EPILEPSY CURRENTS

Current Review
in Clinical Research

Epilepsy Currents
2021, Vol. 21(6) 4 05­–415
Treatment of Super-Refractory Status ª The Author(s) 2021
Article reuse guidelines:
Epilepticus: A Review sagepub.com/journals-permissions
DOI: 10.1177/1535759721999670
journals.sagepub.com/home/epi

Juan G. Ochoa, MD1*, Michelle Dougherty, MD2,

Alex Papanastassiou, MD3, Barry Gidal, PharmD4,
Ismail Mohamed, MD5, and David G. Vossler, MD6,7

1
University of South Alabama, Mobile, AL, USA
2
Neurotech LLC, Waukesha, WI, USA
3
UT Health San Antonio, TX, USA
4
University of Wisconsin, Madison, WI, USA
5
Department of Pediatrics, University of Alabama, Birmingham, USA
6
University of Washington, Seattle, WA, USA
7
Treatments Committee, American Epilepsy Society, Chicago, IL, USA
*Correspondence: Juan G. Ochoa, University of South Alabama, University Hospital 2451 USA Medical Center Drive, Mobile, AL
36617, USA; e-mail: jochoa@health.southalabama.edu

Abstract
Purpose: Super-refractory status epilepticus (SRSE) presents management challenges due to the absence of randomized con-
trolled trials and a plethora of potential medical therapies. The literature on treatment options for SRSE reports variable success
and quality of evidence. This review is a sequel to the 2020 American Epilepsy Society (AES) comprehensive review of the
treatment of convulsive refractory status epilepticus (RSE). Methods: We sought to determine the effectiveness of treatment
options for SRSE. We performed a structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) for studies on
reported treatments of SRSE. We excluded antiseizure medications (ASMs) covered in the 2016 AES guideline on the treatment
of established SE and the convulsive RSE comprehensive review of the 2020 AES. Literature was reviewed on the effectiveness of
vagus nerve stimulation, ketogenic diet (KD), lidocaine, inhalation anesthetics, brain surgery, therapeutic hypothermia, per-
ampanel, pregabalin (PGB), and topiramate in the treatment of SRSE. Two authors reviewed each therapeutic intervention. We
graded the level of the evidence according to the 2017 classification scheme of the American Academy of Neurology. Results: For
SRSE (level U; 39 class IV studies total), insufficient evidence exists to support that perampanel, PGB, lidocaine, or acute vagus
nerve stimulation (VNS) is effective. For children and adults with SRSE, insufficient evidence exists to support that the KD is
effective (level U; 5 class IV studies). For adults with SRSE, insufficient evidence exists that brain surgery is effective (level U, 7 class
IV studies). For adults with SRSE insufficient, evidence exists that therapeutic hypothermia is effective (level C, 1 class II and 4 class
IV studies). For neonates with hypoxic-ischemic encephalopathy, insufficient evidence exists that therapeutic hypothermia
reduces seizure burden (level U; 1 class IV study). For adults with SRSE, insufficient evidence exists that inhalation anesthetics are
effective (level U, 1 class IV study) and that there is a potential risk of neurotoxicity. Conclusion: For patients with SRSE
insufficient, evidence exists that any of the ASMs reviewed, inhalational anesthetics, ketogenic diet, acute VNS, brain surgery, and
therapeutic hypothermia are effective treatments. Data supporting the use of these treatments for SRSE are scarce and limited
mainly to small case series and case reports and are confounded by differences in patients’ population, and comedications, among
other factors.

Keywords
super-refractory status epilepticus, SRSE, treatment effectiveness, children, adults

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2406
164
Introduction
conditions—a national population-based study. Epilepsia. 2010;
51(5):853-861.
Status epilepticus (SE) is part of a continuum of seizure activity
7. Sillanpää M, Anttinen A, Rinne JO, et al. Childhood-onset epi-
that is classified based on response to treatment. Established SE
lepsy five decades later. A prospective population-based cohort
is defined as one seizure lasting longer than 5 minutes or 2 or
study. Epilepsia. 2015;56(11):1774-1783.
more seizures happening back to back with no return to base-
8. Reyes A, Kaestner E, Edmonds EC, et al. Diagnosing cognitive
line.1 Refractory status epilepticus (RSE) is defined as SE that
disorders in older adults with epilepsy. Epilepsia. 2021;62(2):
does not respond to an adequate dose of a benzodiazepine and
460-471.
administration of one other appropriately chosen antiseizure
9. Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of
medication (ASM). Super-refractory status epilepticus (SRSE)
vascular risk. Curr Treat Options Neurol. 2010;12(4):300-308.
is defined as seizure activity greater than 24 hours despite
treatment with an anesthetizing ASM.2 This includes cases in
which seizures recur with an attempted withdrawal of the
anesthetics.3,4
Super-refractory status epilepticus is a neurological emer-
gency with high potential for morbidity and mortality if not
recognized early. Approximately 23% to 48% of established
patients with SE progress to RSE, and 22% of patients with
RSE transition to SRSE.5 In some cases, SRSE may develop
because of inadequate treatment of RSE, but in others, the
progression to SRSE is due to the underlying etiology such
as infection, inflammatory, or anatomical/structural cause.4 A
small retrospective study of SRSE in children found that 47%
had immune-mediated encephalitis.6
Super-refractory status epilepticus carries a substantial risk
of poor neurological outcomes. In a review of 596 cases, 35%
returned to baseline, 13% had a severe neurological deficit,
13% had mild neurological deficit, 4% had undefined deficit,
and 35% died.7 One study found progressive brain atrophy in
19 patients with SRSE who underwent serial imaging.8
Uncontrolled seizure activity upregulates N-methyl- D -
aspartic acid (NMDA) receptors, resulting in glutamate-
mediated increased in intracellular calcium that has been
associated with increased excitation, apoptosis, and necrosis
of neurons. In addition, g-aminobutyric acid (GABA) receptors
are internalized from the extracellular membrane to the cytosol,
reducing the effectiveness of the GABA agonists that target
them, such as benzodiazepines and barbiturates.4
The treatment of SE was unchanged for decades and
included the use of benzodiazepines plus phenytoin/fospheny-
toin.9 The current guidelines include other intravenous (IV)
medications such as levetiracetam and valproic acid.10,11 The
treatment of RSE and SRSE is more heterogeneous and lacks
support from controlled studies2,12,13 and American Epilepsy
Society (AES) treatment of RSE comprehensive review.14 This
is a very important topic to review since mortality and health
care cost is significantly higher for SRSE than RSE and non-
RSE due to prolonged hospital stay requiring intensive care
unit (ICU) level care.15
Methods
Group Constituents
Members of the AES Treatments Committee formed the Super
Refractory Status Epilepticus Taskforce to conduct this litera-
ture review and assessment.
Epilepsy
Epilepsy Currents
Epilepsy 21(6)
Currents
Currents 21(3)
Scope
10. Mintzer S, Skidmore CT, Abidin CJ, et al. Effects of antiepileptic
drugs on lipids, homocysteine, and C-reactive protein. Ann
In 2016, the AES Guidelines Committee published the revised
Neurol. 2009;65(4):448-456.
guidelines for the treatment of SE, which focuses on the initial
11. Mintzer S, Maio V, Foley K. Use of antiepileptic drugs and lipid-
management of SE.11 Subsequently, the AES Treatments Com-
lowering agents in the United States. Epilepsy Behav. 2014;34:
mittee published the comprehensive review on the treatment of
105-108.
RSE.14 The current work was conducted as a sequel to these
12. Sanchez PE, Zhu L, Verret L, et al. Levetiracetam suppresses
recent publications in order to analyze the existing literature
neuronal network dysfunction and reverses synaptic and cognitive
supporting the use of treatments of SRSE not covered in our
deficits in an Alzheimer’s disease model. Proc Natl Acad Sci
earlier guidelines and published review and to identify areas for
U S A. 2012;109(42):E2895-E2903.
future research. We specifically review the studies on effec-
tiveness of hypothermia, ketogenic diet (KD), vagus nerve sti-
mulation (VNS), brain surgery, inhalational anesthetics, and
other ASMs such as topiramate, pregabalin (PGB), lidocaine,
and perampanel.
Databases Searched
The group reviewed numerous guidelines published in epilepsy
and other areas of neurology and discussed the bibliographic
databases, which would likely yield the largest numbers of
publications. In order to minimize bias, the Cochrane Hand-
book of Systematic Reviews of Interventions was used to guide
this systematic review.16 Cochrane Library review authors are
encouraged to use MEDLINE, Embase, and the Cochrane Cen-
tral Register of Controlled Trials. The present study used not
only MEDLINE, Embase, and the Cochrane Library but also
CINAHL (Cumulative Index to Nursing and Allied Health Lit-
erature) in order to identify articles published in other journals
that might not be captured in the first 3 databases. Embase
database search dates include 1974 to May 2020; MEDLINE
from May 1, 2020; Cochrane Database from 2005 to May 2020;
and Cochrane Central Register of Controlled Trials from 2014
to May 2020.
Search Strategies
Search strategies included “Status Epilepticus”[Major]) AND
(super [tiab] OR super-refractory [tiab] OR superrefractory
[tiab] OR benzodiazepine-resistant [tiab] OR Midazolam-
Resistant [tiab] OR lorazepam-resistant [tiab] OR LOR-
resistant [tiab] OR refractory* [tiab] OR prolonged [tiab] OR
intractable [tiab] OR treatment-resistant [tiab] OR treatment-
refractory [tiab])) OR SRSE [ti] OR RSE [ti]) OR (((epilep* [ti]
OR seizure* [ti]) AND (super [tiab] OR super-refractory [tiab]
OR superrefractory [tiab] OR benzodiazepine-resistant [tiab] OR
Midazolam-Resistant [tiab] OR lorazepam-resistant [tiab] OR
LOR-resistant [tiab] OR refractory* [tiab] OR prolonged [tiab]
OR intractable [tiab] OR treatment-resistant [tiab] OR treatment-
refractory [tiab])) NOT medline [sb])) NOT ((animals[mh]
NOT humans[mh]))) NOT ((comment[pt] OR editorial[pt]
OR letter[pt] OR in vitro techniques[mh] OR news[pt] OR
“Introductory Journal Article” [Publication Type] OR
“Ephemera” [Publication Type] OR “Newspaper Article” [Pub-
lication Type] OR “Congresses” [Publication Type] OR
Ochoa et al
Szaflarski al 407
3
155

Table 1. Evidence
imaging biomarkerof Therapeutic Interventions
for secondary for SRSE.
generalization of seizures. centrality, and that ROC curves discriminate well between
However, the study methods and data/result presentation are individuals with and without active FBTCS. These findings
Therapeutic intervention Level of evidence Comment
complicated and require some attention before we dive deeper also indicate that having active FBTCS changes the brain more
into the discussion
Therapeutic hypothermia of the results. Level C: than complications
Risk of serious having FS alone and venous
including that thethrombosis,
presence and the degree of
pulmonary
The authors present data of a1 large Class IIbut
study
overall heteroge- embolism,theinfection,
changesand mayparalytic
be usedileus as a biomarker for disease severity.
neous group of TLE patients—MRI-negative 3 Class IV studiespatients, patients As complicated as these analyses are, the authors provide
13 Case reports
with hippocampal sclerosis, dysembryoplastic neuroepithelial meticulous description of the procedures performed and of the
Vagus nerve stimulation Level U: Potential bias in the systematic review publication
tumors, and cavernomas. While not necessarily
27 Class IV studiesa major prob- results in the main body of the manuscript with additional
lem, combining
Ketogenic diet all these groups Levelprior to showing thatRetrospective
U: Children their details andincluded
small sample in the
sizesupplement.
studies However, more important
task-related fMRI activations are5not different
Class IV studies(and that thala- are implications of this study. Since fMRI has been a mainstay
mic activations are not different) creates Level U:aAdults:
potential confounder of presurgical language and verbal memory evaluation for
that is not addressed in the study. Further, 3 Class IVthey utilize their “go- years,6 most epilepsy centers obtain fMRI as part of their pre-
studies
Lidocaine Level U:
to” fMRI task—verb fluency—to assess language lateralization Most studies are focused
surgical patient onstaging
neonatalprotocol.
seizures However, we cannot expect
5 Class IV studies
including thalamic involvement in the task. However, since that psychophysiologic interaction, graph theory, and ROC
Inhalational anesthetics Level U: Risk of potential neurotoxicity
there is no performance tracking16with Classthis covert task, there curve analyses of the task-related fMRI data will be performed
IV studies
is no surgery
Brain way of knowing how wellLevel the participants
U: performed Focal in theofcourse
theresection of such evaluation.
a well-localized ictal zone inRather, whatcortex
noneloquent the study
is shows
task and how performance on the7task Classinfluenced
IV studies the observed is that the task fMRI data can be used not only to perform a
recommended
fMRI activations. To offset this,
Perampanel they
Level U: tested letter fluency as role
Possible rather simplistic
in the treatmentanalysis of language
of postanoxic SRSE lateralization but also to
part of their neuropsychological4 Class IV
battery—there were some identify the negative effects of pathophysiology (here seizures)
Pregabalin
group differences including significant Level U: differences between Riskleft
of induction
on brain of myoclonic
networks. statusWhether epilepticus
independently or in combination
3 Class IV studies
TLE with and without generalized seizures. with other measures (eg, functional connectivity or thalamic
Topiramate Level U: Enteral administration is well tolerated
In the primary analysis, they1 compared Class IV fMRI activation stereoelectroencephalography), future research could teach us
patterns in patients with FBTCS within 6 Case the last year to patients if/how such results could be applied to evaluating disease
reports
with no FBTCS (ie, only with focal seizures [FS]) in the last severity, staging in presurgical evaluation, predicting out-
Abbreviation:
year to findSRSE,that super-refractory
the activationstatus epilepticus.
patterns were different between comes, or deciding the treatment approaches (eg, resection vs
the groups with higher fMRI activation and more leftward implantable devices).
activation[ti])))
comment in patients with FS including differences
AND ((“2018/09/01”[Date in thalami. the Perhaps
- Entry]: “3000”[Date more importantly,
rat pilocarpine model.21 Another these findings
experiment teach
on usratssome-
with
Of interest is the fact that some of the
- Entry]) AND (english[Filter])) Filters: English. peak activations fell into spontaneous SE after electrical stimulation demonstrated aabout
thing about the disease itself. They provide information sig-
the anterior thalamic nuclei that, as we all know, are the target nificant the pathophysiology
reduction of duration of temporal lobe seizures,
and severity of motor ofabout the
seizures
of deep brain stimulation. In the post hoc analyses, they showed after negative
external cooling enhanced by low-dose benzodiazepine.on
effects of seizures not only on local but also 22
Evidence Classification
that FS patients’ thalamic activations were similar to healthy remote executive brain regions (ie, confirm the proposed a
controls were
Articles performing the same
classified as classtaskI but active FBTCS
(prospective, partici- long-time ago “nociferous cortex hypothesis”7), and outline the
randomized
pants had overall
controlled trials), lower
class thalamic activations
II (prospective whengroup
matched comparedcohortto Efficacy
negativeineffects
SRSE. The HYBERNATUS
of FBTCS study was and
on brain connectivity the only ran-
pathways
either ofclass
study), thoseIIItwo (allgroups. Important trials),
other controlled is that having
or classFBTCS
IV (evi- domized controlled trial of therapeutic
in of information transfer. While previously such negative effects hypothermia for
23
the lastfrom
dence year uncontrolled
was the most studies,
significant determinant
case series or of thalamic
reports, patients with SRSE. This was a class
or have been documented in resting-state studies, this effort II study of 268 adults
activation.
expert The study
opinions) would be
according to very easy to
the 2017 understand
Edition Clinicaland with extendspropofol-resistant
those findings to SRSE conducted
cognitive tasks atand 11task-based
centers across
con-
interpretGuideline
Practice had they Process
stopped Manual
their analyses here. However,
of the American Academy the nectivity. This study shows that the task data can behypother-
France. Patients were randomly assigned to receive used not
 
authors
of performed
Neurology. 17
Eachseveral useful
article but very complicated
was adjudicated by 2 authors or, in mia
analyses onlyatto32localize
C to 34 andClateralize
or normothermia plus standard
brain functions treatment.
but also to mea-
thatcase
the undoubtedly make theby
of disagreement, This study was designed to compare
3 authors. of the results difficult. sure the effects of the disease on brain networks and its
interpretation the functional outcome as
These additional, in-part confirmatory in-part follow-up anal- severity. measured by the Glasgow Outcome Scale after 90 days
yses are psychophysiologic interaction, graph theory, and between the 2 groups. There was no significant difference in
Results
receiver operating characteristic (RUC) curve analyses. The the outcomes between the 2 treatment Jerzy P.groups. Also,MD,
Szaflarski, therePhD
was a
understanding
Database searches andidentified
interpretation
no classof these analyses
I, 1 class II, andismultiple
neither higher number of reported adverse effects in the hypothermia
intuitive
class IV nor simple.
studies While
on the usedisentangling these analyses
of other therapeutic trials in not group without significant difference in the 90-day mortality
is the
part of thisofcommentary,
treatment SRSE. Tablefor1 the purpose
depicts of better of
a summary evidence and
understand- ORCID iD impairment.23
functional
ingtherapeutic
of their approach, we can briefly
interventions for SRSE.state that psychophysiologic Jerzy OneP.study reviewed
Szaflarski, MD,13 PhDarticles of case reports with a limited
https://orcid.org/0000-0002-5936-
interaction is a between regions connectivity analysis for fMRI number
6627 of patients. There was inconsistent evidence to support
24
data that is context-dependent. Graph theory analysis, as the efficacy of hypothermia for SRSE. In a series of 4 adults
Therapeutic Hypothermia
explained previously in great detail, 5
allows mathematical with SRSE refractory to midazolam or barbiturate, infusions
Therapeutic
analysis and hypothermia
description ofhas been proposed
complex systems usingas a therapy
terms such for wereReferences
treated with endovascular cooling to a target temperature.
SRSE based
as “hubs,” on data from
“centrality,” animal studies,
and “betweenness.” showing
Finally, that The
the term authorsL,felt
1. Caciagli thatLA,
Allen therapeutic
He X, et al.hypothermia
Thalamus and was successful
focal in
to bilateral
hypothermia
ROC—probably hasmostprotective
recognized effects against the edema
by neurologists—is and aborting
a binary seizures: SEa in all 4 patients.
multiscale cognitive Adverse
imagingeffects were shivering,
study. Neurology. 2020;
inflammatory reaction
classifier that allows associated
diagnostic with SE between
discrimination groups. coagulopathy,
and prevented and venous thromboembolism.25
95(17):e2427-e2441.
18-20
SE-induced
These analyses neuronal
show that, injury in most
in patients active FBTCS, Mild
with animals. there 2. A case series
Blumenfeld H,of 5 children
Varghese GI, reported
Purcaro MJ, thatet1al.
patient died
Cortical and
and 4
sub-
hypothermia has also shown thalamo-temporal
is greater context-dependent an increase in latency of onset children
and thalamo- corticalsuccessfully
networks in recovered after hypothermia
human secondarily therapy.26
generalized tonic-clonic
of seizures
motor and SE, as
connectivity, well thalamic
higher as decrease in spike
degree and frequency
betweenness in Anotherseizures.retrospective study included
Brain. 2009;132(Pt 4):999-1012.31 cases of neonates with
4408
164 Epilepsy
Epilepsy Currents
Epilepsy 21(6)
Currents
Currents 21(3)

hypoxic-ischemic encephalopathy
conditions—a national (HIE) study.
population-based who underwent con-
Epilepsia. 2010; exacerbated
10. Mintzer S,by KD is CT,
Skidmore recommended,
Abidin CJ, et particularly in children
al. Effects of antiepileptic
tinuous electroencephalogram (EEG) monitoring. About half
51(5):853-861. without
drugsa on
clear underlying
lipids, etiologyand
homocysteine, RSE.39 protein. Ann
for C-reactive
of
7. them received
Sillanpää cooling
M, Anttinen therapy.
A, Rinne JO, There was a significant
et al. Childhood-onset epi- Enteral
Neurol. feeding is typically used for initiation and mainte-
2009;65(4):448-456.
40-43
reduction of the
lepsy five electrographic
decades seizure burden
later. A prospective in cooledcohort
population-based neo- nance
11. of KD,
Mintzer S, Maio although
V, Foley K.IVUseadministration
of antiepileptic of theand
drugs KDlipid-
has
nates withEpilepsia.
study. HIE.27
moderate2015;56(11):1774-1783. alsolowering
been described
agents ininthepatients
United who would
States. not Behav.
Epilepsy tolerate2014;34:
enteral
8. Therapeutic hypothermia
Reyes A, Kaestner has EC,
E, Edmonds beenetassociated withcognitive
al. Diagnosing serious feeding, secondary to ileus, or reduced gastrointestinal motility
105-108.
complications
disorders inincluding venous
older adults with thrombosis, pulmonary
epilepsy. Epilepsia. embo-
2021;62(2): due Sanchez
12. to coma-inducing Verret L, et 44-46
PE, Zhu L,medications. al. Levetiracetam suppresses
lism, infection, and paralytic ileus.20 In order to minimize com-
460-471. There arenetwork
neuronal several challenges
dysfunction andwhen attempting
reverses synaptic andtocognitive
achieve
plications, the recommended
9. Lopinto-Khoury temperature
C, Mintzer S. Antiepileptic target
drugs has been
and markers of ketosis in critically
deficits ill patientsdisease
in an Alzheimer’s secondary
model.toProc
concomitant
Natl Acad med-
Sci
  Options Neurol. 2010;12(4):300-308.
between 32risk.
vascular C and
Curr 35
TreatC, and hypothermia duration should ications.
U S A.For example, carbohydrate contents from concomitant
2012;109(42):E2895-E2903.
be limited to 24 to 48 hours.28 In patients with SRSE, insuffi- medications may prevent or delay the onset of ketosis, some IV
cient evidence exists to support the efficacy of therapeutic ASMs contain propylene glycol (ie, IV phenytoin and IV lor-
hypothermia (level C,1 class II study, 3 class IV studies, and azepam), which can produce lactic acidosis, making it difficult
13 case reports). to induce ketosis. The use of steroids may delay the onset of
ketosis, and propofol infusion in combination with or within 24
hours of KD administration is considered relatively contraindi-
Vagus Nerve Stimulation cated due to increased risk of propofol infusion syndrome.39,47
Vagus nerve stimulation was approved in 1997 by the US Food Early side effects include metabolic acidosis, hypoglycemia,
and Drug Administration (FDA) for adjunctive treatment of hyponatremia, and hyperlipidemia, and careful monitoring of
drug-resistant focal epilepsy.29 Experimental studies demon- blood glucose, serum lipids, liver functions, acid–base status,
strated that VNS was capable of seizure termination.30 Electri- electrolytes, urine, and serum ketones is recommended.41,42,48
cal stimulation of the human hippocampus at a rate of 30 Hz
produced a significant decrease in the occurrence of epilepti- Efficacy in SRSE in adults. There is only 1 prospective multicenter
form discharges compared to baseline.31 There are few case study investigating the feasibility, safety, and efficacy of a KD
reports and case series in which VNS was implanted acutely for for SRSE in adults. The diet was initiated via gastrostomy tube
the treatment of SRSE. A recent systematic review of 26 arti- in 15 patients, with a median duration of SRSE of 10 days
cles and abstracts included 38 patients and demonstrated a lack before KD initiation. There was no control group. Ketosis was
of evidence for efficacy of VNS in this scenario.32 Seizure achieved with a median of 2 days after initiation. Of the 14
cessation occurred in 28 of 38 cases; the patients were patients who completed KD treatment, 11 had resolution of
implanted within an average of 18 days. The average time for SRSE, with a median of 5 days.48 Thakur et al described 10
“response” was 1 week after implantation.33 This review is adult patients initiated on KD treatment. The median duration
problematic as all publications were retrospective and poorly of SE before initiation of KD was 21.5 days, and the median
controlled, the concomitant treatment was vaguely described, number of ASMs used before initiation of KD was 7. Nine
the electrographic outcome is not available in many cases, and patients achieved ketosis, and SE ceased in all patients achiev-
the main author in this review has a significant conflict of ing ketosis, with a median of 3 days. Two patients developed
interest. Another review article in 2015 reported similar find- hypertriglyceridemia and 1 had transient acidosis that resolved
ings with only 2 cases of seizure cessation within 24 hours of without interrupting dietary treatment. 47 Data from case
stimulation.33 In conclusion, insufficient evidence exists to reports, case series, and 2 other retrospective studies demon-
support that VNS is effective for the treatment of SRSE (level strated similar efficacy.46,49,50
U, 27 class IV studies).
Efficacy of KD in SRSE in children. There are no prospective or
randomized trials assessing the efficacy of KD in SRSE in chil-
Ketogenic Diet dren. Data are available from several retrospective studies and
Ketogenic diet has been used in the treatment of medically case series in children with SRSE of different etiolo-
refractory epilepsy in children since 1921 in the United States.34 gies.41,42,51,52 There is no consensus on the timing of initiation
How the diet exerts its antiseizure effect is not entirely known, of KD in SRSE, although typically started via the enteral route
but a number of possible mechanisms of action have been pro- after days of failed anesthetic treatment. Of particular interest is
posed. Ketogenic diet appears to modulate glutamate release35 its use in febrile infection–related epilepsy syndrome (FIRES)
and has anti-inflammatory36,37 and neuroprotective effects,38 where there are several studies suggesting its efficacy.53,54 Park
which is of particular importance to its use in SRSE. The largest et al reported 16 children with SRSE, including 10 patients with
experience using KD therapy for the treatment of SRSE has been FIRES who were treated with KD. The patients were in SRSE
in children, but it has also recently been used in adults. with a median of 23 days (range, 3-420 days) prior to KD initia-
As the diet involves an energy shift from the use of carbo- tion. Ketosis was achieved within 2 to 6 days. Of the 16 patients,
hydrates to lipids, it might induce deterioration in some patients 9 achieved seizure freedom, 6 had >50% seizure reduction, and
with disorders of fat metabolism. Screening for metabolic dis- 1 had <50% seizure improvement. Eleven patients reported side
orders as a possible etiology of SRSE and potentially effects, with the most common being gastrointestinal
Ochoa et al
Szaflarski al 409
5
155

disturbances.
imaging biomarker Other early side effects
for secondary included lipidofaspiration
generalization seizures. Inhalational Anesthetics
centrality, and that ROC curves discriminate well between
pneumonia,
However, the hypercholesterolemia,
study methods and elevated data/result liver enzymes, and
presentation are individuals with and without active FBTCS. These findings
Inhalational anesthesia (in decades past halothane, and in recent
complicated and 53
hypoproteinemia. Nabbout
require some et al reportedbefore
attention 10 patients
we dive with RSE
deeper also indicate that having active FBTCS changes the brain more
years isoflurane) has been used occasionally for the treatment of
and
intoSRSE due to FIRES.
the discussion of theInresults.
7 patients, seizures stopped within 2 than having FS alone and that the presence and the degree of
SRSE when other treatments have failed. The exact mechanism
to 4The days following
authors present thedataonsetof ofa large
ketonuria and 4 to
but overall 6 days
heteroge- the changes may be used as a biomarker for disease severity.
by which these agents suppress seizures is not completely under-
following
neous group the ofonset
TLEofpatients—MRI-negative
the diet. Patients recovered consciousness
patients, patients As complicated as these analyses are, the authors provide
52 stood, but clinical experience has demonstrated a very rapid
within 24 to 48 hours
with hippocampal following
sclerosis, seizure cessation.
dysembryoplastic neuroepithelial meticulous description of the procedures performed and of the
The KD suppression of seizure activity under EEG monitoring. The most
tumors, and has also been While
cavernomas. used for notthe treatmenta of
necessarily majorSRSE prob-of results in the main body of the manuscript with additional
different etiologies, including patients common complication is hypotension that may require the use of
lem, combining all these groups prior with preexisting
to showing epi-
that their details included in the supplement. However, more important
lepsy and immune-mediated encephalitis. 51,55
Appavu et al pressors.62-64 Isoflurane is highly effective in stopping epileptic
task-related fMRI activations are not different (and that thala- are implications of this study. Since fMRI has been a mainstay
reported on KDare treatment in 10 creates
childrena potential
with SRSE. Median activity in up to 92.9% and 94.4% of adult and pediatric patients,
mic activations not different) confounder of presurgical language and verbal memory evaluation for
duration
that is notofaddressed
SE priorintotheKD wasFurther,
study. 18 days. they Nine patients
utilize their “go-had respectively.
years,6 most In most patients,
epilepsy the seizures
centers obtain fMRIreturned
as part of after cessa-
their pre-
resolution of SRSE, with
to” fMRI task—verb a median
fluency—to of 7language
assess days after diet initia-
lateralization tion of inhalational anesthetics. In all, 30%
surgical patient staging protocol. However, we cannot expect inhaled Xenon has
tion, and 8 thalamic
including patients were weaned off
involvement in anesthesia
the task. However,within 15 since days been associated with 100% seizure control
that psychophysiologic 65interaction, graph theory, and ROCin all neonates with
of dietisinitiation
there and within
no performance 1 day of
tracking withachieving
this covert ketonuria. 51
task, there seizures due to asphyxia.
curve analyses There isfMRI
of the task-related a concern for potential
data will be performed toxi-
In way
is no conclusion,
of knowing for children
how well with
the SRSE (level performed
participants U, 5 class the IV city associated with the use of inhalation anesthetics.
in the course of such evaluation. Rather, what the study shows A case-
studies)
task andand howadults (level U,on_3_
performance theclass IV studies),the
task influenced insufficient
observed controlled
is that the study reported
task fMRI data 8can
patients
be used with
notSRSE
only to treated
performwitha
evidence exists to support
fMRI activations. To offset thatthis,
the they
KD is effective.
tested letter Studies
fluencyare as anesthetic agents and matched with similar patients
rather simplistic analysis of language lateralization but also to not receiving
limited
part of by their
their retrospective nature,
neuropsychological small samplewere
battery—there size,some and isoflurane.
identify theIsoflurane cases showed
negative effects more magnetic
of pathophysiology (hereresonance
seizures)
concomitant
group differences use ofincluding
other agents, although
significant KD was utilized.
differences betweenThe left imaging
on brain66 networks. Whether independently or in compared
(MRI) hippocampal signal abnormalities combination to
optimal
TLE with timing for KD generalized
and without initiation remains seizures.unknown. The effec- control. A case report of 2 patients treated
with other measures (eg, functional connectivity or thalamic with isoflurane for
tiveness
In theofprimary
KD withanalysis,some treatment agents compared
they compared to others
fMRI activation over 30 days was associated with future
stereoelectroencephalography), MRI abnormalities,
research could suggesting
teach us
67
or for specific
patterns etiologies
in patients with is also unknown.
FBTCS within theProspective
last year totrials patientsare aif/how
potential neurotoxic effect after prolonged
such results could be applied to evaluating diseaseuse.
needed
with notoFBTCS determine (ie, the
only effectiveness
with focal seizuresof KD for[FS]) SRSE. in the last In conclusion,
severity, staging forin children
presurgical and evaluation,
adults with SRSE predicting(levelout-
U,
year to find that the activation patterns were different between 16 class IV studies), insufficient evidence exists
comes, or deciding the treatment approaches (eg, resection vs to support that
the groups with higher fMRI activation and more leftward anesthetic
implantableagents are effective. There is also a concern for
devices).
Lidocaine
activation in patients with FS including differences in thalami. potential neurotoxicity,
Perhaps more importantly, which makesthese this therapeutic
findings teach approach
us some-
Lidocaine,
Of interest isa the classfactIbthat anti-arrhythmic
some of the peak and local anesthetic
activations fell into less desirable. Indeed, the main goal to treat
thing about the disease itself. They provide information SRSE aggressively
about
agent, reversibly
the anterior thalamic binds a specific
nuclei that, asreceptor
we all know,site inare thethe pore
targetof is
theto pathophysiology
prevent potential brain damage.lobe seizures, about the
of temporal
sodium
of deep channels of axons,Inblocking
brain stimulation. the postion hocmovement
analyses, they through showedthe negative effects of seizures not only on local but also on
pore.
that FS This is not tothalamic
patients’ be confused with ASMs,
activations were whichsimilarenhance
to healthy the remote executive brain regions (ie, confirm the proposed a
rapid
controls phase of sodium
performing thechannel
same task inactivation
but active in FBTCS
the central ner-
partici- long-time
Brain ago “nociferous cortex hypothesis”7), and outline the
Surgery
vous
pantssystem
had overall(eg, lower
phenytoin, thalamic carbamazepine,
activations when lamotrigine,
compared and
to negative effects of FBTCS on brain connectivity and pathways
others),
either ofor lacosamide,
those two groups. which enhances
Important slow
is that inactivation
having FBTCS of in Surgical approaches
of information transfer.in While
the management
previously such of SRSE negativehaveeffects
been
sodium
the last channels
year was in theneurons. The reasondeterminant
most significant for this additive effect
of thalamic reported when first-, second-, and third-line
have been documented in resting-state studies, this effort pharmacological
of lidocaineThe
activation. likely
study stemswould from be theverydrug’s
easy to amine chain, and
understand not management
extends thoseoffindings
seizurestoarecognitive
ineffective. tasksDifferent surgical con-
and task-based pro-
present
interpretinhad othertheycommonly
stopped their used analyses
sodium channel–based
here. However,anti- the cedures have been used for SRSE, including
nectivity. This study shows that the task data can be used not focal resection,
epileptic drugs.56 Literature
authors performed several useful on thebut use
veryof lidocaine
complicated in the treat-
analyses lobar
only toorlocalize
multilobarand resection, functional/anatomical/modified
lateralize brain functions but also to mea-
ment of SE is focused
that undoubtedly make the on interpretation
its use for neonatal seizures
of the results and is
difficult. hemispherectomy, corpus callosotomy,
sure the effects of the disease on brain andnetworks
multiple subpial
and its
68
the scope of this review. 57
These additional, in-part confirmatory in-part follow-upaanal-
beyond Yamamoto et al 58
in sur- transections
severity. with or without focal resection. Surgical inter-
vey of 194 neonatal ICUs at university
yses are psychophysiologic interaction, graph theory, and hospitals in Japan found ventions have been performed at least 2 weeks after persistent
that lidocaine
receiver was useful
operating in the treatment
characteristic (RUC) curve of neonatal
analyses.SE. The SE in all but one case who was operated
Jerzy within 8MD,
P. Szaflarski, daysPhDof the
Data in adults are limited to case
understanding and interpretation of these analyses is neither reports with mixed effi- onset.68,69 Resection has been used primarily in the setting of
cacy. Cervenka et al 59
reported on the
intuitive nor simple. While disentangling these analyses is not use of IV lidocaine, Rasmussen encephalitis with epilepsia partialis continua.70,71
coadministered
part of this commentary, with otherfor ASMs including
the purpose of IV anesthesia
better understand- in a ORCID
In patientsiDwith seizure focus in eloquent cortex, such as motor
49-year-old with SRSE. Lidocaine was
ing their approach, we can briefly state that psychophysiologic ineffective in control- or language
Jerzy areas, resection
P. Szaflarski, MD, PhD is not ideal and will result in post-
https://orcid.org/0000-0002-5936-
ling SE. Lidocaine
interaction is a between was effective in a case report
regions connectivity of a for
analysis 15-year-
fMRI operative
6627 neurological deficit. In these cases, it has been shown
old
data that is context-dependent. Graph theory analysis,mg/
with FIREM. Lidocaine was started at a dose of 1.25 as that multiple subpial transections are effective at decreasing
kg/h,
explainedresulting in a progressive
previously in great detail, 5
resolutionallows of mathematical
SE and EEG clinical seizure activity.72 Multiple subpial transection is
improvement from the first
analysis and description day of administration
of complex systems usingallowing terms such the References
thought to be effective due to decreased synchronization
barbiturate
as “hubs,” coma to be completely
“centrality,” removed inFinally,
and “betweenness.” the subsequent
the term through
1. CaciaglitheL,transected
Allen LA,cortex
He X, preventing
et al. Thalamus spread
and of seizure
focal from
to bilateral
60 73
days. Lidocainemost
ROC—probably was also effective
recognized byinneurologists—is
a 23-year-old after fail-
a binary theseizures:
foci to adjacent cortex.
a multiscale Maimaging
cognitive et al reported a case of a2020;
study. Neurology. 25-
61
ure of pentobarbital
classifier that allows coma. diagnostic discrimination between groups. year-old woman who had partial anterior callosotomy who
95(17):e2427-e2441.
For analyses
These children show and adults
that, inwith SRSE,
patients withinsufficient
active FBTCS, evidence
there presented
2. Blumenfeld withH,persistent
Varghese generalized
GI, Purcaro MJ, SE lasting over 1and
et al. Cortical month
sub-
exists to support
is greater that the lidocaine
context-dependent is effective (level
thalamo-temporal andU, 5 class
thalamo- andcortical
was finally treated
networks with completion
in human secondarily of the corpus
generalized callosot-
tonic-clonic
IV studies).
motor connectivity, higher thalamic degree and betweenness omy. She returned
seizures. following the procedure.72
to baseline4):999-1012.
Brain. 2009;132(Pt
6410
164 Epilepsy
Epilepsy Currents
Epilepsy 21(6)
Currents
Currents 21(3)

In summary, focal
conditions—a surgical
national resection study.
population-based is recommended for
Epilepsia. 2010; population.
10. Mintzer S,For adultsCT,
Skidmore andAbidin
children
CJ, etwith SRSE,
al. Effects of insufficient
antiepileptic
patients with a well-localized ictal zone in noneloquent cortex
51(5):853-861. evidence exists
drugs on to support
lipids, the efficacy
homocysteine, of perampanel
and C-reactive protein.(level
Ann
and persistence
7. Sillanpää M, of convulsive
Anttinen or nonconvulsive
A, Rinne SRSE and fail-
JO, et al. Childhood-onset epi- U, 4Neurol.
class IV studies).
2009;65(4):448-456.
ure lepsy
of proper pharmacological
five decades therapypopulation-based
later. A prospective (level U, 7 class IV
cohort 11. Mintzer S, Maio V, Foley K. Use of antiepileptic drugs and lipid-
studies).
study.There is no2015;56(11):1774-1783.
Epilepsia. evidence to recommend the use of corpus lowering agents in the United States. Epilepsy Behav. 2014;34:
callosotomy for SRSE.
8. Reyes A, Kaestner E, Edmonds EC, et al. Diagnosing cognitive
Pregabalin
105-108.
disorders in older adults with epilepsy. Epilepsia. 2021;62(2): No Sanchez
12. class I, II,
PE,orZhu
III studies have
L, Verret been
L, et performed on suppresses
al. Levetiracetam PGB as a
460-471. treatment
neuronalfornetwork
SRSE.dysfunction
A literature
andsearch
reversesidentified onlycognitive
synaptic and 3 orig-
Perampanel
9. Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of inaldeficits
articlesinonan this subject. disease
Alzheimer’s Reviewmodel.
articles were
Proc Natlexcluded.
Acad Sci
Perampanel is a selective,
vascular risk. Curr Treatnoncompetitive a-amino-3-hydroxy-
Options Neurol. 2010;12(4):300-308. NovyU Sand Rossetti81 retrospectively found 10 of 230 patients
A. 2012;109(42):E2895-E2903.
5-methyl-4-isoxazolepropionic acid (AMPA) receptor antago- with RSE treated with PO PGB at their center over a 3.5-year
nist. Increased trafficking of NMDA and AMPA receptor span. One patient was treated twice daily (bid) for a total of 11
subunits to the synaptic membrane contributes to increased episodes. Pregabalin was used after other ASMs had failed in
glutamate-mediated excitatory activity. Therefore, targeting all cases, and 9 of 11 episodes were considered refractory.
AMPA receptors may offer alternative treatments for patients Pregabalin was given PO for simple partial SE via nasogastric
with SRSE.1 Perampanel is available only as an oral (PO) for- tube for patients in stupor/coma. Episodes were very likely
mulation that can be administered via nasogastric tube in controlled in 5 patients, possibly controlled in 3, and not con-
patients with SRSE. The gastrointestinal absorption and con- trolled in 3.81
sequent bioavailability of perampanel given by enteral feeding Swisher et al reported a retrospective review in which they
tube could be reduced by slowed gastric emptying, impaired identified 23 patients with SE related to primary or metastatic
intestinal blood flow, and reduced intestinal motility.74 The brain tumors. In all patients, phenytoin and levetiracetam were
literature describing the use of perampanel is limited to small used initially, then PGB was given. After administration of all 3
retrospective studies and a few case reports. ASMs, SE was controlled in 16 (70%) of 23 patients an average
Strzelczyk et al described the use of perampanel, adminis- of 24 hours after the addition of the third drug.82 This same
tered via nasogastric tube, in 23 patients with SRSE; 6 patients group reported a series of 21 patients who received PGB for the
responded. Resolution of SRSE on EEG occurred with a med- treatment of nonconvulsive SE or seizures. They found PGB
ian time of 3 days, with a median dose of 6 mg.75 Rohracher was more effective in aborting seizures than nonconvulsive SE
et al described 12 patients, including 5 patients with SRSE (2 patients, 18%). Of the 9 patients with brain tumors, 6
treated with perampanel. Perampanel was given after a median responded, whereas all 4 with posthypoxic seizures did not.83
number of 4 ASMs (range: 2-7). Median initial dose was 4 mg One concern is that de novo myoclonic SE has been reported
titrated up to a median of 12 mg in increments of 2 to 4 mg/d. in patients without epilepsy treated with PGB. Knake et al84
Of the 12 patients, 2 responded. No adverse cardiorespiratory reported 2 patients with chronic pain with PGB-induced myo-
changes or changes in laboratory parameters related to the clonic SE. Likewise, Baysal Kirac et al85 described 2 chronic
administration of perampanel were observed.76,77 pain patients treated with PGB who developed myoclonic SE.
Beretta et al78 described 8 postanoxic patients with SRSE. In conclusion, for the treatment of SRSE, insufficient data
Patients were treated with a single daily dose of perampanel, exist to support the efficacy of PGB (level U, 3 class IV stud-
administered via nasogastric tube. Perampanel was started with ies). Induction of myoclonic SE has been reported in patients
a median initial dose of 6 mg (range 6-12 mg). In 6 patients, without epilepsy following administration of PGB.
SRSE resolved within 72 hours following administration of
perampanel without changes in comedications. A mild chole-
static injury was observed in 5 patients. Similarly, there are
Topiramate
case reports describing resolution of postanoxic SRSE follow- Topiramate was approved by the FDA in 1997 for both focal
ing administration of perampanel.79,80 It should be recognized and generalized seizures in patients aged 2 years and older.
that with a very long half-life of approximately 105 hours, if This agent appears to have multiple mechanisms of action that
only maintenance dosing is provided once daily (ie, with no may contribute to its antiseizure activity, including rapid inac-
loading dose), it will take approximately 525 hours (3 weeks) to tivation of voltage-gated sodium channels, augmentation of
achieve a steady-state plasma concentration of perampanel. GABA currents (independent of benzodiazepine receptors),
This makes it hard to interpret studies reporting resolution of inhibition of carbonic anhydrase, and blockade of excitatory
SRSE after only 72 hours. postsynaptic AMPA/kainate receptors.86
In conclusion, the current data supporting the use of peram- Several studies have evaluated topiramate use in both neo-
panel in the treatment of SRSE are scarce and limited to small natal seizures and RSE and SRSE in adult patients. In neonates,
case series and case reports and confounded by differences in Perry et al reported that in infants with EEG confirmed SE,
patients’ population, comedications, timing of administration, seizures were terminated within 24 hours following an enteral
and dosages of perampanel. Preliminary data suggest it may loading dose of 5 mg/kg bid for 2 days. Patients were then
have a role in the treatment of postanoxic SRSE, although started on a maintenance dose of 2.5 mg/kg bid.87 Lower initial
larger prospective studies are needed to assess its utility in this and target maintenance doses of 2 to 3 and 5 to 6 mg/kg/d,
Ochoa et al
Szaflarski al 411
7
155

88
respectively,
imaging biomarker have also been reported
for secondary to be efficacious.
generalization of seizures. knowledge,
centrality, and no that
evidence-based
ROC curvesreview discussed
discriminate wellthe broad
between
Although
However, limited
the study anecdotal
methodsdata and suggest
data/result benefit in preterm
presentation are range of treatments
individuals with and forwithout
SRSE and no guidelines
active FBTCS. These exist regarding
findings
infants (maintenance
complicated and require doses
some of attention before 89
3.5-8 mg/kg/d), wethis diveASM deeper is the
alsooptimal
indicateapproach
that having toactive
treatmentFBTCS of this
changes serious condition.
the brain more
not
intowithout potential
the discussion of serious
the results. adverse effects in these patients, Similar
than havingto recent review
FS alone andof that
RSEthe by presence
the AES Treatments
and the degree Com- of
including
The authorsirritability,
presentfeedingdata ofproblems,
a large but metabolic acidosis,
overall heteroge- mittee,
the changes we systematically
may be used as reviewed a biomarker theforworld’s
disease literature
severity.
90
and,
neousmoregrouprecently, necrotizing enterocolitis.
of TLE patients—MRI-negative patients, In patients
adults, regarding the treatment
As complicated of SRSE.
as these analyses are, the authors provide
although several small
with hippocampal retrospective
sclerosis, reviews and/or
dysembryoplastic case series
neuroepithelial When SEdescription
meticulous persists afterof the theprocedures
first 24 hours performedand fail andtypical
of the
have
tumors,evaluated topiramate
and cavernomas. While in RSE, evidence aismajor
not necessarily sparseprob- for treatments,
results in the the main
evidence body is more
of thediluted. In desperation
manuscript to offer
with additional
91
SRSE.
lem, combining all these groups prior to showing that their adetails
therapy for these
included in patients, clinicians
the supplement. have explored
However, multiple
more important
For the treatment
task-related of RSE, data
fMRI activations are nothave been conflicting,
different (and that thala- with unconventional
are implications treatments
of this study. that lackfMRI
Since evidencehas been of efficacy
a mainstay or
Hottinger and colleagues
mic activations reporting
are not different) in a retrospective
creates study that
a potential confounder safety. Among the
of presurgical therapies
language andreviewed here, weevaluation
verbal memory found mostly for
6
topiramate successfully
that is not addressed terminated
in the study. Further, RSE theyinutilize
overtheir 70%“go- of class
years,IV studies.
most Somecenters
epilepsy therapies carryfMRI
obtain a significant
as part of health
their risk.
pre-
patients
to” fMRIwhen topiramate
task—verb was given
fluency—to assess as language
the fourth to seventh
lateralization For example,
surgical patienttherapeutic
staging protocol.hypothermia
However, may we cause
cannotvenous
expect
ASM at doses
including ranging
thalamic from less than
involvement in the400task.
to 799 mg/d.92since
However, thrombosis and pulmonary
that psychophysiologic embolism;
interaction, graphinhalation
theory,anesthetics
and ROC
93
Conversely,
there Madzar et tracking
is no performance al did not withobserve any meaningful
this covert task, there may
curvecause
analyses neurotoxicity. Other therapies
of the task-related fMRI datasuch will be as performed
lidocaine,
efficacy
is no wayofoftopiramate
knowing how in RSE. well the participants performed the PGB,
in the perampanel,
course of such andevaluation.
VNS had very littlewhat
Rather, datathe to support
study shows their
Inand
task onehow of the largest published
performance on the task datainfluenced
sets, Fechner and col-
the observed use. Ketogenic
is that the taskdiet fMRI hasdata
beencan used bemainly
used not in children
only to with performclassa
leagues retrospectively
fMRI activations. evaluated
To offset this, adjunctive
they testeduse of topiramate,
letter fluency as IV evidence.
rather Brain
simplistic surgeryofmay
analysis be reserved
language for patients
lateralization withto
but also a
given
part ofboththeir POneuropsychological
and via nasogastricbattery—there tube, in n ¼ 106 were patients
some well-defined super-refractory
identify the negative effects of seizure focus in a(here
pathophysiology noneloquent
seizures)
classified as either
group differences including ¼ 66) ordifferences
RSE (nsignificant SRSE (n ¼ 40). The
between left cortex
on brain after other treatments
networks. Whether have failed. or in combination
independently
authors
TLE with denoted
and without a positive response
generalized to topiramate in those
seizures. Similar
with other tomeasures
the recent review
(eg, of RSEconnectivity
functional by the AES or Treatments
thalamic
patients
In thewhoseprimary SE analysis,
terminated when
they topiramate
compared fMRI was the last
activation Committee, we systematically reviewed
stereoelectroencephalography), the world’s
future research couldliterature
teach us
ASM added
patterns with nowith
in patients additional
FBTCSchanges within the to background
last year to patientsASMs. regarding
if/how such the results
treatment of SRSE.
could be appliedThe methodology
to evaluatingused for
disease
Using
with no this criterion,
FBTCS (ie, the
onlymedian
with focaltime seizures
from the[FS]) onsetinofthe SElast
to this comprehensive
severity, staging inreview has limitations.
presurgical evaluation, We predicting
used a librarian out-
initiation
year to find of that
topiramate
the activationwas about 8 days
patterns were(1-30 days).between
different Initial to search
comes, or for publications
deciding about SRSE
the treatment approachesand assigned
(eg, resection a small vs
topiramate
the groups doses ranged fMRI
with higher from 25 to 500 mg,
activation and with
morea leftwardmedian number
implantableof taskforce
devices).members to conduct independent searches
initial doseinofpatients
activation 100 mg. withTreatment
FS including duration ranged in
differences between
thalami. 1 for Perhaps
each therapy.moreAs a result, it isthese
importantly, possible that each
findings teach small group
us some-
and 70 days,
Of interest with
is the facta that
mediansomeofof12 thedays
peakand with a fell
activations median
into did
thingnotabout
conduct identical
the disease search
itself. They strategies.
provide In addition, about
information some
86
maintenance dose of 400
the anterior thalamic nuclei mgthat,(25-900
as wemg/d).
all know, are the target groups did not track theofexact
the pathophysiology numberlobe
temporal of articles
seizures, identified
about nor the
Overall,
of deep brain these authors reported
stimulation. In the post a positive
hoc analyses,responsetheyto TPM
showed catalog
negativetheeffects
reasonsoffor excluding
seizures not them
only beyond
on localrelying but also on theon
in 32%
that FS of patientsthalamic
patients’ with RSE and 20% were
activations in patients
similarwith SRSE.
to healthy inclusion and exclusion
remote executive criteria listed
brain regions in section
(ie, confirm the “Methods.”
proposed a
7
Although
controls generally
performing thewell
sametolerated,
task but hyperammonemia
active FBTCS partici- has Our methodology
long-time and reporting
ago “nociferous cortex meet most of
hypothesis” ),the
andInstitute
outline the of
been
pants commonly
had overall observed.
lower thalamic Fechner et al noted
activations whenthis in 35.8%
compared to Medicine and PRISMA
negative effects of FBTCS standards,
on brainbut given these
connectivity andlimitations,
pathways
of treated
either patients,
of those and particularly
two groups. Important is in that
those concomitantly
having FBTCS in we consider thistransfer.
of information a reviewWhilerather than a systematic
previously such negative review. effects
receiving
the last year valproic
was the acid.
mostSimilarly,
significant Hottinger
determinant and of colleagues
thalamic In conclusion,
have been documented mostly in insufficient
resting-state evidencestudies, exists
thison the
effort
reported
activation. hyperammonemia
The study would in be20% veryof treated
easy topatients.
understand and efficacy of alternative
extends those findings treatments
to cognitive fortasks
SRSE andbesides
task-based the treat-
con-
Mild hyperchloremic
interpret had they stoppedacidosis has also
their analyses been
here. noted, and
However, the ments reported
nectivity. This in recent
study comprehensive
shows that the taskreview data can of RSE
be used and not
no
rarely,
authorspancreatitis.
performed several In summary,useful but limited
verydata suggest that
complicated ent-
analyses guidelines exist regarding
only to localize and lateralizethe optimal approachbut
brain functions to also
treatment
to mea- of
eral
that administration
undoubtedly make of topiramate to patients
the interpretation withresults
of the SRSEdifficult.
may be this
sureserious condition.
the effects of the disease on brain networks and its
of some value. Importantly, this agent
These additional, in-part confirmatory in-part follow-up anal- seems to be generally severity.
well
yses tolerated. In conclusion, for
are psychophysiologic the treatment
interaction, graph of SRSE
theory,insuf- and Acknowledgments
ficient, data exist to support the efficacy
receiver operating characteristic (RUC) curve analyses. of topiramate (levelThe U, Jerzy P. Szaflarski, MD, PhD
Dr James Lamb provided a very valuable contribution to writing this
1understanding
class IV studyand andinterpretation
6 case reports). of these analyses is neither review. The authors also thank our librarian Heidi Tibollo, RN, for her
intuitive nor simple. While disentangling these analyses is not help with reference search.
part of this commentary, for the purpose of better understand- ORCID iD
Discussion
ing their approach, we can briefly state that psychophysiologic Jerzy P. Szaflarski, MD, PhD https://orcid.org/0000-0002-5936-
Declaration of Conflicting Interests
Super-refractory
interaction is a between status epilepticus is the end of
regions connectivity a continuum
analysis for fMRI of 6627
sustained seizure activity that is increasingly
data that is context-dependent. Graph theory analysis, as difficult to treat. The author(s) declared the following potential conflicts of interest
The overallpreviously
approach in to SRSE should5 allows
be similar to that of with respect to the research, authorship, and/or publication of this
explained great detail, mathematical
article:
ReferencesJ. Ochoa: Consultant for Compumedics. M. Dougherty:
typical
analysisSEand anddescription
RSE, with of thecomplex
additionsystems
of therapy not terms
using previously such
Employment at Neurotech, LLC; Owner, cEEG Monitoring Company.
used up to that
as “hubs,” point. Similar
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neurologists—is a binary seizures:
ership, a multiscale
unpaid, for Druksys;cognitive imaging
patent for device study.
to treatNeurology. 2020;
chronic subdural
studies,
classifierwhere selection
that allows bias likely
diagnostic affected thebetween
discrimination results.groups.
Treat- 95(17):e2427-e2441.
hematomas, in process, currently held by institution employer. B.
ment
Theseoptions
analysesare show selected
that, inatpatients
the clinician’s
with active discretion
FBTCS,based there 2. Blumenfeld
Gidal: H, for
Consultant Varghese GI, Purcaro
Aquestive, MJ,Greenwich,
Eisai Inc., et al. Cortical
and and sub-
SK Life
upon their context-dependent
is greater training, personal experience, thalamo-temporal expert and opinion,thalamo-and cortical networks in human secondarily generalized tonic-clonic
Science; End Point Review Committee for Sunovion Pharmaceuticals
published case reports
motor connectivity, or small
higher uncontrolled
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and grant/contract with UCB4):999-1012.
Brain. 2009;132(Pt Inc. I. Mohamed: PI with expected
8412
164 Epilepsy
Epilepsy Currents
Epilepsy 21(6)
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Currents 21(3)

research support from

conditions—a Marinus
national Pharmaceuticals;
population-based travel
study. compensation
Epilepsia. 2010; 12. Mintzer
10. Holtkamp M. Pharmacotherapy
S, Skidmore CT, Abidin CJ, etforal.refractory and super-
Effects of antiepileptic
as sub-PI for research study meeting for UCB GmBH. D. Vossler: PI
51(5):853-861. refractory
drugs statushomocysteine,
on lipids, epilepticus inandadults.
C-reactive 2018;78(3):
Drugs. protein. Ann
with research support
7. Sillanpää to institution
M, Anttinen A, Rinne forJO,
Accorda, Biogen, Eisai, Pfizer,
et al. Childhood-onset epi- 307-326.
Neurol. doi:10.1007/s40265-017-0859-1
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SK Life Science, UCB, and Vertex; consultant or speaker’s bureau
lepsy five decades later. A prospective population-based for
cohort 13. Mintzer
11. Aroor S,S, Shravan K, Mundkur
Maio V, Foley K. Use ofSC, Jayakrishnan
antiepileptic drugsC,and
Rao SS.
lipid-
Greenwich Biosciences, Neurelis, Otsuka,
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lowering agents instatus epilepticus:
the United States.aEpilepsy
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network JL, Boggs
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deficits status epilepticus:
in an Alzheimer’s diseasea comprehensive
model. Proc Natl review
Acad by Sci
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U Epilepsy Society Treatments Committee. Epilepsy
S A. 2012;109(42):E2895-E2903.
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to localize epileptic encephalopathy
and lateralize in school
brain functions but age
also children
to mea-
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Ochoa et al
Szaflarski al 415
11
155

88. Kahriman
imaging M, Minecan
biomarker D, Kutluay E,
for secondary Selwa L, Beydoun
generalization A. Effi-
of seizures. 91. Brigo F, and
centrality, Bragazzi
thatNL,
ROC Igwe SC, Nardone
curves R, Trinkawell
discriminate E.Topiramate
between
cacy of the
However, topiramate in childrenand
study methods withdata/result
refractory status epilepticus.
presentation are in the treatment
individuals with and of generalized
without active convulsive
FBTCS. status epilepticus
These in
findings
Epilepsia.and
complicated 2003;44(10):1353-1356.
require some attention doi:10.1046/j.1528-1157.
before we dive deeper alsoadults: a systematic
indicate that having review withFBTCS
active individual Patientthe
changes Data Analysis.
brain more
into2003.11803.x
the discussion of the results. thanDrugs.
having 2017;77(1):67-74.
FS alone and that doi:10.1007/s40265-016-0672-2
the presence and the degree of
89. The
Riesgo R, Winckler
authors presentMI,data
Ohlweiler L, et but
of a large al. Treatment of refrac-
overall heteroge- 92.
the Hottinger
changes may A, Sutter
be usedR, Marsch S, Rüeggfor
as a biomarker S. disease
Topiramate as an
severity.
torygroup
neous neonatal seizures
of TLE with topiramate. Neuropediatrics.
patients—MRI-negative 2012;
patients, patients adjunctive
As treatment
complicated as in patients
these with refractory
analyses are, the status epilepticus:
authors provide
with43(06):353-356.
hippocampal doi:10.1055/s-0032-1327771
sclerosis, dysembryoplastic neuroepithelial an observational
meticulous descriptioncohortof study. CNS Drugs.
the procedures 2012;26(9):761-772.
performed and of the
90. Courchia
tumors, B, Kurtom W,While
and cavernomas. Pensirikul A, Del-Moral
not necessarily T, Buch
a major M.
prob- doi:10.2165/11633090-000000000-00000
results in the main body of the manuscript with additional
lem,Topiramate
combining forall
seizures
these ingroups
pretermprior
infants
to and the development
showing that their 93. Madžar
details D, Kuramatsu
included JB, Gerner ST,
in the supplement. Huttner HB.
However, moreAssessing the
important
of necrotizing
task-related fMRIenterocolitis.
activations Pediatrics. 2018;142(1):e20173971.
are not different (and that thala- are value of topiramate
implications in study.
of this refractory
Sincestatus epilepticus.
fMRI has been Seizure. 2016;
a mainstay
micdoi:10.1542/peds.2017-3971
activations are not different) creates a potential confounder 38:7-10. doi:10.1016/j.seizure.2016.03.003
of presurgical language and verbal memory evaluation for
that is not addressed in the study. Further, they utilize their “go- years,6 most epilepsy centers obtain fMRI as part of their pre-
to” fMRI task—verb fluency—to assess language lateralization surgical patient staging protocol. However, we cannot expect
including thalamic involvement in the task. However, since that psychophysiologic interaction, graph theory, and ROC
there is no performance tracking with this covert task, there curve analyses of the task-related fMRI data will be performed
is no way of knowing how well the participants performed the in the course of such evaluation. Rather, what the study shows
task and how performance on the task influenced the observed is that the task fMRI data can be used not only to perform a
fMRI activations. To offset this, they tested letter fluency as rather simplistic analysis of language lateralization but also to
part of their neuropsychological battery—there were some identify the negative effects of pathophysiology (here seizures)
group differences including significant differences between left on brain networks. Whether independently or in combination
TLE with and without generalized seizures. with other measures (eg, functional connectivity or thalamic
In the primary analysis, they compared fMRI activation stereoelectroencephalography), future research could teach us
patterns in patients with FBTCS within the last year to patients if/how such results could be applied to evaluating disease
with no FBTCS (ie, only with focal seizures [FS]) in the last severity, staging in presurgical evaluation, predicting out-
year to find that the activation patterns were different between comes, or deciding the treatment approaches (eg, resection vs
the groups with higher fMRI activation and more leftward implantable devices).
activation in patients with FS including differences in thalami. Perhaps more importantly, these findings teach us some-
Of interest is the fact that some of the peak activations fell into thing about the disease itself. They provide information about
the anterior thalamic nuclei that, as we all know, are the target the pathophysiology of temporal lobe seizures, about the
of deep brain stimulation. In the post hoc analyses, they showed negative effects of seizures not only on local but also on
that FS patients’ thalamic activations were similar to healthy remote executive brain regions (ie, confirm the proposed a
controls performing the same task but active FBTCS partici- long-time ago “nociferous cortex hypothesis”7), and outline the
pants had overall lower thalamic activations when compared to negative effects of FBTCS on brain connectivity and pathways
either of those two groups. Important is that having FBTCS in of information transfer. While previously such negative effects
the last year was the most significant determinant of thalamic have been documented in resting-state studies, this effort
activation. The study would be very easy to understand and extends those findings to cognitive tasks and task-based con-
interpret had they stopped their analyses here. However, the nectivity. This study shows that the task data can be used not
authors performed several useful but very complicated analyses only to localize and lateralize brain functions but also to mea-
that undoubtedly make the interpretation of the results difficult. sure the effects of the disease on brain networks and its
These additional, in-part confirmatory in-part follow-up anal- severity.
yses are psychophysiologic interaction, graph theory, and
receiver operating characteristic (RUC) curve analyses. The Jerzy P. Szaflarski, MD, PhD
understanding and interpretation of these analyses is neither
intuitive nor simple. While disentangling these analyses is not
part of this commentary, for the purpose of better understand- ORCID iD
ing their approach, we can briefly state that psychophysiologic Jerzy P. Szaflarski, MD, PhD https://orcid.org/0000-0002-5936-
interaction is a between regions connectivity analysis for fMRI 6627
data that is context-dependent. Graph theory analysis, as
explained previously in great detail,5 allows mathematical
analysis and description of complex systems using terms such References
as “hubs,” “centrality,” and “betweenness.” Finally, the term 1. Caciagli L, Allen LA, He X, et al. Thalamus and focal to bilateral
ROC—probably most recognized by neurologists—is a binary seizures: a multiscale cognitive imaging study. Neurology. 2020;
classifier that allows diagnostic discrimination between groups. 95(17):e2427-e2441.
These analyses show that, in patients with active FBTCS, there 2. Blumenfeld H, Varghese GI, Purcaro MJ, et al. Cortical and sub-
is greater context-dependent thalamo-temporal and thalamo- cortical networks in human secondarily generalized tonic-clonic
motor connectivity, higher thalamic degree and betweenness seizures. Brain. 2009;132(Pt 4):999-1012.