based on CrCl, then brivaracetam.
increase total daily dose
by 50% and divide Q6h.
757
Table 2  (continued)
758

IV (non-drip) Dosing Clinically relevant pharma- Approx. half-life Dose adjustment in renal Dose adjustment in hepatic Comments
antiseizure medi- LD = loading dose cokinetic interactions with (h) in non-critically impairment (maintenance impairment (maintenance
cations MD = maintenance dose other antiseizure medica- ill doses) doses)
tions HD = hemodialysis

Lorazepam LD: 0.5–2 mg IV over 2 12 Not applicable. Not applicable Rapid redistribution. IV
min; repeat every 5 min formulation contains 80%
until seizures stop, up to propylene glycol; may
3 doses cause metabolic acidosis.
MD: not applicable Do not administer IM or SC
(IM midazolam preferred if
IV access not available).
Phenobarbital LD: 5–15 mg/kg IV (up to Strong inducer of UGT, 80 Consider dose reduction. Consider dose reduction Prolonged half-life (up to
60 mg/min); max dose CYP 3A4, 2B6, 2C9, HD: give full daily dose 140 h).
1500 mg. If still seizing, 2A6, 1A2. Dose adjust- in evening after hemodi- May cause hypotension.
give an additional 5–10 ments of ASMs including alysis. IV formulation contains 70%
mg/kg phenytoin and valproate propylene glycol; may
MD: 1–3 mg/kg/day given might be necessary. cause metabolic acidosis.
q day or divided q12h or May obtain phenobarbital
q8h drug level.
Phenytoin LD: 15–20 mg/kg IV (up to Induces CYP 1A2, 2B6, 2C, 15 None. Consider dose reduction May cause rash, fever, hypo-
50 mg/min; 25 mg/min in 3A3/4. Generally avoid tension, or arrhythmias.
elderly and patients with use with most CYP3A4 IV formulation contains
preexisting cardiovascular substrates. Coadminis- 40% propylene glycol; may
conditions) tration with valproate cause metabolic acidosis.
MD: 200–600 mg/day displaces phenytoin from Only compatible in saline
divided q12h or q8h protein binding sites. (unlike fosphenytoin).
Induces metabolism of Incompatibilities include
valproate. D5W, potassium, insulin,
heparin, norepinephrine,
cephalosporins, dobu-
tamine.
Severe tissue injury may
occur with extravasation,
including rare purple glove
syndrome.
Obtain peak phenytoin level
(free and total) 2 h post IV
loading dose.
P. Bravo et al.
Table 2  (continued)
IV (non-drip) Dosing Clinically relevant pharma- Approx. half-life Dose adjustment in renal Dose adjustment in hepatic Comments
antiseizure medi- LD = loading dose cokinetic interactions with (h) in non-critically impairment (maintenance impairment (maintenance
cations MD = maintenance dose other antiseizure medica- ill doses) doses)
tions HD = hemodialysis
Valproate LD: 20–40 mg/kg IV (over Phenytoin and valproate 12 None. Caution in hepatic impair- Highly plasma protein
5–10 min); max 4000 mg. may displace each other ment bound (up to 90%). May
If still seizing, give addi- from protein binding sites. cause hyperammonemic
tional 20 mg/kg IV (max Valproate markedly inhib- encephalopathy (treated
2000 mg) over 5 min its lamotrigine metabo- with L-carnitine supple-
MD: 2000–6000 mg lism ↑↑ lamotrigine levels mentation), hepatotoxicity,
divided q8h–q6h and risk of side effects thrombocytopenia, and
including rash. platelet dysfunction.
Concurrent use with carbap-
enems (meropenem, doripe-
nem, imipenem, ertapenem)
may result in markedly
decreased valproic acid
plasma concentrations.
May obtain valproate total
level 2 h post IV loading
dose.
Highly teratogenic and asso-
ciated with other adverse
fetal effects.
Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus

Adapted from the Yale New Haven Hospital status epilepticus protocol 2020 with permission of Abdalla Ammar, PharmD; Lawrence J. Hirsch, MD; Emily J. Gilmore, MD; the Yale New
Haven Hospital Department of Pharmacy Services; and the Yale University Dept of Neurology [128]
CRRT​ continuous renal replacement therapy, HD hemodialysis, IM intramuscular, IV intravenous, LD loading dose, MD maintenance dose, NCSs nonconvulsive seizures, NCSE nonconvulsive
status epilepticus, SC subcutaneous
759
 760

Table 3  Intravenous anesthetic drugs used for refractory NCSs and NCSE [128]
IV anesthetic drugs Dosing Clinically relevant pharma- Approximate- Dose adjustment in Dose adjustment in Comments
LD = loading dose cokinetic interactions with half life (h) in renal impairment hepatic impairment (main-
MD = maintenance dose other antiseizure medications non-critically (maintenance doses) tenance doses)
ill HD = hemodialysis

Ketamine LD: 1.5 mg/kg IV push over 2.5 None. Consider dose reduction. NMDA antagonist; provides an
3–5 min (max 150 mg); infusion with a different mecha-
repeat until seizures stop; nism of action (non-GABA). May
max total load of 4.5 mg/kg have sympathomimetic properties
MD: initial 1.2 mg/kg/h, range but can also cause hypotension
0.3–7.5 mg/kg/h; titrate to when HR/SBP ≥0.9
seizure suppression. Simultaneous benzodiazepine infu-
sion
recommended for synergism.
May ↑ICP (conflicting evidence).
Midazolam LD: 0.2 mg/kg IV (push over 7 Consider dose Consider dose reduction. Rapid redistribution. Active
1–2 min); max 20 mg Repeat reduction: risk of metabolites. May be administered
0.2–0.4 mg/kg boluses (max active metabolite via alternate routes: 0.2 mg/kg (up
40 mg per bolus) q5min until accumulation. to 10 mg) IM, intranasal, or buccal
seizures stop; max total load routes; all well absorbed rapidly.
of 2 mg/kg
MD: 0.1–2.9 mg/kg/h; titrate to
seizure suppression
Pentobarbital LD: 5 mg/kg IV (up to 50 mg/ 22 None. Consider dose reduction. Prolonged half-life (up to 50 h;
min); max 500 mg. Repeat dose dependent). May cause
until seizures stop; max total hypotension, ileus, myocardial
load of 25 mg/kg suppression, immunosuppression,
MD: 0.5–10 mg/kg/h; titrate to thrombocytopenia. IV formulation
seizure suppression contains 40% propylene glycol;
may cause metabolic acidosis.
P. Bravo et al.
 Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus 761

rather than adding a sedating agent to a patient who could

Adapted from the Yale New Haven Hospital status epilepticus protocol 2020 with permission of Abdalla Ammar, PharmD; Lawrence J. Hirsch, MD; Emily J. Gilmore, MD; the Yale New
nate, triglycerides, creatine kinase,
with hypersensitivity to egg or soy

(> 48 h) or high doses (> 80 mcg/

arrest, rhabdomyolysis, renal fail-
demia, pancreatitis, and propofol
May cause respiratory depression,
end up losing their airway as a result of this intervention.

ure). Contraindicated in patients

products. Monitor pH, bicarbo-

infusion syndrome (metabolic

lipase with prolonged therapy

acidosis, bradycardia, cardiac
hypotension, hypertriglyceri-
As some cases of NCSs and NCSE remain refractory to
multiple trials of different ASMs, it is possible that some

kg/min or 5 mg/kg/h).
of those ASMs may need to be re-introduced or main-
tained, especially those that have demonstrated at least
a modest effect in the seizure burden. At this point, it is
paramount for clinicians to document which ASMs have
Comments

made a more significant impact. Once seizures are con-

trolled, and only after IV drips are successfully weaned
to off for > 24 h and seizure free > 48 h, at that point it
hepatic impairment (main-

is reasonable to consider weaning those ASMs that were

the least effective, especially when multiple ASMs had
Dose adjustment in

to be introduced. Most of the time, this weaning process

requires further intermittent monitoring with cEEG. The
tenance doses)

decision to wean any ASM at this point should always be

contrasted with the risk of further seizures. Occasionally,
None.

it is not possible to wean any ASM in the acute phase, but

it will still be very important for the treating clinicians to
IV intravenous, LD loading dose, MD maintenance dose, NCSs nonconvulsive seizures, NCSE nonconvulsive status epilepticus
(maintenance doses)

document the pattern of success with different ASMs so

HD = hemodialysis
Dose adjustment in
renal impairment

that weaning can be attempted in a rational order as an out-

patient once the underlying acute condition has resolved.
None.

4.4 Refractory SE, Super‑refractory SE, New‑onset

Refractory Status Epilepticus (NORSE)
and Beyond
Approximate-
half life (h) in

0.6 (extended
non-critically

longed use)

Haven Hospital Department of Pharmacy Services; and the Yale University Dept of Neurology [128]
with pro-

These topics have been reviewed in great detail [103,

117–120] including in a recent comprehensive review by the
ill

American Epilepsy Society Treatments Committee [121].

Definitions and available evidence in management of refrac-
other antiseizure medications
Clinically relevant pharma-
cokinetic interactions with

tory SE in such reviews encompass a broad spectrum of SE,

including convulsive SE, and therefore a lengthy discussion
in the topic is out of the scope of this review. Neverthe-
less, as NCSE with coma often evolves into refractory and
super-refractory SE, it is important to discuss a few studies
relevant to the use of IV anesthetic drugs.
In a retrospective study evaluating 171 ICU patients
with SE, excluding post-cardiac arrest patients, 37% were
LD:1–2 mg/kg IV over 5 min;

treated with IV anesthetic drugs. Patients treated with IV

seizures stop up to total LD

(1.8–12 mg/kg/h); titrate to

max 200 mg. Repeat until

anesthetic drugs had more infections and a 2.9-fold rela-

MD: 30–200 mcg/kg/min
MD = maintenance dose

tive risk of death, independent of possible confounders and

seizure suppression
LD = loading dose

without significant effect modification by different grades

of SE severity and etiologies [122]. However, after adjust-
of 10 mg/kg

ing for the refractoriness of seizures, there were no longer

any significant findings. Thus, it is most likely that patients
IV anesthetic drugs Dosing

with more severe seizures simply needed more aggressive

treatment with IV anesthetic drugs, and that these patients
Table 3  (continued)

had worse outcomes. Furthermore, barbiturates were used

to induce an isoelectric EEG in that series, an unusually
aggressive approach [123].
Propofol

In another retrospective study evaluating 467 consecu-

tive adult cases with SE lasting 30 min or longer, 35%
 762

Table 4  Enteral antiseizure medications used for refractory NCSs and NCSE [128]
Enteral antisei- Dosing Clinically relevant pharma- Approximate-half life (h) Dose adjustment in renal Dose adjustment in hepatic Comments
zure medica- LD = cokinetic interactions with in non-critically ill impairment (maintenance impairment (maintenance
tions loading dose other antiseizure medica- doses) doses)
MD = maintenance dose tions HD = hemodialysis

Cannabidiol LD: not usually given CYP3A4 and CYP2C19 58 None. Consider dose reduction. Concomitant use of higher
MD: 2.5–20 mg/kg/day substrate. Phenytoin and doses of cannabidiol and
divided q12h other CYP3A4 induc- valproate increases the risk
ers ↓↓levels. Valproic of transaminase elevations
acid and other CYP3A4 and hepatocellular injury.
inhibitors ↑↑ levels. Consider discontinuation
or dose adjustment of can-
nabidiol and/or valproate
if liver enzyme elevations
occur. AST and/or ALT
> 3 times ULN and total
bilirubin > 2 times ULN,
discontinue treatment. Sus-
tained AST and/or ALT >
5 times ULN, discontinue
treatment.
Carbamazepine LD: 400–800 mg Major CYP3A4 substrate; 24 Consider dose reduction in Consider dose reduction: Strong association between
MD: 400–1600 mg/day major CYP2C19/3A4 8 (with prolonged use due severe renal impairment undergoes extensive the risk of develop-
divided q12h inducer. Phenytoin and to auto-induction; 2–4 (CrCl < 10 ml/min): hepatic metabolism. ing Stevens-Johnson
other CYP3A4 induc- weeks) reduce dose by 25%. syndrome/TEN and the
ers ↓↓levels. Valproic presence of HLA-B*1502
acid and other CYP3A4 allele (documented mostly
inhibitors ↑↑ levels. in Asian decent).
Dose-dependent hypona-
tremia; decreased
incidence compared to
oxcarbazepine.
May obtain carbamazepine
drug level.
Clobazam LD: 20–40 mg Felbamate: ↑plasma con- Clobazam: 16, Caution in severe renal Consider dose reduction: Decreased sedation com-
MD: 20–60 mg/day centrations of N-desmethylclobazam: 39 impairment (CrCl < 30 undergoes extensive pared to other benzodiaz-
divided q12h N-desmethylclobazam. ml/min). hepatic metabolism. epines.
May obtain clobazam
and active metabolite
(N-desmethylclobazam)
drug level.
Clonazepam LD: 1–2 mg. Major CYP3A4 sub- 30 Caution in severe renal Consider dose reduction:
MD: 1.5–3 mg/day divided strate. Phenytoin and impairment (CrCl < 30 undergoes extensive
q12h or q8h other CYP3A4 inducers ml/min). hepatic metabolism.
↓↓levels.
P. Bravo et al.
Table 4  (continued)
Enteral antisei- Dosing Clinically relevant pharma- Approximate-half life (h) Dose adjustment in renal Dose adjustment in hepatic Comments
zure medica- LD = cokinetic interactions with in non-critically ill impairment (maintenance impairment (maintenance
tions loading dose other antiseizure medica- doses) doses)
MD = maintenance dose tions HD = hemodialysis

Gabapentin LD: 1200–3600 mg 6 Reduce dose based on None. Occasional peripheral

MD: 2400–4800 mg CrCl. edema.
divided q8h–q6h HD: dose based on CrCl,
administer supplemental
dose post HD.
Oxcarbazepine LD: 600–1200 mg. ↑ concentrations of pheno- 5 Consider 50% dose reduc- ER formulation not recom- Dose-dependent hypona-
MD: 600–2400 mg/day barbital and phenytoin. tion in severe renal mended. tremia; more common in
divided q12h–q6h impairment. HD: IR elderly.
formulations preferred. May obtain oxcarbazepine
drug level.
Perampanel LD: 6–12 mg. 105 Use not recommended in Consider dose reduction in May cause behavioral issues/
MD: 12 mg/day severe renal impairment mild to moderate hepatic agitation.
(CrCl < 30 ml/min). impairment. Use not
recommended in severe
hepatic impairment.
Pregabalin LD: 150–300 mg 6 Reduce dose. None. Occasional peripheral
MD:150–600 mg/day HD: dose based on CrCl, edema.
divided q8h–q6h administer supplemental
dose post HD.
Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus

Topiramate LD: 200–400 mg. Use with zonisamide and 21 Reduce dose by ~50%. Consider dose reduction. May cause metabolic acido-
MD: 200–600 (reports up other carbonic anhydrase HD: supplemental dose sis; caution with propofol,
to 1600) mg/day divided inhibitors may worsen may be necessary. acetazolamide, zonisamide
q12h to q6h metabolic acidosis. and metformin. May cause
renal stones. May be asso-
ciated with oligohidrosis,
with risk of hyperther-
mia, mainly in pediatric
patients.
May obtain topiramate drug
level.
763
Table 4  (continued)
764

Enteral antisei- Dosing Clinically relevant pharma- Approximate-half life (h) Dose adjustment in renal Dose adjustment in hepatic Comments
zure medica- LD = cokinetic interactions with in non-critically ill impairment (maintenance impairment (maintenance
tions loading dose other antiseizure medica- doses) doses)
MD = maintenance dose tions HD = hemodialysis
Vigabatrin LD: 1500 mg 10 (but sustained effect for Reduce dose based on None. Can only be ordered by
MD: 1000–3000 mg/day days) CrCl. vigabatrin REMS Program
divided q12h certified prescribers; addi-
tional information can be
found at www.​vigab​atrin​
rems.​com.
Potential progressive
permanent peripheral
vision loss after months
to years of use; regular
ophthalmology examina-
tions recommended with
prolonged use.
May markedly reduce liver
function test (ALT/AST)
in patients with docu-
mented liver disease. It is
not recommended to use
plasma liver function test
activity as an index of liver
cell damage.

Adapted from the Yale New Haven Hospital status epilepticus protocol 2020 with permission of Abdalla Ammar, PharmD; Lawrence J. Hirsch, MD; Emily J. Gilmore, MD; the Yale New
Haven Hospital Department of Pharmacy Services; and the Yale University Dept of Neurology [128]
HD hemodialysis, LD loading dose, MD maintenance dose, NCSs nonconvulsive seizures, NCSE nonconvulsive status epilepticus
P. Bravo et al.
Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus
Fig. 2  Mechanisms of action of most commonly used antiseizure
medications and intravenous anesthetic drugs for nonconvulsive sei-
zures and nonconvulsive status epilepticus. *Topiramate and val-
developed new disability and 14% died. After accounting
for etiology, severity and comorbidities, therapeutic coma
was highly associated with worse outcome at hospital dis-
charge, including new disability and mortality. This effect
was most marked for patients with milder seizure types
(complex partial SE rather than generalized convulsive SE
or nonconvulsive SE in coma); thus, the authors concluded
that therapeutic coma should be used cautiously in complex
partial SE but that it was “fully justified” in those with gen-
eralized convulsive SE or NCSE in coma [124].
In a “natural” experiment, outcome of refractory SE
was compared (retrospectively) in two different countries
where use of therapeutic coma differed. A total of 236
patients including all etiologies of SE, except post-anoxic,
were included. Both institutions had similar demograph-
ics, co-morbidities, SE characteristic and SE severity score.
Although therapeutic coma was used in 25% in one of the
765
proate have multiple mechanisms of action with varying degrees of
potency. Red dots: inhibitory neurotransmitter (GABA); Green dots:
excitatory neurotransmitter (glutamate)
institutions (in the USA) and 10% in the other institution
(Switzerland), there was no difference in mortality and
therapeutic coma associated with increased hospital length
of stay [125].
Another retrospective study evaluating duration and depth
of therapeutic coma, predominantly with propofol for refrac-
tory SE in 182 patients treated at two academic institutions,
demonstrated that shorter but deeper therapeutic coma for
refractory SE may be more effective and safer [126]. Longer
duration of the first trial of IV anesthetic drugs was indepen-
dently associated with higher chance of seizure recurrence
following the first wean, although without poor functional
neurological outcome upon discharge or increased mortal-
ity. Furthermore, higher doses during the first trial were
independently associated with fewer in-hospital complica-
tions and associated with a shorter duration of mechanical
ventilation and total length of stay. The best cut-off time
766
Fig. 3  Suggested stepwise approach for treatment of nonconvul-
sive seizures and nonconvulsive status epilepticus with and with-
out coma/stupor. A seizure burden guided algorithm for treatment
of NCSE with categorization of parental ASMs, enteral ASMs, and
IV anesthetic drugs into different tiers based on efficacy and toler-
ability. The choice of ASM should also be based on mechanism of
action (see Fig. 2), renal versus hepatic metabolism, hemodynamic/
hematologic/cardiac status (see Tables 2, 3, 4) and level of conscious-
for duration of IV anesthetic drugs was 35 h (shorter being
better).
Finally, long-term prognosis related to deep sedation
with IV anesthetic drugs was further evaluated in a recent
longitudinal observational study evaluating 61 patients with
refractory SE [127]. Deep sedation was defined as burst
P. Bravo et al.
ness/airway status. This choice of ASMs, especially if effective in
SE cessation, extends beyond the acute treatment phase; long-term
tolerability based on concurrent co-morbidities must be taken into
account (medication choices based on the Yale-New Haven Hospital
status epilepticus protocol; used with permission of Abdalla Ammar,
PharmD; Lawrence J. Hirsch, MD; Emily J. Gilmore, MD; the Yale
New Haven Hospital Department of Pharmacy Services; and the Yale
University Dept of Neurology [128]). ASMs antiseizure medications
suppression or isoelectric EEG and was observed in 39.3%
of patients; 62.3% of these underwent > 48-h induced coma.
The remainder of the patients (60.7%) had seizure suppres-
sion pattern on EEG, defined as all other EEG patterns with-
out evidence of seizure activity and not meeting criteria for
deep sedation. Multiple regression analysis demonstrated
that deep sedation was associated with worse long-term
Pharmacotherapy for Nonconvulsive Seizures and Nonconvulsive Status Epilepticus
prognosis (1 and 2 years, p < 0.05) including lower survival
(p < 0.05).
In summary, there is a lack of randomized clinical trials
in the use of IV anesthetic drugs for NCSE/NCSs. Their use
should be cautious and likely tailored towards decreasing/
suppressing seizure burden rather than suppressing brain
activity.
5 Future Directions
Based on both animal and human studies, it is evident that
NCSs and NCSE are associated with worse outcomes, espe-
cially when prolonged or frequent (high seizure burden),
including long-term outcomes such as function, cogni-
tion, and epilepsy. However, prospective randomized trials
addressing the relationship between appropriate pharma-
cotherapy and improvement in outcome are still lacking.
Earlier and faster diagnosis and treatment lead to more
rapid cessation of seizures and likely better outcomes. The
substantial heterogeneity in the different forms of NCSE as
well as all the multiple underlying etiologies will continue to
challenge the development of appropriate studies. With the
available evidence, clinicians are urged to continue to main-
tain a high level of suspicion for NCSs and NCSE in acutely
ill neurological and medical patients, identify promptly, treat
quickly with full loads of medications, monitor appropri-
ately, and continue to treat wisely, always balancing benefits
and risks of aggressive therapy.
Declarations
Funding None.
Conflict of interest/competing interests Dr. Bravo and Dr. Vad-
diparti have no conflicts of interest/competing interests. Dr. Hirsch
has received consultation fees for advising from Accure, Aquestive,
Ceribell, Marinus, Medtronic, Neuropace and UCB; royalties from
Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and
from Wiley for co-authoring the book “Atlas of EEG in Critical Care”,
by Hirsch and Brenner; and honoraria for speaking from Neuropace
and Natus.
Ethics approval Not applicable.
Consent to participate Not applicable.
Availability of data and material Not applicable.
Author contributions Dr. PB contributed to the draft of the entire
manuscript and design of all figures; Dr. AV contributed to the draft of
Sect. 4.1 (Evidence on pharmacotherapy for NCSs and NCSE) includ-
ing Table 1 and design of Fig. 3; Dr. LJH contributed to the draft and
revision of the entire manuscript as well as design of all figures and
tables. All authors have reviewed and read the final version of this
manuscript.
767
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