Lattanzi 2021
Lattanzi 2021
Lattanzi 2021
DOI: 10.1111/epi.16999
B R I E F CO M M U N I CAT I O N
Correspondence
Simona Lattanzi, Neurological Clinic, Abstract
Department of Experimental and Clinical The study aimed to identify distinct phenotypes within nonconvulsive status epilep-
Medicine, Marche Polytechnic University,
ticus (NCSE). Consecutive episodes of NCSE in patients at least 14 years old were
Via Conca 71, 60020 Ancona, Italy.
Email: alfierelattanzisimona@gmail.com included. The level of consciousness was assessed through the Glasgow Coma Scale
(GCS). Etiology of NCSE was defined as symptomatic (acute, remote, progressive) or
Funding information
“Dipartimento di eccellenza 2018-2022,”
unknown. Electroencephalographic (EEG) recordings were searched for lateralized
Ministry of Education, University, and periodic discharges (LPDs), generalized sharply and/or triphasic periodic potentials
Research, Italy, to the Department of (GPDs), and spontaneous burst suppression (BS). According to treatment response,
Biomedical, Metabolic, and Neural
Sciences, University of Modena and NCSE was classified as responsive, refractory, or superrefractory. Average linkage
Reggio Emilia hierarchical cluster analysis was performed with Pearson correlation as similarity
measure. Two hundred twenty-nine episodes of NCSE were included. Three clusters
were identified. The first cluster linked GCS score 3–8, presence of spontaneous BS
on EEG, acute symptomatic etiology, and treatment superrefractoriness. The second
cluster gathered GCS score 9–12, presence of LPDs or GPDs on EEG, unknown
etiology, and treatment refractoriness. The third cluster associated GCS score 13–15,
absence of LPDs, GPDs, and spontaneous BS on EEG, and progressive and remote
symptomatic etiology with treatment responsiveness. Phenotyping the heterogene-
ity of NCSE into electroclinical clusters can contribute to understanding correlations
between pathologic and clinical domains, assessing the intrinsic severity of NCSE
episodes, and estimating the likelihood of treatment responsiveness.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited and is not used for commercial purposes.
© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy
KEYWORDS
hierarchical cluster analysis, phenotypes, status epilepticus
The local ethics committee approved the study (556/2018/ Refractory 26 (11.3)
OSS/AOUMO–RF-2016-02361365). Superrefractory 21 (9.2)
Note:: Data are presented as n (%).
Abbreviations: CNS, central nervous system; GCS, Glasgow Coma Scale; GPD,
2.4 | Data Availability generalized sharply and/or triphasic periodic potential; LPD, lateralized periodic
discharge.
F I G U R E 1 Dendrogram based on the hierarchical cluster analysis of clinical data from 229 episodes of nonconvulsive status epilepticus (SE).
The horizontal axis denotes the linkage distance. Distance is calculated and rescaled from 0 to 25 according to the measure of similarity (Pearson
correlation) and the cluster algorithm (average linkage). The dendrogram shows three clusters: (1) Glasgow Coma Scale (GCS) score 3–8, presence
of spontaneous burst suppression (BS) on electroencephalogram (EEG), acute symptomatic etiology, treatment superrefractoriness; (2) GCS
score 9–12, presence of lateralized periodic discharges (LPDs)/generalized sharply and/or triphasic periodic potentials (GPDs) on EEG, unknown
etiology, treatment refractoriness; and (3) GCS score 13–15, no LPDs/GPDs/spontaneous BS on EEG, progressive and remote symptomatic
etiology, treatment responsiveness
EEG, and progressive and remote symptomatic etiology with Introduced in 1974 at the University of Glasgow by Teasdale
treatment responsiveness. and Jennett to classify traumatic brain injury,6 the GCS be-
came one of the most widely used and validated assessment
tools to objectively describe the extent of impaired con-
4 | D IS C U SS ION sciousness in acute medical and trauma patients.
The Axis I (semiology) of the current classification system
Three distinct phenotypes have been recognized within the of SE considers the degree of impaired consciousness as one
NCSE, and differences in the level of consciousness, EEG main criterion and makes a clear-cut dichotomous distinc-
activity, etiology, and responsiveness to treatment distin- tion between NCSE with coma and NCSE without coma.1
guish the clusters. The findings suggest that the degree of Exploratory studies have, however, shown that different de-
consciousness impairment can be accompanied by distinctive grees of consciousness impairment can be related to a different
EEG patterns and underlie different etiologies, which carry a prognosis.13 In a cohort of adult patients with SE, case fatality
differential responsiveness to treatment. was lower among patients presenting fully awake and awake
The degree of impaired consciousness contributed to with reduced cognition than in somnolent, stuporous, or coma-
mark differences across the phenotypes. tose patients.14 In a prospective study aimed at characterizing
Consciousness impairment is a continuous variable, which a critically ill cohort with SE by the illness severity scoring
can be assessed either qualitatively or quantitatively.1 A sys- systems, the GCS was the only component to remain signifi-
tem of classification that is relatively observer-independent cantly different between patients with and without return to
can overcome the limits of subjective assessments of quan- baseline.15 So far, no data exist correlating the responsiveness
titative consciousness (e.g., somnolent, stuporous, comatose, to treatment with the level of consciousness, however assessed.
deeply comatose), which define each level of consciousness The given EEG pattern mirrored the depth of unrespon-
by evaluating observations and responses that are subject to siveness. Spontaneous, non- medically induced BS, which
wide variations in interpretation. The GCS provides a struc- indicates severe brain dysfunction, was linked with the low-
tured method for assessment of the level of consciousness. est GCS scores, and the “benign” EEG pattern lacking BS,
LATTANZI et al.
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LPDs, and GPDs correlated with normal or mildly impaired the representativeness and generalizability of the study results
consciousness. The presence of LPDs or GPDs, which be- to the general NCSE population and different settings.
long to the so-called “ictal–interictal continuum,” where ictal Finally, considering HCA, this is a technique primarily
activity merges with an interictal or “irritative” state,16 clus- aimed at exploring associations rather than proving causality;
tered with a moderate degree of consciousness impairment. it involves arbitrary decisions, and results can be influenced
The prognostic implications of the EEG patterns are likely by chosen distance functions. In this regard, although “model-
to be related to the underlying etiology. The association of based” clustering algorithms can offer the advantage of identi-
acute symptomatic etiology with the worst-case cluster is in fying subgroups based on a probabilistic model and a posteriori
line with evidence that most cases of comatose NCSE are membership rather than dissimilarity measures, it is worth
acute symptomatic with a severe underlying acute brain dis- emphasizing that HCA is easy to understand and implement
order and a very poor response to treatment.13 Conversely, and does not require specific conditional independence mod-
remote and progressive symptomatic causes appeared to be eling assumptions to be met.21,22 Furthermore, the algorithm
less prone to evolve into RSE. Interestingly, the link between of HCA produces a clear graphical depiction of the clusters,
treatment refractoriness and unknown etiology resembled displaying the order by which segments are grouped together.
“cryptogenic” new onset RSE, which is a condition with new Importantly, the hierarchical tree or dendrogram allows appre-
onset of RSE without a clear acute or active structural, toxic, ciation of the relative distance, degree of similarity, and mutual
or metabolic cause in a patient without active epilepsy.17 relationships between the variables and thus provides useful
So far, most of the research in the field of SE has focused cues and insights to interpret and understand the pathophysio-
on the prediction of functional outcome, and the available logical mechanisms and clinical reasons that may underlie and
clinical scoring systems have been developed to prognosti- explain the clustering.3,23,24 Moreover, we considered widely
cate survival versus death and functional postdischarge out- shared electroclinical variables that are easily reproducible and
come. All these scores have poor accuracy in the prediction testable in subsequent validation studies.
of treatment refractoriness,18 and none integrates data on ei- Phenotyping the heterogeneity of NCSE into distinctive
ther consciousness level, EEG activity, or etiology. electroclinical clusters can contribute to identifying and un-
Although preliminary, the findings of this analysis build up derstanding correlations between pathologic and clinical do-
the actual classification system of SE. They pave the way for mains, assessing the intrinsic severity of SE episodes, and
thinking of SE within the framework of a multidimensional estimating the likelihood of response to pharmacological
systematization that subsumes and integrates at once clinical, intervention. The continuous exploration and advancements
EEG, and etiological axes, and suggest that a more nuanced in the characterization of NCSE may offer useful advice to
categorization of the degree of consciousness impairment in inform clinical practice.
patients with NCSE can contribute to providing prognostic Prospective studies are warranted to externally validate the
insights and be informative of the likelihood of treatment re- reliability and predictive accuracy of the identified clusters and
sponsiveness. Of note, the advantages of the GCS include its provide useful complement with data on additional variables.
simplicity, short administration time, reliability, validity, stabil-
ity, cost-free availability, and ease of access.19 Different lim- ACKNOWLEDGMENTS
its of the study also need to be acknowledged, including the This study received funding from the Italian Ministry of
recruitment at a single tertiary care center and the collection Health (“Status epilepticus: improving therapeutic and qual-
of a limited set of variables in a real-world setting, which may ity of care intervention in the Emilia- Romagna region,”
have resulted in potential sources of biases. Of note, the lack project code RF-2016-02361365) and was supported by the
of data about the prehospital administration of benzodiazepines grant “Dipartimento di eccellenza 2018-2022,” Ministry of
did not allow evaluating the potential confounding effect on Education, University, and Research, Italy, to the Department
the level of consciousness as measured by the GCS at presen- of Biomedical, Metabolic, and Neural Sciences, University
tation. Although misdiagnosis can occur and cases may have of Modena and Reggio Emilia.
been inappropriately categorized as acute symptomatic, this
risk is minimized by the adoption of a definition of acute etiol- CONFLICT OF INTEREST
ogy that distinguishes the time interval between the insult and S.L. has received speaker's or consultancy fees from Eisai, GW
SE occurrence according to the underlying clinical conditions. Pharmaceuticals, and UCB Pharma and has served on advisory
The average age of the included population was quite old, and boards for Angelini Pharma, Arvelle Therapeutics, BIAL, and
most episodes of NCSE occurred in females. Although these GW Pharmaceuticals. F.B. has acted as a consultant for Eisai.
demographic characteristics substantially confirmed the overall E.T. has received speaker's honoraria from UCB, Biogen,
distribution of SE incidence, with the highest estimates after Gerot-
Lannach, BIAL, Eisai, Takeda, Newbridge, Sunovion
60 years of age and the prevalence of female sex in cases of Pharmaceuticals, LivaNova, and Novartis; consultancy funds
NCSE,14,20 the recruitment at a single tertiary center may limit from UCB, Biogen, Gerot- Lannach, BIAL, Eisai, Takeda,
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