On Seizure Semiology

Received: 6 May 2021
| Revised: 23 June 2021

| Accepted: 23 June 2021
DOI: 10.1111/epi.16994
C R I T I CA L R E V I E W – I N V I T E D CO M M E N TA RY
On seizure semiology
Aileen McGonigal1,2 | Fabrice Bartolomei1,2 | Patrick Chauvel3
1
Inserm, INS, Institut de Neurosciences
des Systèmes, Aix Marseille Univ, Abstract
Marseille, France The clinical expression of seizures represents the main symptomatic burden of epi-
2
Clinical Neurophysiology, APHM, lepsy. Neural mechanisms of semiologic production in epilepsy, especially for com-
Timone Hospital, Marseille, France
3
plex behaviors, remain poorly known. In a framework of epilepsy as a network rather
Department of Neurology, University of
Pittsburgh Medical Center, Pittsburgh, than as a focal disorder, we can think of semiology as being dynamically produced
PA, USA by a set of interconnected structures, in which specific rhythmic interactions, and not
just anatomical localization, are likely to play an important part in clinical expression.
Correspondence
Aileen McGonigal, This requires a paradigm shift in how we think about seizure organization, including
Clinical Neurophysiology, APHM, from a presurgical evaluation perspective. Semiology is a key data source, albeit with
Timone Hospital, Marseille, France.
significant methodological challenges for its use in research, including observer bias
Email: [email protected]
and choice of semiologic categories. Better understanding of semiologic categoriza-
tion and pathophysiological correlates is relevant to seizure classification systems.
Advances in knowledge of neural mechanisms as well as anatomic correlates of dif-
ferent semiologic patterns could help improve knowledge of epilepsy networks and
potentially contribute to therapeutic innovations.
KEYWORDS
behavior, epilepsy, neural networks, seizure classification, semiology
1 | IN T RO D U C T IO N and surgical treatments of epilepsy are judged on their abil-

ity to suppress the clinical expression of seizures.3 Seizure
The French word “sémiologie” (from the Greek semeîon semiology was the original data source in the ancient study
meaning sign) was used originally as a general term in medi- of epilepsy: Descriptions of different patterns exist from as
cine from the 18th century onward to express the symptoms early as 2000 BCE, including motor signs and their corpo-
and signs associated with disease, and became adopted in real localization and lateralization, alteration of conscious-
medical writings elsewhere in Europe throughout the 19th ness, somatosensory features and autonomic changes, and
century.1 The term has come to be employed internationally attempts to hypothesize the origins of these.4 From the end
in its English form, particularly in the context of epilepsy, as of the 19th century into the 20th century, in refining knowl-
meaning the pattern of symptoms and signs produced during edge of the cerebral basis of epilepsy, the value of semio-
seizures. logic analysis was understood by many investigators: Notable
To state the obvious, epileptic seizures are made mani- landmarks include the work of John Hughlings Jackson (cor-
fest through their tangible semiologic expression, which is relation of seizure semiology with neuroanatomical findings
the cardinal feature of epilepsy: “disease is only revealed by including postmortem investigation),5 Wilder Penfield (study
the symptoms it produces.”2 Success or failure of medical of signs triggered by intraoperative cortical stimulation),6
Fabrice Bartolomei and Patrick Chauvel contributed equally to this work.
© 2021 International League Against Epilepsy
Epilepsia. 2021;62:2019–2035. wileyonlinelibrary.com/journal/epi | 2019

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2020 McGONIGAL et al.
Henri Gastaut (categorization of semiology and correlations

with surface electroencephalography [EEG]),7 and Jean Key points
Bancaud, in collaboration with Jean Talairach (anatomi-
• Neural mechanisms of semiology are poorly
cal electroclinical correlations of seizures recorded on ste-
known, especially for complex ictal behaviors.
reoelectroencephalography (SEEG).8,9 The work of Henri
• Network approaches are better suited than the
Gastaut merits special mention, as among many other con-
focus model to investigating neural correlates of
tributions his detailed observations and precise definition10
semiology.
of semiologic features and electroclinical correlations led to
• In a network context, specific rhythmic interac-
the first proposed classification of seizure types in the mid-
tions of activity between structures and not just
1960s. Gastaut's emphasis on specific semiologic subtypes
anatomic localization appear important.
has remained a key component throughout subsequent revi-
• Methodological challenges of investigating semi-
sions of the International League Against Epilepsy (ILAE)
ology are significant, including observer bias and
seizure classification until the present.11–13
categorization.
Although seizure semiology is the tangible expression of
• Better knowledge of neural substrates of semiol-
epilepsy, and a key element in epilepsy diagnosis, classifi-
ogy could help lead to therapeutic advances aimed
cation, and localization, it can paradoxically appear an elu-
at network modification.
sive and somewhat challenging entry point to understanding
seizure organization, especially where correlation between
semiology and EEG is not evident. In epileptic seizures, con-
gruence can be observed in terms of the grouping and the
evolution of clinical signs: Semiologic expression does not indeed considered “inseparable” by Gastaut,7 who effec-
occur haphazardly but follows a sequence that is related to tively thus put forward a form of multiscale framework
the cerebral progression of the seizure discharge,14 with the implying underlying pathophysiological mechanisms. His
organization of semiologic elements having been compared classification underscored the importance of precise di-
to “words in a meaningful sentence.”15 We could also think agnosis for individual patients in terms of prognosis and
of clinical seizure phenomenology as representing a specific treatment, as well as the need to compare data internation-
behavioral architecture, with its own spatial and temporal ally in a clinical research perspective. He emphasized the
dynamic.16 On the other hand, although clearly linked to ce- likely interplay of cortical and midline subcortical struc-
rebral seizure activity, how exactly semiologic architecture tures within anatomically connected systems with regard
maps onto cerebral dynamics remains elusive for many sei- to both seizure organization and semiologic production.7
zure patterns. Indeed, he preferred the term “partial” to “focal” seizures,
This article attempts to provide an overview of our “in order to emphasize that the participating neural system
current understanding of semiology as a data source in may be distributed to a variable extent throughout a seg-
epileptic seizures, with an emphasis on focal epilepsy, ment of the entire three-dimensional cerebral volume. It
especially with regard to neural correlates. This is espe- therefore cannot be represented geometrically as a locus,
cially relevant in a context of presurgical evaluation, but even less as a focus.”7
also in terms of how semiology is used in classification On the other hand, it was commented by Luders and
systems, and more generally in a perspective of neurosci- colleagues that the ILAE seizure classification, devel-
entific progress. oped as a direct result of Gastaut's work,13 was not well
adapted for use in a presurgical context, in which the zones
of seizure onset, propagation, and clinical expression re-
2 | SEMIOLOGY AND SEIZURE quired to be elucidated.18 In this localizationist approach,
CLASSIFICATION SYSTEMS anchored in a practical need to better identify and select
candidates for epilepsy surgery, a specific semiologic clas-
Semiology is the core feature of seizure classification sys- sification system19 was proposed by Luders and coworkers
tems. Henri Gastaut's proposal for seizure classification,17 that aimed at addressing the perceived limitations18 of the
the precursor to subsequent ILAE classification schemes, existing ILAE classification scheme. Following progres-
was based on a phenomenological approach, incorporat- sive revisions of the ILAE seizure classification system up
ing “site of origin, the extent of spread of the excessive until the present,12 the issue of how best to represent semi-
neuronal discharge, and the consequent clinical symptom- ologic information within a seizure classification scheme
atology.”7 Thus from the outset, clinical expression and remains energetically debated within the epileptology
EEG were analyzed together and assumed to be linked, community.20
|
McGONIGAL et al. 2021
3 | N E U R A L N E T WO R K S VS seizure types and semiologic patterns have highlighted the

EP IL E P TIC FOC U S : R E L E VA NC E importance of temporal aspects of seizure organization,
TO S EM IO LOGIC A NA LYS IS that is, concerning discharge frequency, lag, and synchrony
between signal in different structures (Table 1), as well as
3.1 | Concept of epileptogenic networks spatial (anatomical) aspects (Table 2). These studies, espe-
cially those utilizing signal analysis methods in relation to the
When thinking about semiology and its relation to cerebral period of clinical expression of the seizure, have suggested
organization, the concept of the network basis of epilepsy is some putative mechanisms of semiologic production.
fundamentally different from the epileptic focus model.
It has been progressively accepted by clinicians that there
is much evidence in favor of epilepsy being a network disor- 3.2 | Concept of symptomatogenic zone
der21–23; this idea is decades old, having been explored for-
mally using mathematical24 and animal models25 of epilepsy In contrast to this epileptogenic network view, which was
from the 1970s onward. In a clinical context, Susan Spencer the hallmark of the French SEEG school, the domain of
and collaborators, based on observations from depth elec- correlating semiology with intracranial EEG data was sub-
trode recordings and subdural grids in the 1980s and 1990s, sequently developed by Luders et al34–36 as well as other
highlighted the concept of the epilepsy network, consider- groups37–40 using a different investigative method, recording
ing this to be a “functionally and anatomically connected, from the brain using subdural grids and/or mesial tempo-
bilaterally represented, set of cortical and subcortical brain ral depth electrodes. A system of “zones” was expounded
structures and regions in which activity in any one part af- by Luders et al27 that included representation of how se-
fects activity in all the others.”21 Spencer21 linked semiologic miologic output was linked to cerebral seizure organiza-
output to this network organization, pointing out that “the tion. However, it is important to note that the origin of the
network as a whole is responsible for the clinical and electro- “zones” model can in fact be traced back to Bancaud as
graphic phenomena that we associate with human seizures.” described above, who had initiated this novel framework
However, many years prior to this, the concept of network decades earlier. Luders defined symptomatogenic zone as
organization of seizures and its expression via specific semi- “the area of cortex that, when activated by an epileptiform
ologic patterns had already begun to be investigated by Jean discharge, produces the ictal symptoms”; the definition of
Bancaud26 based on his observations with Jean Talairach and epileptogenic zone by this school was considered pragmati-
coworkers9 from the early 1960s onward, using SEEG for cally as the minimum amount of cortex that must be resected
presurgical epilepsy evaluation. Bancaud and Talairach ob- to render the patient seizure-free.27 These constructs were
served that seizure activity may be recorded simultaneously strongly influenced by data from direct cortical stimula-
or near-simultaneously in distant (yet connected) structures, tion studies and their clinical correlates,41 as well as study
and that initial organization of the seizure could be more or of cases becoming seizure-free following epilepsy surgery.
less separate from a cerebral lesion, if present.9,27,28 This This approach therefore tended to employ a “focus” model
framework derived from SEEG observations distinguished of epilepsy, albeit one that recognized the variable spatial
lesional zone (interictal slow activity), irritative zone (interic- extent of seizure onset as well as an anatomical separation
tal spikes), and epileptogenic zone (initial organization of the between epileptogenic zone and symptomatogenic zone. In
seizure), which were linked and could overlap to a variable this framework, the relation between structures involved in
degree.9,23,28 A key concept of the SEEG method was “ana- seizure onset and those involved in semiologic production
tomical electroclinical correlation,” comparing semiology as was essentially conceptualized as a linear and mechanistic
it evolved with the characteristics of the signal in different process occurring within the spatial domain, and the symp-
anatomical locations, not only considering seizure onset but tomatogenic zone model did not attempt to address issues
also the period of early spread of the discharge.9,28,29 With of pathophysiological mechanisms other than inferring local
the advent of digital EEG, quantification of SEEG signal functional anatomical correlations.
allowed mathematical analysis of signals in different ana- The fundamental difference between Luders’ focal defi-
tomical structures across time. SEEG studies particularly em- nition of the EZ, and that proposed previously by the SEEG
ploying novel, nonlinear signal analyses from the late 1990s school—which represented initial seizure organization within
onward30,31 permitted the formal demonstration of specific a set of connected structures, as well as more complex mech-
neural networks in the genesis and propagation of seizures.32 anisms involved in producing clinical signs—was indeed ac-
Notably, rather than “epilepsy network,” the more specific knowledged by Luders et al.27 Some of these differences in
term "epileptogenic network" has been proposed based on the focal vs network epilepsy models can be attributed directly
study of underlying pathophysiologic processes using brain to choice of recording method and the view thus afforded of
biomarkers of epileptogenicity.23,33 SEEG studies of different seizure organization with regard to clinical expression.28
TABLE 1 Examples of studies examining semiology in conjunction with signal analysis of SEEG (temporal aspects of seizure organization)
2022
|
Epilepsy Number of Signal analysis of SEEG during period of

Authors Year Semiologic pattern localization subjects Main anatomical structures Control group semiologic expression

Bartolomei et al86 2002 Humming Temporal 3 Superior temporal gyrus No Rhythmic discharge over STG (6 Hz or
lobe (STG), prefrontal cortex 15 Hz). Increased coherence between
STG and prefrontal cortex
Bartolomei et al90 2005 Fear behavior Prefrontal 3 Ventromesial orbitofrontal No Sudden loss of synchrony between
cortex cortex, anterior cingulate, orbitofrontal cortex and amygdala at
amygdala (limbic system) seizure onset/clinical onset
Arthuis et al71 2009 Impaired Temporal 12 Temporal structures, parietal Compared at group Excessive synchrony (h2), ie, functional
consciousness lobe lobe, thalamus level according to coupling, between temporal and extra-
degree of altered temporal structures, notably parietal
consciousness cortex and thalamus in seizures with
marked alteration of consciousness
Lambert et al88 2012 Impaired Parietal lobe 10 Superior and inferior parietal Compared at group Increased synchrony was associated with
consciousness lobules, precuneus, parietal level according to progressively greater degrees of altered
operculum, supplementary degree of altered responsiveness at subgroup level.
motor area consciousness A statistically significant nonlinear
relationship was found between h2 values
and degree of alteration of consciousness,
suggesting a threshold effect cf Arthuis
et al71
Bonini et al89 2016 Impaired Frontal lobe 24 Internal and external prefrontal Compared at group At subgroup level, seizures characterized
consciousness cortex, premotor cortex, level according to by marked altered consciousness
parietal cortex degree of altered were associated with highest levels of
consciousness synchrony. Significant correlation was
found between consciousness scores and
correlation values (h2) of the prefrontal
and the parietal region but not with the
premotor cortex (cf Arthuis et al71 and
Lambert et al88
(Continues)
McGONIGAL et al.
TABLE 1 (Continued)
Epilepsy Number of Signal analysis of SEEG during period of

Authors Year Semiologic pattern localization subjects Main anatomical structures Control group semiologic expression
Hagiwara et al120 2017 Motor signs Insula 5 Insula, premotor and prefrontal Seizures with/without Nonlinear regression analysis was applied
McGONIGAL et al.
cortex “frontal semiology” to insular seizures with/without frontal

were compared presentation
The three patients with frontal semiology
showed strong couplings with the mesial
frontal as well as cingulate regions,
including the medial orbitofrontal cortex,
pre-SMA/SMA, and the anterior to
posterior cingulate. The two patients
with the insular semiology only showed
couplings between the insula and
cingulate regions
Bartolomei et al95 2017 Ictal aggression Temporal 1 Bilateral temporal and frontal No Aggression occurred in the last part of the
lobe structures seizure, during which period functional
connectivity study (h2 estimation of
interdependencies) showed bilateral
massive hypersynchronization between
frontal and temporal regions
Aupy et al87 2018 Oro-alimentary Temporal 15 Medial basal temporal lobe, 2/15 patients had Increased coherence occurred between
automatisms lobe opercular cortex seizures compared mediobasal temporal structures and
(OAA) with and without insulo-opercular cortex prior to onset of
OAA rhythmic chewing movements
Roux et al121 2019 Ictal coughing Temporal 1 Mesial temporal structures No Functional connectivity study (h² estimation
lobe of interdependencies) showed that
during coughing, a network of cortical
and subcortical regions was involved,
particularly the perisylvian cortices and
the caudate nucleus
Zalta et al76 2020 Antero-posterior Frontal lobe 1 Prefrontal cortex Compared with non- Delta range rhythmic body rocking was
rocking rocking seizures in associated with cortical delta oscillatory
same patient activity and phase-coupled high-gamma
energy
Note: Table updated from Ref.16

| 2023
TABLE 2 Examples of SEEG electroclinical studies examining semiology in conjunction with sublobar organization (anatomic correlates)
2024
|
Brain region involved in No. of No. of

Authors Year seizure organization subjects seizures Main findings

122
Maillard et al 2004 Temporal lobe 55 187 Subgroups defined by clinical and SEEG features: mesial type (initial epigastric
sensation and delayed appearance of oro-alimentary and gestural automatisms as
well as later (if any) altered consciousness); lateral type (early auditory illusions or
hallucinations, earlier altered consciousness, more frequent generalization); mesial-
lateral type (initial epigastric sensation and early altered contact, long seizure
duration). This study built on observations from SEEG signal analysis work31
Bartolomei et al123 2011 Parietal lobe 17 34 Neural network patterns with respect to seizure semiology,123 applying the previously
developed Epileptogenicity Index (EI)124 to quantify fast discharge at seizure onset.
Seizures predominantly arising from superior parietal lobule were often associated
with vestibular symptoms, whereas hyperkinetic motor behavior was associated
with inferior parietal involvement
Bonini, McGonigal 2014 Frontal lobe 54 374 Using automated cluster analysis of clinical signs and of brain areas involved in seizure
et al74 onset and early propagation, correlation was seen along a rostro-caudal gradient
from frontal pole to precentral cortex. Four groups of patients were described,
proceeding from central cortex and moving rostrally: Group 1 (elementary motor
signs, no gestural motor behavior); Group 2 (association of elementary motor signs
and gestural motor behavior, often with mainly proximal tonic signs and facial
contraction); Group 3 (no elementary motor signs, gestural motor behavior often
with a distal expression, which could have an integrated appearance); Group 4
(no elementary motor signs; gestural motor behavior that occurred in a context of
emotional expression, most often fearful, with an integrated appearance)
Marchi et al125 2016 Occipital lobe 29 194 Used the EI124 quantification method. Widespread organization of the EZ was
typical, with temporal and/or parietal cortex quite commonly being involved
(“occipital-plus epilepsy”). Altered conscious level was more common when onset
involved widespread posterior neocortex; automatic motor behavior and/or verbal
automatisms more often seen with occipitotemporal organization
Wang et al57 2020 Insulo-opercular cortex 37 310 Used automated cluster analysis of clinical signs and of brain areas, based on a
novel methodology of brain parcellation including connectivity parameters
(Brainnetome). Four main semiologic subgroups of insulo-opercular seizures were
identified, organized along an anteroventral to posterodorsal axis. Semiology,
particularly sensory symptoms but also motor signs, significantly correlated with
insulo-opercular subregion localization
(Continues)
McGONIGAL et al.
TABLE 2 (Continued)
Brain region involved in No. of No. of

Authors Year seizure organization subjects seizures Main findings
55
Singh et al 2020 Insula 12 25 Review of semiology defined clinical groups, agglomerative cluster and principal
McGONIGAL et al.
component analysis of semiological features was performed in twelve patients with

“pure” insula epilepsy (n = 9) or insular and only deepest opercular involvement
(n = 3) Quantitative epileptogenicity, intra-insular and extra-insular propagation
were computed via time frequency analysis and epileptogenicity mapping. The
largest principal component separated anterior insula manifestations including early
hypermotor signs, early recovery and no aura from posterior insula features of early
dystonia, early tonic motor features and sensorimotor aura
Peltola et al56 2020 Insula 11 79 Only pure insular epilepsies were selected. Epileptogenicity index was used to
define seizure onset zone and seizure discharge type was assessed. Hyperkinetic
signs, speech modifications, and viscerosensory symptoms were related to an
anterior insular seizure-onset zone. Pain, asymmetric tonic, focal clonic, and tonic
symptoms were more frequent in patients with a posterior insular seizure onset
Machado et al77 2020 Prefrontal cortex 31 51 Investigation of dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex
(VLPFC), dorsomedial prefrontal cortex (DMPFC), ventromedial prefrontal cortex
(VMPFC), and orbitofrontal cortex (OFC). The seizure onset zone (SOZ) was
determined from one or two seizures in each patient, using the epileptogenicity
index (EI) method. Note that this methodology differed from that of Bonini
et al,74 as early spread was not considered. Optimal clustering was 4 subgroups of
prefrontal seizures: a “pure DLPF” group, a “pure VMPF” group, a “pure OFC”
group, and a “global prefrontal” group. No significant difference was found in the
distribution of ictal signs between the different groups
Note: Table updated from Ref.16

| 2025
|
3.3 | Network or focus model for or objects during the seizure). This multi-level and dynamic
investigating neural correlates of semiology? interaction, which brings with it significant methodological
challenges for analyzing semiology, could evoke the idea
There is a somewhat contradictory and ambiguous relation of “embodiment,” a concept posited in the cognitive neuro-
between the epileptogenic network model and the epileptic sciences.47 Each seizure is a newly occurring event, prone
focus model in clinical practice, both probably representing to be influenced by the patient's state and environmental
different aspects of reality (perhaps akin to the co-existence conditions, and yet as seizures repeat over time, a certain
of wave and particle theories of light). The conceptual and core stability of semiologic expression is typically observed
scientific appeal of epilepsy networks notwithstanding, the both within and between patients (the latter being the basis
idea of an “epileptic focus” can seem logical, intuitive, and of seizure classification systems). This reproducible “cho-
even necessary as a working model for clinicians. The focal reography,” which lends itself to phenomenological study,
epilepsy model seems to fit with the observed success of focal indicates that a particular configuration of neural circuitry is
surgical resection in many cases, initiated by the earliest epi- being brought into play each time, which may be reinforced
lepsy surgical resections in the 19th century42 and reinforced by seizure repetition through a process of neuroplasticity,28
following the development of widespread epilepsy surgery albeit with degrees of variability related to the dynamic na-
programs based on high surgical success rates in mesial tem- ture of the system. Semiology does not arise from an iso-
poral epilepsies.43 Indeed, it has been commented that, in lated structure but from a system defined and constrained by
an epilepsy surgical framework, “thinking of networks then its connectivity, in which pathophysiological activity tends
seems impractical, because resection is ultimately focal.”44 to be organized in a structured and reproducible way across
However, this ambiguity may become increasingly impor- seizures.28,48
tant to resolve if progress is to be made in understanding and When one considers epilepsy to be a disorder of brain
treating epilepsy. This seems an important goal in light of networks, in which a seizure may be seen as an expression
increasing numbers of complex, often extratemporal cases of a dynamic system,23,49 seizure semiology also reflects a
being evaluated for epilepsy presurgical evaluation45 and the dynamic process operating on a different scale, character-
significant proportion of patients with “focal” pharmacore- ized by both spatial and temporal aspects within the cog-
sistant epilepsy who are not cured by surgery.46 nitive and behavioral domains16,50 (Figure 1). Attempts to
When thinking about how to analyze neural correlates of understand correlations between brain activity and clinical
seizure semiology, what is the optimal conceptual framework signs during seizures must therefore take into account infor-
and methodological approach? The genesis of complex se- mation collected across multiple scales51,52: behavioral fea-
miologic patterns (eg, gestural motor behaviors, altered con- tures, anatomical spread of seizure discharge, and temporal
sciousness, emotional signs, and so on) cannot be attributed organization of electrical changes (eg, discharge frequency
directly to electrical alterations limited to a restricted volume and synchrony between structures). Scientific study of neu-
of cortex: By definition, the emergence of such patterns re- ral correlates of semiology thus ideally requires a method
quires larger scale distributed networks to be brought into allowing meaningful comparison of recorded spontaneous
play, even if such a process may nevertheless be triggered seizure semiology with concomitant spatiotemporal evalua-
from discharge arising within a restricted volume of cortex, tion of neural activity, employing appropriate categorization
according to connectivity of the epileptogenic network. It of semiologic
would seem impossible to adequately explain neural cor- features and optimal measurement of the onset and spread
relates of this type of clinical expression by the “symp- of seizure discharge. The biggest challenges in this context
tomatogenic zone” model, without taking into account the include not only issues of cerebral sampling and network
role of distributed cortico-subcortical circuits; epileptogenic analysis, but also how best to observe, describe, and quantify
network-based analyses thus appear better suited to investi- semiologic features.
gating these.
5 | WHAT CAN SEEG TELL US

4 | S EIZ U R E SE MIO LO GY A S A ABOUT THE NEURAL CORRELATES
DY NA M IC DATA S OU RC E OF SEM IOLOGY?
The semiologic expression of each epileptic seizure repre- Stereoelectroencephalography (or SEEG), because of its
sents a set of complex interactions between the brain (elec- multilobar sampling, including medial and lateral structures
trical discharge), body (paroxysmal physical and/or mental and sometimes also subcortical structures, has contributed
symptoms and signs), and the environment (effect of spe- important data on neural correlates of semiology that can-
cific time, circumstances, and interactions with people and/ not be achieved using other intracranial recording techniques
|
F I G U R E 1 Use of a multi-scale framework to think about spatial and temporal features in epileptic seizure expression. The center panel
illustrates temporal and spatial scales of organization in the nervous system (adapted from Lytton et al52). Both semiologic expression and cerebral
epileptic activity can be mapped onto this spatiotemporal framework. Semiology involves the higher level dimension shared by cognition and
behavior, whereas cerebral electrical discharge involves the local circuit, area, and system levels. Apart from the spatiotemporal features of the
seizure discharge, other factors influencing electroclinical expression can be bottom-up (driven by neuronal changes) or top-down (driven by
environmental factors)
that share its millisecond temporal resolution. The detailed SEEG methodology is highly dependent on hypotheses of
analysis of semiology as it unfolds during the whole course epilepsy organization, which strongly influence implantation
of the seizure with reference to sequential signal changes strategy: Erroneous hypotheses can lead to misleading or un-
(anatomical electroclinical correlation) has traditionally been helpful results, if key structures are not optimally sampled.
the foundation of the SEEG method9 and the remainder of the As knowledge and also technical capacity evolve, both
article discusses SEEG data. As such, the emphasis here is within individual teams and in the wider epileptological
on semiology in the context of focal seizures, because SEEG community, implantation strategies tend to adapt over time
data has primarily come from patients undergoing presurgi- to take this into account. A case in point is the demonstration
cal evaluation for intractable focal epilepsies. There is a bidi- of the role of the insula in various seizure types,53 its stimu-
rectional relation between SEEG exploration and semiologic lation mapping features54 and, more recently, descriptions of
analysis: At the individual patient level, semiology critically larger series of insular seizures with electroclinical correla-
informs implantation strategy and is an essential component tions across insular subregions55,56 including in terms of their
of clinical SEEG interpretation; and on the other hand, SEEG connectional57 architecture. These are aspects that were un-
data amassed over many cases and over time inform us about known in the early decades of SEEG use because the insula
the neural correlates of semiology through studying electro- tended to be not often explored partly because of vascular
clinical patterns that are recognizably similar across patients. constraints. Because certain electroclinical features suggest-
Ideally each aspect should contribute to advancing the other, ing different insular subregions are now recognized, as well
since better recognition of semiologic patterns and their cor- as technical improvements including vascular imaging, the
relates should hopefully lead to refinement of implantation indications for implanting this region have therefore changed,
strategies for future patients. A main caveat here is evidently thus continuing to add to available electroclinical data. More
the intrinsic sampling limitations of the method with the risk generally, mean number of SEEG electrodes implanted per
of missing important information from unexplored regions,14 case has tended to increase across time, related to evolving
both cortical and subcortical. Another important issue is that indications for exploration and technical advances.58
|
Investigation of semiologic patterns and their correlates structures are much less often sampled than cortical struc-
using SEEG has followed two main approaches: (1) grouping tures, growing interest has led to increasing EEG data in a clin-
patients with a similar semiologic picture or a common semi- ical context from structures including the thalamus, putamen,
ologic feature and looking at cerebral correlates of seizures and caudate nucleus.69,70 SEEG studies of synchrony during
including temporal features of discharge (Table 1); and (2) seizures have confirmed a link between degree of thalamic
grouping patients with similar anatomical organization of the involvement and degree of alteration of consciousness, for
epileptogenic zone (EZ) or seizures arising from a particu- example (see Table 1).71 Recent work has highlighted the po-
lar brain system and looking at clinical correlates (Table 2). tential role of basal ganglia within a strictly topographically
Single case reports can also be of interest because of specific organized framework according to cortical localization of
features that can be analyzed within a single patient. seizures and cortico-subcortical connectivity.70
Taken together, these studies have two main goals: improv- Current concepts of brain function are based on the
ing knowledge of anatomical correlates (with direct clinical principle that each part of the brain has a different set of
implications for future patients); and shedding light on pos- specializations and that the specializations of a brain re-
sible neural mechanisms underlying semiologic production gion depend on its connections.72 Regions of primary and
(which improves neuroscientific understanding of epilepsy). unimodal cortex have sparse connectivity between them, in
The latter objective has benefited from signal analysis studies contrast to multimodal and transmodal regions of cortex,
(Table 2), especially using connectivity measures that assess which are densely connected to allow binding of distrib-
codependency of signal between connected structures; see uted information.72 Following on from this distinction be-
Ref. 23 for review. The present review focuses mainly on data tween unimodal and multimodal cortex, a spatial hierarchy
from spontaneous seizures, but useful information on possi- of semiology with regard to cortical involvement of seizure
ble mechanisms of semiology has also been gathered from organization could be posited, in which more elementary
SEEG stimulation studies including signal analysis.59, 60 signs with highly specific relation to cortical localization
are likely to involve unimodal cortex; whereas more com-
plex signs or constellations of signs, which are relatively
5.1 | Semiologic hierarchy with respect to nonspecific for individual cortical regions (eg, hyper-
cortical localization kinetic motor behavior73) or which may depend on wide-
spread cortical involvement (eg, altered consciousness66,71)
Cases in which seizure semiology is highly specific for cer- would be related to dynamic effects involving higher-level,
tain spatially restricted cortical regions often involve elemen- multi-modal or transmodal cortex and their cortical and
tary signs (such as somatosensory, visual or auditory aura, subcortical connections.
or focal clonic jerks) arising in relation to seizure activity How might gradations between these more complex ex-
within primary cortex. In such cases, habitual semiology can pressions of semiology and the spatial hierarchy of their
often also be reproduced by local direct cortical stimulation, neural correlates be demonstrated? This would require ap-
and indeed these were the types of presentation leading to the proaches that take into account sufficient numbers of cases,
very early cases of epilepsy surgery.42 In focal primary motor with adequate semiologic categorization and optimally sam-
cortex seizures, clinical expression of elementary motor pled brain regions at seizure onset and during emergence of
signs appears to depend on ictal discharge frequency as well semiology (early spread). In reality, such approaches are al-
as anatomical localization.61 Some more complex signs aris- ways limited by clinical factors, since the minimal cerebral
ing from nonprimary cortex can also be highly specific for (SEEG) exploration for individual patients is performed on
anatomical location and can also often be readily reproduced the basis of clinical need, limiting spatial sampling within
by cortical stimulation (eg, déjà vu arising from networks and across subjects; in addition, complex semiologies are
involving mesial temporal structures, especially entorhinal heterogeneous and achieving series with sufficient data can
cortex59). In frontal lobe, stimulation of different regions of be challenging. However, even without signal analysis, SEEG
cingulate cortex has been shown to produce complex motor data have shown correlation between clusters of semiologic
behaviors and emotional signs (especially laughter).62,63 signs and co-involved brain structures in frontal epilepsy,
On the other hand, the majority of more complex semio- indicating that behavioral signs and in particular motor be-
logic patterns involving for example gestural or hyperkinetic haviors are organized along a rostrocaudal gradient accord-
motor behavior, emotional change, and/or altered conscious- ing to their complexity,74 in keeping with current thinking on
ness tend to involve associative cortex, usually associated frontal lobe functional and anatomical hierarchy.75 This type
with seizure propagation within more extensive networks and of observation confirms the interest of pursuing this line of
more complex seizure dynamics.50 It is recognized that sub- semiologic analysis even when clinical patterns are complex
cortical mechanisms must play a role in clinical expression and brain sampling necessarily limited, since semiologic out-
of many forms of focal seizure.7,64–68 Although subcortical put seems to be tightly linked to early cortical seizure activity
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despite the likelihood of large scale cortical and subcortical and oroalimentary automatisms,87 which are character-
networks being involved.28,76 On the other hand, analyzing ized by correlations in specific frequency bands across
seizure onset alone rather than incorporating anatomical co-involved structures during semiologic production.
structures involved in early spread does not appear to cor- 2. In seizures with altered consciousness, the degree of
relate as well with semiologic subgroups, at least in frontal cortical plus/minus thalamic synchrony appears to cor-
seizures.77 relate with the degree of clinical expression, with
excessive synchrony being associated with greater im-
pairment of consciousness, across different lobar seizure
5.2 | Putative mechanisms of localizations.71,88,89
semiologic production 3. In seizures with hyperkinetic motor behavior involving an
emotional character (explosive onset of fear/defense be-
How might seizure activity interact with brain networks havior), sudden transient decorrelation between prefrontal
to produce clinical effects? Seizures may produce both cortex and amygdala at onset of clinical signs was demon-
abnormal inhibition and abnormal activation of involved strated.90 This disruption of functional connections could
regions and their connected structures.65 Attempting to then result in the disruption of emotional regulation lead-
untangle the possible mechanisms of how seizure dis- ing to the release of altered behavior.
charge determines clinical expression is difficult, all the 4. Finally, in seizures with rhythmic movements, cou-
more so since neural mechanisms of even physiological pling between frequency bands may reflect a temporal
expressions of complex brain functions remain incom- assembly of neural structures acting as an oscillator
pletely understood, for example, motor behavior,78 emo- (rhythmic pattern generator).91 This is exemplified
tion,79 and consciousness.80 Looking at expression of other by an analysis of prefrontal seizures with rhythmic
neurological conditions such as movement disorders68 and body rocking, in which phase lag coupling was dem-
parasomnias81 may help to illuminate this question. For onstrated between gamma band activity within the
example, stereotypies (abnormally repetitive behaviors) epileptogenic zone and propagation regions, and the
have been increasingly well characterized in terms of their delta-band rocking frequency (quantified using video
anatomical and neurobiological substrates, involving cor- analysis).76
ticostriatal circuits that deal with learning of sequences.82
Many seizures contain repetitive movements (and indeed These last two mechanisms could fit with and refine
the whole seizure/semiologic architecture could be seen as Tassinari's proposal of the presence of central pattern gener-
being reinforced by repetition over time), so the stereotyp- ators that would “generate rhythmic movements and express
ies model could be an interesting one for studying these species-specific innate emotions.”92,93 Such central pattern
mechanisms in epilepsy.83 generators are generally presumed to be subcortical, and pos-
How has SEEG analysis informed us about possible mech- sibly common to both some forms of epilepsy and some para-
anisms of semiologic production? A main line of research has somnias.94 However, rather than being brought into play via a
investigated not only spatial (anatomic structures involved) nonspecific top-down effect of loss of inhibition, SEEG data
but also temporal features of electrical seizure organization suggest that these would depend on interaction between corti-
using signal analysis. This could be thought of as not only cal activity and subcortical circuits in a topographically orga-
looking at where the network is, but how it reverberates. nized way.70,83 This means that cortical electrophysiological
Several possible mechanisms have been suggested for signatures are likely to be detectable even for those seizures
seizure patterns beyond the simplest clinical expressions of in which clinical expression is strongly linked to subcortical
unimodal cortex. These are still under investigation, and it components of the specific cortico-subcortical network, as
should be noted that current evidence is stronger for some may be the case, for example, for ictal rocking behaviors91
patterns than others (based on numbers of cases analyzed, use and emotional expression such as defense behaviors90 and
of a control situation, and so on (Table 1)). ictal aggression.95
Additional indirect evidence in favor of specific complex
1. The concept of binding has been proposed previously motor and/or emotional patterns being encoded within pre-
as a putative mechanism for some forms of semiologic dominantly subcortical circuits comes from SEEG stimula-
production,50,84 that is, functional coupling at specific tion studies, in which complex semiology can be triggered
(physiological-range) frequencies between connected with extremely short latency following train stimulation,
structures, leading to a certain clinical output according especially in frontal seizures, with habitual semiology oc-
to the function of the thus-activated anatomical network. curring before the cortical discharge emerges, contrary to
This mechanism has been suggested by SEEG studies the observed time course in the same patients’ spontaneous
of neural correlates of dreamy state,85 ictal humming,86 seizures.96
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6 | M ET H O D OLOGICA L is complex and difficult to work with for various reasons.

CHA L L E NG E S OF IN V E ST IGAT I NG The majority of semiological information in clinical practice
S EM IO LO GY of course comes in narrative form, notoriously prone to inac-
curacies compared to recorded seizures.97 When dealing with
If progress is to be made in investigating neural correlates of recorded seizures, there are various considerations concern-
semiology, it is important to be aware of certain methodo- ing quality of data, including technical conditions, adequate
logical considerations (Table 3). Semiology as a data source ictal examination,98 and ability of individual expert observers
TABLE 3 Methodological challenges of using semiology as a data source in clinical research
Methodological issues Challenges Examples of main issues

Semiological analysis Recording conditions • Insufficient ictal testing (consciousness, language)
• Patient covered by bedsheet or off camera
• Poor lighting; low camera resolution
Observer bias • Seizures with emotional behavior, especially facial expression (may be
more difficult to perceive other signs)
• “Unnatural” patterns of motor semiology may be more difficult to
observe and describe
• Seizure semiology that is difficult to perceive, because of few signs or
because of multiple signs evolving very rapidly
• Well-known signs versus rarely seen signs or patterns of unknown
significance
• Observer's level of experience and expertise
• Inter-observer agreement
Description of semiology • Seizures with a complex and/or idiosyncratic appearance
• Signs of which the significance remains unknown (risk of
under-reporting)
• Ambiguity of some current terms, eg, “automatism” and “hyperkinetic
seizure”
• Nonspecificity of some current categories in terms of localization
• How to quantify semiology? eg, intensity of emotional signs, degree of
alteration of consciousness
Numbers of data • Individual patient: compare seizures with and without a specific sign?
• Small vs large case series
• Should a control group be used?
SEEG data Spatial sampling limitations • Cerebral sampling completely dependent on preimplantation
hypotheses
• Paradigm of the “missing electrode”
• Some regions are technically difficult to explore (eg, vascular
constraints)
• Subcortical structures are relatively little explored
• Level of experience and knowledge influences implantation strategy
Period of analysis of SEEG • Choice of optimal time period?
• Seizure onset, early spread? What duration?
• Should period of analysis depend on signal, on semiology, or both?
• How many seizures to ensure reproducibility of pattern?
Signal analysis • Choice of method?
• Quantification of fast versus slow activity at seizure onset
• Connectivity measures (H2)
• Phase lag coupling
• Coherence
Conceptual issues Neural network versus focal/ • Methodology of investigating mechanisms and anatomic substrates
symptomatogenic zone model will be shaped by conceptual model
Mainly cortical vs cortico- • Concepts of seizure localization and semiologic expression very
subcortical view influenced by level of expertise and experience in individual teams
(inter-center variability)
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to perceive key signs99 or patterns, especially for seizure not yet widely used but may become more available if they
types involving complex motor behavior.100 prove effective. Refining current use of autonomic record-
A main methodological challenge relates to description ing during seizures (eg, electrocardiographic analysis, res-
and interpretation of semiologic signs, and especially choice piration, electrodermal response), possibly including use of
of category. This is important for accurate description and wearable devices,114 could also be informative. Modelization
for meaningful comparison across series. Terms such as “hy- approaches are of interest because they can potentially over-
perkinetic” and “automatism” can be useful in some circum- come the problem of spatial sampling49; such models would
stances, but despite having been formally defined,101 may benefit from being able to incorporate semiologic data, but
prove to be unhelpful or even misleading due to lack of preci- present approaches do not yet include these because of the
sion and consensus as to their meaning. One issue is in con- challenges of sufficiently simplifying and quantifying com-
flating an individual semiologic feature with the description plex behavioral data.
of the overall seizure, for example the term “hyperkinetic sei- Analyzing larger case series seems important for achiev-
zure”: whereas this category is included in the current ILAE ing higher power in demonstrating differences between dif-
classification,12 it does not correspond to any known local- ferent semiologic subtypes and their brain correlates, bearing
ization, etiology, or pathophysiological correlation. Ideally a in mind that most semiologic series in the SEEG literature
useful semiologic category should be helpful clinically, with to date report on around 20–50 subjects, often less. Beyond
good inter-observer and intra-observer reliability and should encouraging more multi- center collaboration, the poten-
refer to a cohesive pattern or group of signs whose occur- tial use of larger scale international databases adapted to a
rence might be linked pathophysiologically. A goal for clini- multi-scale approach115 could be of future interest. For this
cal research approaches and for future classification systems to occur, various practical issues would need to be resolved,
would be to incorporate such semiologic features as knowl- including how to protect patient confidentiality. In addition,
edge progresses. analyzing large amounts of video data is onerous and would
ideally be supplemented by some automated approaches if
this becomes more reliable.
7 | F U TU R E R E S E A RCH
DI R EC T IO N S
8 | EVOLVING CONCEPTS AND
There is much potential for further study of semiology and THERAPEUTIC IM PLICATIONS
its neural correlates. Epilepsy is a privileged model for study-
ing the brain-behavior relation, given ready means of analyz- An important element for making progress in elucidating
ing semiology with concomitant (causal) brain activity using neural correlates of semiology may be evolution of current
video-EEG or SEEG; this is in contrast to nonepileptic sei- concepts. As discussed earlier, the network model of epilepsy
zure disorders102 and psychiatric disorders more generally.103 appears better suited than the focus model to understanding
Electroclinical data can be complemented with other sources relations between electrical seizure organization and clinical
including functional imaging studies in the ictal104,105 and/or expression. Because thinking about epilepsy in terms of net-
interictal period.67 An advantage of using functional imaging work theory represents a paradigm shift, it may be useful to
is its whole-brain approach, which can be used in a comple- reconsider how we use some current language. An example
mentary way with other data, relevant, for example, to better is the term “symptomatogenic zone,” used by many clini-
understanding of the role of the basal ganglia and other sub- cians in a presurgical context, which in fact proves not to be
cortical structures in epilepsy and potentially in semiology compatible with the network model of seizures and semiol-
production.104–106 In fact, “interictal semiology” (eg, psychi- ogy: We can recall that the term was defined by Luders and
atric107,108 and cognitive109 symptoms) could be an interest- collaborators as “the area of cortex that, when activated by
ing line of study, the neural correlates of which may prove to an epileptiform discharge, produces the ictal symptoms.”27
be related to epilepsy organization108 and even ictal semiol- This appears imprecise in light of the data discussed earlier,
ogy.107 Mapping approaches using intracerebral data to study because not only spatial but also temporal features of dis-
cortical correlates of cognition and emotion could also help charge affect clinical expression; and not only cortical but
to advance knowledge of the neural correlates of higher brain also subcortical structures likely shape clinical expression. In
functions.110 addition, for some semiologic features (such as altered con-
For future advances in semiological analysis, harnessing sciousness), the mechanism appears not to be activation but
technological advances in quantifying semiology via video rather dysfunction or inhibition of cortical networks.
analysis seems of interest,111 for example, facial expression112 Semiology can teach us much more about epilepsy, and
and body/limb movements.91,113 These methods require ex- about the brain, than we currently know. Using behavioral
pert supervision and/or specific technical capacities and are data to drive research and improve understanding of the
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10. Gastaut H. Dictionary of epilepsy; 1973.

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On Seizure Semiology

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On Seizure Semiology

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Received: 6 May 2021

| Revised: 23 June 2021

Aileen McGonigal1,2 | Fabrice Bartolomei1,2 | Patrick Chauvel3

1 | IN T RO D U C T IO N and surgical treatments of epilepsy are judged on their abil-

Fabrice Bartolomei and Patrick Chauvel contributed equally to this work.

© 2021 International League Against Epilepsy

Epilepsia. 2021;62:2019–2035. ﻿ wileyonlinelibrary.com/journal/epi | 2019

Henri Gastaut (categorization of semiology and correlations

3 | N E U R A L N E T WO R K S VS seizure types and semiologic patterns have highlighted the

Epilepsy Number of Signal analysis of SEEG during period of

Epilepsy Number of Signal analysis of SEEG during period of

cortex “frontal semiology” to insular seizures with/without frontal

Brain region involved in No. of No. of

Brain region involved in No. of No. of

component analysis of semiological features was performed in twelve patients with

5 | WHAT CAN SEEG TELL US

6 | M ET H O D OLOGICA L is complex and difficult to work with for various reasons.

TABLE 3 Methodological challenges of using semiology as a data source in clinical research

Methodological issues Challenges Examples of main issues

10. Gastaut H. Dictionary of epilepsy; 1973.

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Epilepsia. 2021;62:2019–2035. wileyonlinelibrary.com/journal/epi | 2019