RESEARCH—HUMAN—CLINICAL STUDIES

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Nonepileptic, Stereotypical, and Intermittent
Mathieu Levesque, MD‡∗ Symptoms (NESIS) in Patients With Subdural
Christian Iorio-Morin, MD,
§∗
Hematoma: Proposal for a New Clinical Entity With
PhD, FRCSC
Christian Bocti, MD, FRCPC‡
Therapeutic and Prognostic Implications
Caroline Vézina, MD¶
Charles Deacon, MD, FRCPC‡ BACKGROUND: Transient neurological symptoms (TNS) are frequent in patients with
subdural hematomas (SDH) and many will receive a diagnosis of epilepsy despite a
‡
Division of Neurology, Department of negative workup.
Medicine, Université de Sherbrooke,
OBJECTIVE: To explore if patients with TNS and a negative epilepsy workup (cases)
Centre de Recherche du Centre Hospi-
talier Universitaire de Sherbrooke, Sher- evolved differently than those with a positive EEG (controls), which would suggest the
brooke, Canada; § Division of Neurosur- existence of alternative etiologies for TNS.
gery, Department of Surgery, Université
METHODS: We performed a single-center, retrospective, case-control study of patients
de Sherbrooke, Centre de Recherche
du Centre Hospitalier Universitaire de with TNS post-SDH. The demographics and clinical and semiological features of cases
Sherbrooke, Sherbrooke, Canada; ¶ Divi- and controls were compared. The outcome and response to antiepileptic drugs were also
sion of Family Medicine, Department of
assessed and a scoring system developed to predict negative EEG.
Family Medicine, Université de Sherb-
rooke, Centre de Recherche du Centre RESULTS: Fifty-nine patients with SDH-associated TNS were included (39 cases and
Hospitalier Universitaire de Sherbrooke, 20 controls). Demographic characteristics were comparable in both groups. Dysphasia
Sherbrooke, Canada
and prolonged episodes were associated with a negative EEG. Clonic movements,
∗
These authors contributed equally to
impaired awareness, positive symptomatology, complete response to antiepileptic drugs,
this work. and mortality were associated with a positive EEG. Using semiological variables, we created
a scoring system with a 96.6% sensitivity and 100% specificity in predicting case group
This work has been previously presented
patients. The differences observed between both groups support the existence of an alter-
as a poster presentation at the Mayo
Neurocritical Care Conference in Orlando, native etiology to seizures in our case group. We propose the term NESIS (NonEpileptic,
Florida, on May 10 to 12, 2018; as a poster Stereotypical, and Intermittent Symptoms) to refer to this subgroup and hypothesize that
presentation at the Canadian
TNS in these patients might result from cortical spreading depolarization.
Neurological Sciences Federation 2018
Annual Meeting in Halifax, Canada, on CONCLUSION: We describe NESIS as a syndrome experienced by SDH patients with
June 24 to 27, 2018; as a podium specific prognostic and therapeutic implications. Independent validation of this new entity
presentation at the Québec Neurology
is now required.
Association Conference in La Malbaie,
Canada, on September 15, 2018; and as a KEY WORDS: Transient neurological symptoms, Subdural hematoma, Epilepsy, Clinical score, Nonepileptic
podium presentation at the Congress of stereotypical, Intermittent symptoms
Neurological Surgeons Annual Meeting
in Houston, Texas, on October 9, 2018.
Neurosurgery 0:1–8, 2019 DOI:10.1093/neuros/nyz355 www.neurosurgery-online.com

Correspondence:
Mathieu Levesque, MD
poor.3 In clinical practice, transient neurological

S
Division of Neurology ubdural hematoma (SDH) is a common
Department of Medicine condition in medical practice with a symptoms (TNS), in the context of SDH,
Université de Sherbrooke, reported incidence of 14.1 to 20.6/ are frequently encountered by neurologists and
Centre de Recherche du Centre
Hospitalier Universitaire de Sherbrooke,
100 000 patient years.1,2 Despite its significant neurosurgeons. Most of these patients are given a
3001 12e Avenue Nord, prevalence, literature regarding SDH remains presumptive diagnosis of focal provoked seizures
Sherbrooke, Canada J1H 5N4.
Email:
Mathieu.Levesque2@USherbrooke.ca

Received, March 22, 2019.
Accepted, June 27, 2019.
Copyright 
C 2019 by the
Congress of Neurological Surgeons
ABBREVIATIONS: AED, antiepileptic drugs; CI, confidence interval; CSD, cortical spreading depression; CT,
computed tomography; ECoG, electrocorticography; EEG, electroencephalogram; GCS, Glasgow coma scale; MRI,
magnetic resonance imaging; NESIS, Nonepileptic, Stereotypical, and Intermittent Symptoms; OR, odds ratio;
ROC, receiver operating characteristic; SAH, subarachnoid hemorrhage; SDH, subdural hematomas; TBI, traumatic
brain injury; TNS, transient neurological symptoms

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LEVESQUE ET AL

or lesional epilepsy, despite a negative workup. Literature reports

an incidence of epilepsy post SDH evacuation that can reach TABLE 1. Demographics and Clinical Characteristics of Patients

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25%.4
Controls Cases
Interestingly, clinical experience suggests that a significant (n = 20) (n = 39) P
proportion of these patients do not present or evolve as one would
expect with epilepsy. Response to antiepileptic drugs (AED) Median age at SDH diagnosis 68.5 (18-84) 75 (20-92) .39
appears under the expected 70% reported in literature and the Sex .28
rate of negative electroencephalogram (EEG) appears way higher Female 9 (45%) 12 (31%)
Male 11 (55%) 27 (69%)
than would be expected in literature (50%).5 These observa-
Smoking 3/10 (30%) 16/34 (47%) .47
tions suggest the presence of an alternative etiology to epilepsy Comorbidities
to explain such TNS in a subgroup of the SDH population. Hypertension 12 (60%) 25 (64%) .76
Diabetes 7 (35%) 7 (18%) .15
Objectives Atrial fibrillation 2 (10%) 7 (18%) .70
Coronary artery disease 5 (25%) 13 (33%) .51
The goal of this study was to verify if, among the population Peripheral artery disease 0 (0%) 6 (15%) .09
of patients with TNS post SDH, a homogeneous subgroup of Past stroke 4 (20%) 6 (15%) .72
patients unlikely to suffer from epilepsy could be distinguished Previous SDH 2 (10%) 2 (5%) .60
from patients with proven epilepsy. This would support the Prior diagnosis of epilepsy 1/19 (10%) 1 (3%) .99
existence of an alternative pathophysiological entity to which Medication at SDH diagnosis
Antiplatelet 2/18 (11%) 17/38 (45%) .03
diagnostic and therapeutic approaches could be better tailored.
Anticoagulant 4/18 (22%) 9/38 (45%) .99
Our second objective was to create a scoring system that could Antiepileptic 3/19 (16%) 1/39 (3%) .05
be prospectively used in a trial setting to screen and identify these Type of SDH .10
patients unlikely to suffer from epilepsy. Acute 13/20 (65%) 16/38 (42%)
Membrane-associated (chronic) 7/20 (35%) 22/38 (58%)
Concomitant SAH 6 (30%) 8 (21%) .42
METHODS SDH location .75
Right 6 (30%) 12 (31%)
Research Ethics Board Approval Left 9 (45%) 14 (36%)
This study was approved by our Research Ethics Board (Comité Bilateral 5 (25%) 13 (33%)
d’éthique de la recherche du CIUSSS de l’Estrie-CHUS, FWA #00005894 Median SDH maximal thickness (mm) 15.5 (4-30) 16.5 (8-38) .16
and IRB00003849 under protocol #RSS-2016-703). This study did not Median midline shift (mm) 7.5 (0-23) 7 (0-21) .49
require patient consent. Median GCS 12 (4-15) 14 (3-15) .01

Study Design, Setting, and Participants
We performed a retrospective, case-control study of patients operated
for SDH at the Centre Hospitalier Universitaire de Sherbrooke between
1996 and 2017, who underwent at least one routine EEG for TNS during
the course of their hospital stay. Patients with negative EEGs (including
normal EEG, nonspecific slowing or other nonspecific findings) were
assigned to our case group whereas patients whose EEGs showed signs
of ictal or interictal abnormalities formed our control group. We used
the EEG reports to classify the patients, as the raw EEG data were not
available for all patients.
Clinical Data
Baseline patient data recorded at the time of SDH evacuation were
collected (Table 1), including: age, sex, magnesium blood level, hyper-
tension, diabetes, past stroke, coronary artery disease, peripheral artery
disease, epilepsy, past SDH, atrial fibrillation, smoking, antiplatelets
usage, anticoagulant usage, AED usage, localization of the SDH
(left, right or bilateral), type of SDH (acute or chronic, membrane-
associated6 ), Glasgow coma scale (GCS), concomitant subarachnoid
hemorrhage (SAH), SDH maximal thickness (in millimeters), midline
shift (in millimeters), and radiological deterioration on computed
tomography (CT) or magnetic resonance imaging (MRI).
Clinical characteristics were analyzed in relation to the symptoma-
tology of the TNS (Table 2) including the semiology (positive or negative
symptoms, the type of symptoms [speech, motor, sensory, and visual]),
Bold type represents variables for which a statistically significant difference was found.
the presence or absence of clonic movements, the presence or absence
of migrating characteristics to the symptomatology, impaired awareness,
symptom duration (dichotomized as more or less than 5 min), the
number of episodes (mean, median, dichotomized as more or less than
5), the stereotypy (wherein complete stereotypy represented an identical
semiology at each episode), the response to lamotrigine, topiramate,
and all other AED, the mortality at discharge, unfavorable orientation
at discharge (death or discharge to locations other than home), TNS
improvement at last follow-up, the duration of the hospital stay and the
final diagnosis posed by the treating team and consultants (mass effect,
epilepsy, cortical spreading depression [CSD], ischemic, or other).
Statistical Methods
Prior to the analysis, range checks were performed on all variables and
errors in data entry were corrected. Descriptive statistics of continuous
variables are presented using the distribution’s median with range,
whereas those of categorical variables are presented using frequency tables
with total number of events and valid percentages.
Variables were compared between cases and controls in a univariate
analysis using Fisher’s exact test, Chi-square, and the Mann-Whitney
U test as appropriate. A binomial logistic regression was performed to
calculate the odds ratio (OR) with 95% CI for each of the variables shown
in Table 2.

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 NESIS IN SUBDURAL HEMATOMA: A NEW CLINICAL ENTITY

TABLE 2. Semiology and Outcome of the Transient Neurological Symptoms

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Univariate analysis

Variable Controls (n = 20) Cases (n = 39) OR (95% CI) P

Semiology
Symptoms
Positive symptoms 16/19 (84%) 8/37 (22%) 0.052 (0.012-0.223) <.001
Speech symptoms 4/17 (24%) 22/37 (60%) 4.767 (1.301-17.467) .02
Motor symptoms 16/17 (94%) 22/38 (58%) 0.086 (0.010-0.716) .02
Sensory symptoms 0/17 (0%) 10/37 (27%) NA .02
Visual symptoms 0/17 (0%) 3/38 (8%) NA .54
Clonic movement 13/16 (81%) 2/35 (6%) 0.014 (0.002-0.094) <.001
Impaired awareness 13/14 (93%) 5/34 (15%) 0.013 (0.001-0.125) <.001
Duration of symptoms ≥5 min 3/11 (27%) 26/29 (90%) 23.11 (3.875-137.836) .001
≥5 episodes 2/11 (18%) 13/29 (45%) 3.656 (0.669-19.974) .14
Symptom migration 1/15 (7%) 4/18 (22%) 4.0 (0.396-40.424) .24
Complete stereotypy 4/11 (36%) 15/30 (50%) 1.750 (0.422-7.253) .44
Diagnosis
Diagnosis recorded in chart NA .11
Epilepsy 16/20 (80%) 15/39 (39%)
Mass effect 1/20 (5%) 8/39 (21%)
Ischemia 0/20 (0%) 7/39 (18%)
CSD 0/16 (0%) 4/39 (10%)
Other 3/20 (15%) 5/39 (13%)
CT deterioration 7/19 (37%) 3/37 (8%) 0.151 (0.034-0.681) .01
MRI deterioration 7/10 (70%) 5/13 (39%) 0.268 (0.046-1.548) .14
Magnesium >0.75 3/19 (16%) 10/34 (29%) 2.222 (0.528-9.351) .28
Outcome
Complete response to topiramate or lamotrigine 0/1 (0%) 2/3 (66%) NA .50
Complete response to another AED 12/18 (67%) 2/19 (11%) 0.063 (0.008-0.462) .007
Duration of hospital stay (days) 16.5 (7-45) 17 (3-77) 0.982 (0.958-1.007) .16
Hospitalization ≥15j 10/18 (56%) 22/38 (58%) 1.100 (0.355-3.408) .87
Unfavorable orientation at discharge 8/17 (47%) 2/35 (6%) 0.068 (0.012-0.379) .002
TNS improvement at last follow-up 10/15 (67%) 29/34 (85%) 4.833 (0.974-23.98) .05
Mortality at discharge 8/19 (42%) 1/38 (3%) 0.021 (0.002-0.270) .003

Bold type represents variables for which a statistically significant difference was found.

Statistical significance was defined at P < .05. Statistical analyses were
performed using IBM SPSS Statistics, version 25 (IBM, Armonk, New
York) and figures rendered using SPSS Statistics, Prism 7.0d (GraphPad
Software Inc, La Jolla, California) and Adobe Illustrator CS6 (Adobe
Systems Inc, San Jose, California).
Diagnostic Criteria Generation
Proposed diagnostic criteria were elaborated by the authors using
statistical significance and OR obtained in the logistic regression to
predict EEG result, as well as clinical features deemed important to
exclude other diagnoses. We created a score with a pre-established
weighting scale in which 1 point was attributed to a nonstatistically
significant tendency with scientific plausibility, 2 points for statistically
significant results with an OR of 1 to 2, 3 points and OR of 3 to 10, and 4
points for an OR >10. Additional criteria were then added or removed by
consensus. The score was tested inside the cohort and a receiver operating
characteristic (ROC) curve analysis performed to determine the optimal
threshold, with a set goal of limiting limit false positive results, as we
believed false positives to be more detrimental than false negatives in our
studied population.
RESULTS
Cohort Demographics and SDH Presentation
Of the 1557 patients admitted for SDH, 572 underwent SDH
evacuation, of which 111 underwent an EEG, which we used as a
surrogate for TNS in the screening process. After chart review, 52
were excluded, leaving 39 case patients with negative EEG, and
20 control patients with positive EEG for a total of 59 true TNS
patients (Figure 1).
The cohort demographics are presented in Table 1. Briefly, the
median age at the time of SDH diagnosis was of 68.5 (range:
18-84) in our control group compared to 75 (range: 20-92) in
our case group. SDH were acute in 29/58 (50%). The median
SDH thickness was 15.5 mm (range: 4-30) in our control group
compared to 16.5 mm (range: 8-38) in our case group. At the
time of diagnosis, antiplatelet and anticoagulant medications were
used by 19/56 (34%) and 13/56 (23%) patients, respectively,
and 4/58 (7%) patients were on antiepileptic medication. Most
demographic characteristics were similar in both groups with

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LEVESQUE ET AL
Patients with SDH
n = 1 557
Patients operated for SDH
n = 572
Patients with EEG
n = 111
Patients used in analysis
n = 59
Cases (negative EEG) Controls (positive EEG)
n = 39
FIGURE 1. Flow diagram of cohort generation.
statistical difference noted only in antiplatelet usage (45% vs
11%) and GCS upon arrival (median of 12 vs 14), both higher in
our case group.
TNS Semiology
The semiology, evolution and prognostic of the TNS are
reported in Table 2. Our results showed clear discrepancies
between the cases (patients with negative EEG) and the controls
(patients with positive EEG), with many variables reaching statis-
tical significance. Prolonged symptom duration ≥5 min (OR
23.11, P = .001), and dysphasia (OR 4.767, P = .02) favored the
case group. On the other hand, patients with negative EEGs were
less likely to have positive symptomatology (OR 0.052, P < .001),
motor symptoms (OR 0.086, P = .02), clonic movements (OR
0.014, P < .001), and impaired awareness (OR 0.013, P < .001)
than our control group. There was a nonsignificant trend towards
more frequent episodes (OR 3.656, P = .14) and symptom
migration (OR 4, P = .24) in our case group.
TNS Etiology and Management
There was a nonsignificant trend towards different explana-
tions by the treating teams for the TNS between both groups.
TNS in the case group were attributed to epilepsy (38%),
ischemia (18%), mass effect (21%), CSD (10%), and other
reasons (13%) compared to the 80% rate of epilepsy diagnosis in
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Excluded from study (Total = 52)
- No TNS n = 16
- No recurrence of TNS post-op n=6
- New stroke explaining symptoms n = 12
- No SDH evacuation n=5
- SDH recurrence explaining symptoms n=4
- Too many missing data n=8
n = 20
the control group (Table 2). Interestingly, patients with negative
EEG had a lower rate of CT deterioration (OR 0.151, P = .01).
Most negative EEGs showed nonspecific focal (39%) or gener-
alized slowing (44%). A total of 94% of patients in the control
group were treated by standard AED compared to 59% in our
case group, in which topiramate or lamotrigine were more likely
to be used. Most physicians chose phenytoin as the first-line and
levetiracetam as second-line agent. At follow-up, 73% of our
control group were still on AED compared to 50% in our case
group. Case patients showed a lower rate of complete response
to AED (OR 0.063, P = .007), yet also had a lower rate of
unfavorable outcome at discharge (OR 0.068, P = .002) and
mortality at discharge (OR 0.021, P = .003).
Diagnostic Criteria Development and Validation
Using the observed differences between the cases and controls
presented in Table 2, we developed a set of criteria to allow
prospective identification of patients in the cases group. We
attributed a weighted point value according to the importance
of the OR and scientific plausibility (see Methods and Figure 2).
Stereotypy was maintained in the definition as it was deemed
important to differentiate TNS (whether epileptic or not) from
other nonSDH-related processes, such as transient ischemic
attacks. The response to AED was removed from the score to
allow classification before a trial of medication. Finally, the score
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FIGURE 2. OR with 95% CI of semiological factors selected for the NESIS scoring system.

A ROC curve analysis was then performed to identify the optimal

TABLE 3. Proposed Scoring System for the Diagnosis of NESIS threshold for diagnosis (Figure 3). The area under the curve
NESIS Point value
was 0.998 (95% CI, 0.993-1.0) suggesting an excellent discrimi-
nation.11 Using a threshold ≥4, cases could be identified within
Features supporting NESIS the development cohort with a sensitivity of 96.6% and a speci-
Negative symptoms +4 ficity of 100%.
Duration ≥5 min +3
Dysphasia +3
Migration +1 DISCUSSION
≥5 episodes +1
Stereotypy +1 Proposing Nonepileptic, Stereotypical, and Intermittent
Features against NESIS
Symptoms (NESIS) as a New Entity in SDH
Impaired awareness −4
Clonic movements −4 Most patients presenting with TNS in the context of SDH
NESIS diagnosis if total score ≥4 and no positive EEG receive a diagnosis of epilepsy and are treated as such, despite
negative investigations and an evolution oftentimes atypical for
an ictal phenomenon. Using a case-control design, we demon-
attributed to symptoms’ duration was lowered from +4 to +3 strated that patients with documented SDH-associated TNS and
because this variable was missing in 9/20 controls, widening negative EEGs have a semiology, response to AED, and prognosis
the OR’s 95% CI to 3.875 to 137.836. This yielded an 8- that is significantly distinct from patients with confirmed epilepsy
item instrument generating scores between −4 and 13 (Table or acute symptomatic seizures. This suggests that they constitute
3 and Figure 2). The score was then calculated for each patient a unique subgroup of patients, which should be defined, studied,
with exclusion of patients having 3 or more missing data (final and approached distinctly. We propose the term NESIS to refer
n = 45). Median score in the cases group was 8 (range: 3- to this specific population. Diagnostic criteria for NESIS are
12) compared to −2.5 (range: −8 to 3) in the control group. suggested in Table 3. These criteria are based on the semiology of

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LEVESQUE ET AL
1.0
Threshold: ≥ 3
Threshold: ≥ 4
0.8
Sensitivity
0.6
0.4
0.2
0.0
0.0 0.2 0.4 0.6 0.8 1.0
1 - Specificity
FIGURE 3. Receiver operating characteristic curve of the NESIS score. Using
a threshold of ≥4, 38/39 NESIS cases are identified, yielding a sensitivity of
96.6% and a specificity of 100%. Lowering the threshold to ≥3 identifies the
missing NESIS case as well as a control case, generating a sensitivity of 100%
with a specificity of 90%.
the TNS and can be used to predict the presence of NESIS and,
thereby, the probability that subsequent EEG performed will be
negative. In a clinical setting, until our criteria are independently
validated, we suggest that a diagnosis of NESIS be supported by
at least 1 negative and no positive EEG to further reject epilepsy.
Potential Etiologies for NESIS
The existence of this homogeneous NESIS subgroup suggests
the existence of an alternative etiology to epilepsy in that subgroup
of patients to explain their symptomatology. In the presence of
TNS, one must consider a limited differential diagnosis including
epilepsy, transient ischemia, and cortical spreading depolarization
(CSD).
CSD is a depolarization wave spreading at a slow velocity
(2-6 mm/min) in the cerebral gray matter. It is followed by
an electrical silence, typically lasting 5 to 20 min, followed by
complete resolution.7 In the intact brain, the depolarization phase
is followed by a repolarization phase resting on the coupling
between energy supply and demand. This normal response can be
lost in the injured brain, wherein the metabolic demand of CSD
cannot be matched by the energy supply pathologically leading
to relative ischemia.8,9 This relative ischemia explains oftentimes
more negative than positive symptoms and the longer duration
of symptoms observed in perilesional CSD.10-12 CSD are most
reliably diagnosed using electrocorticography (ECoG), although
this is not usually performed in the setting of SDH. EEG has been
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shown to have a sensitivity of 70.2% for ECoG-demonstrated
episodes and usually show nonspecific slowing of the electro-
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cerebral activity without spreading.13
CSDs have been documented to occur at high frequency in
various neurological entities including in 75% to 80% of SAH,
90% to 100% of “malign” ischemic strokes and 50% to 60% of
traumatic brain injury (TBI).14 A recent prospective observation
study using ECoG in patients with TBI requiring neurosurgery
showed the presence of CSD had a negative prognostic impact
when it was perilesional (OR 7.58:2.64-21.08), contributing
to the expansion of the penumbra of injured but potentially
salvageable neurons.15
Literature regarding CSD in relation to SDH is lacking and
most papers describing SDH-associated TNS fail to elaborate an
etiological or pathophysiological hypothesis. The earliest report
dates from 1983 and describes 15 cases of TIA-like episodes in
patients with SDH.16 Aphasia was present in 9/15. Another series
of 32 cases published in 1992 similarly noted that that most
patients presented with aphasia and that 0/7 had positive EEG.17
The best documented case was published in 201718 and involves
a patient who experienced, 1 wk after SDH evacuation, transient
left hemiplegia and confusion lasting a few hours. EEG showed no
epileptiform activity, and the patient was started on levetiracetam.
The next day, another episode occurred during quantitative EEG
(qEEG) monitoring. Right hemispheric slowing was observed,
and the alpha/delta ratio was decreased. Transcranial Doppler
(TCD) showed an increased pulsatility index, suggesting high
vascular resistance. The authors attributed the symptoms to
ischemia from microvascular collapse and treated the patient by
stopping her antihypertensive medication and tolerating systolic
blood pressure of 140 mmHg. Although not discussed by the
authors, these paraclinical findings are reminiscent of what is
typically seen in SAH-associated vasospasm, a phenomenon
thought to be in part driven by CSD.19
We believe CSD could explain the TNS in a significant
proportion of our NESIS group. The prolonged, stereotyped, and
repeated semiology observed in NESIS is coherent with CSD,
as is the negative paraclinical investigations, including the 13/13
patients who had MRIs in our series. We do believe that other
supportive elements, such as the migrating characteristics to the
TNS, could have shown statistical significance had the study
been done prospectively, thereby limiting the missing data, as
this variable was rarely sought for or documented. We must also
consider that the relatively low sensitivity of the EEG, which was
used to dichotomize our groups may have misclassified patients
with epileptic etiology. Review of the charts of patients in our
NESIS group scoring under 4, however, showed that their clinical
picture was very suggestive of epilepsy as opposed to the higher
scoring patients which showed a clinic more suggestive of NESIS.
Therapeutic Implications of NESIS
We believe that prospective identification of patients with
NESIS is important because, although they tend to be
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refractory to AED, their prognosis appears better than patients
with confirmed epilepsy. Although the pathogenesis of NESIS
remains to be demonstrated, our hypothesis that NESIS is the
clinical manifestation of CSD has significant pathophysiological,
diagnostic, therapeutic, and prognostic implications.
It would entail that if a medication is to be successful in
the NESIS population, it should have a demonstrated effec-
tiveness against CSD. Animal studies in mice suggest an accel-
erated resolution of CSD with arginine, magnesium,20 lamot-
rigine,21 NMDA inhibitors,22 and topiramate.20,23,24 CSD in
human models have shown potential response to lamotrigine25
and topiramate,26 amongst the most studied targeted therapeutic
options. A recent prospective trial proved that ketamine could
effectively inhibit CSD following brain injury.27 Consequently,
for patients in whom epilepsy is still considered a possibility,
topiramate could be an interesting first-line option, as it would
address both seizures and CSD, can be introduced relatively
quickly, and appears to have a very incisive effect on CSD. For
patients in whom epilepsy is unlikely, propranolol could be tried,
because although the literature is less robust, it has a better
side-effect profile than other medications. Conventional AED
(excluding medications acting on the pathophysiology of CSD
such as topiramate and lamotrigine) should not be used in the
NESIS population given the 11% response rate observed in our
study (vs 67% in the control group).
Strengths and Limitations
Our study is limited by its retrospective design. Missing
data were high for some specific variables, which might have
biased analyses, including stereotypy and symptom duration.
In addition, our case and control groups were defined using
EEG, which, although highly specific, lacks sensitivity.5,28-31 This
might have led to the misclassification of epileptic patients in the
NESIS group. However, this contamination should have lowered
our statistical power because NESIS patients are by definition
excluded from the control group. Furthermore, the presence of
epilepsy does not necessarily exclude the concomitant presence of
CSD and vice versa.32 As the presence of CSD in the NESIS group
was not tested, this phenomenon is presented as a hypothesis only
and will require further study.
The proposed diagnostic system will need to be validated in
an independent cohort. Intentionally, the score was not purely
based on the logistic regressions, as we felt it was important to
keep clinical criteria distinguishing NESIS from not only epilepsy,
but also other etiologies including transient ischemic attacks
(stereotypy, migration) and mass effect (migration, number of
episodes). As further data are collected, some criteria might
eventually be removed if they are found to provide no added value.
To the best of our knowledge, this is the largest study formally
suggesting the existence of an alternative etiology to epilepsy for
TNS in SDH. We are the first to define the NESIS subgroup
and to propose diagnostic criteria allowing prospective identifi-
cation of NESIS for research purposes. The distinction between
epileptic and nonepileptic patients with SDH is critical and has
NEUROSURGERY
NESIS IN SUBDURAL HEMATOMA: A NEW CLINICAL ENTITY
already led to a change in practice at our center, where all 4
diagnoses of CSD were made after the start of our study and none
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in the previous 10 years. The incidence of NESIS is currently
being analyzed retrospectively in the Tranexamic Acid in Chronic
Subdural Hematoma cohort33 and will be prospectively assessed
in the upcoming GENESIS study.3
CONCLUSION
Among patients with TNS associated with SDH, a subpop-
ulation exists in which the symptoms are unlikely to be of an
epileptic nature. We suggest that a novel entity named NESIS be
used to refer to these patients. We developed diagnostic criteria,
which show promise in screening such patients. Replication of our
results in a distinct population will be needed to prove the validity
of our proposed diagnostic criteria. We hypothesize that NESIS
is the clinical manifestation of CSD, which could have significant
diagnostic, therapeutic, and prognostic implications. We hope
that identifying NESIS in SDH patients help improve the under-
standing and care of this diverse and complex population.
Disclosures
The authors have no personal, financial, or institutional interest in any of the
drugs, materials, or devices described in this article.
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Acknowledgments
The authors thank statistician Marie-Pier Garant for her assistance.
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