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Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph
Department of Clinical Neurophysiology, Marqus de Valdecilla University Hospital, Santander, Cantabria, Spain
Department of Neurology, Marqus de Valdecilla University Hospital, Santander, Cantabria, Spain
Department of Radiology, Marqus de Valdecilla University Hospital, Santander, Cantabria, Spain
d
Department of Intensive Medicine, Marqus de Valdecilla University Hospital, Santander, Cantabria, Spain
e
Department of Physiology and Pharmacology, University of Cantabria (UNICAN), Santander, Cantabria, Spain
f
Instituto de Formacin e Investigacin Marqus de Valdecilla (IFIMAV), Santander, Spain
b
c
a r t i c l e
i n f o
Article history:
Accepted 23 June 2011
Available online 19 July 2011
Keywords:
Nonconvulsive status epilepticus
Absence status epilepticus
Complex partial status epilepticus
Coma
Electroencephalogram
Prognosis
h i g h l i g h t s
This study supports the utility of differentiating between proper and comatose nonconvulsive status epilepticus (NCSE).
De novo absence status epilepticus (ASE) induced by nonpsychotropic drugs occurs in a well-dened
clinical scenario.
Comatose NCSE occurs mainly in individuals with acute symptomatic cerebral pathology.
a b s t r a c t
Objective: Nonconvulsive status epilepticus (NCSE) represents an important percentage of status epilepticus in adults, but detailed studies of both NCSE proper and comatose NCSE are lacking. We retrospectively analyzed a prospectively collected series of 50 adult patients with a diagnosis of NCSE whose
electroencephalograms (EEGs) have been interpreted for a period of 10 years by the same investigator.
Methods: Two groups, NCSE proper and comatose NCSE were considered. All clinical, EEGs, neuroimaging
data, antiepileptic treatment and outcome were analyzed.
Results: Thirty-two patients (64%) had NCSE proper and 18 patients (36%) comatose NCSE. The mean age
was 56 years (range 1989 years). Fourteen (44%) were diagnosed with absence status epilepticus (ASE),
one had simple partial status epilepticus (SPSE) and 17 (53%) had complex partial status epilepticus
(CPSE). The mean episode duration (33.2 13.9 versus 60.6 34.0), mean number of antiepileptic drugs
(AEDs) (1.46 0.5 versus 2.77 1.39) and neuroimaging anomalies (50% versus 16%) was signicantly
greater in the partial/focal NCSE proper subgroup than in the ASE subgroup. The mean age (56.0 19.9
versus 69.4 12.1), number of elderly individuals (46% versus 77%), mean duration of the episode
(49.1 30.4 versus 153.3 142.6), mortality rate (6% versus 61%) and admission at ICU (18% versus
83%) was signicantly higher in the comatose NCSE group than in the NCSE proper group (p < .05).
Conversely, a previous history of chronic epilepsy was signicantly more frequent (62% versus 5.6%) in
the NCSE proper group. The mean duration of comatose NCSE was signicantly greater in the surviving
subgroup (102.5 29.1 versus 233.1 65.3; p < .05).
Conclusions: Our study demonstrates that there are sufcient differences regarding age of onset, history
of previous epilepsy, episode duration, mortality rate and clinical presentation between NCSE proper and
comatose NCSE to recommend adoption in clinical practice. These results should be taken into account
when developing future classications and therapeutic trials on NCSE.
Signicance: A distinction between NCSE proper (ambulatory forms of NCSE) and comatose NCSE is useful
in the clinical practice and, therefore, it should taken in account in the design of future investigations on
this heterogeneous epileptic condition.
2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.
This investigation was partially presented as poster at the Innsbruck Colloquium on Status Epilepticus, April 2009.
Corresponding author at: Department of Clinical Neurophysiology, Marqus de Valdecilla University Hospital, Avda. Valdecilla, s/n, 39008 Santander, Cantabria, Spain.
Tel.: +34 942 202520x72674; fax: +34 942 315095.
E-mail addresses: jlfernandez@humv.es, ftorrenfc@hotmail.com (J.L. Fernndez-Torre).
1388-2457/$36.00 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2011.06.020
1. Introduction
Nonconvulsive status epilepticus (NCSE) represents one of the
great challenges in neurology (Meierkord and Holtkamp, 2007),
because of its frequently missed diagnosis (Kaplan, 1996; Drislane,
2000), and controversy regarding intensity of, and approaches to
treatment (Walker, 2001). Since the introduction by Treiman
et al. (1984) and Treiman (1993, 1995) of the term subtle generalized convulsive status epilepticus (SGCSE), and the description of
different states of continuous electrographic activity associated
with minimal or absent motor manifestations in severely ill and
comatose patients (Simon and Aminoff, 1986; Celesia et al.,
1988; Krumholz et al., 1988; Treiman et al., 1990; Young et al.,
1990; Lowenstein and Aminoff, 1992; Drislane and Schomer,
1994; Privitera et al., 1994), there has been a push to consider this
patient group as a different type of NCSE (Kaplan, 1999, 2000,
2003; Fujikawa, 2006; Bauer and Trinka, 2010).
The purpose of our study was to describe the electroclinical differences between non-comatose and comatose forms of NCSE in
adults.
2. Patients and methods
2.1. Patients
The Department of Clinical Neurophysiology at Marqus de Valdecilla University Hospital provides adult neurophysiologic service
to 591,886 inhabitants in an urban and rural area of the region of
Cantabria, located in the north of Spain. It is the only neurophysiology department in the area. All patients older than 16 years who
between 2002 and 2008 were diagnosed as having NCSE were included in the study and followed clinically until April 2009. In
addition, six patients (Cases 2, 3, 23, 28, 32 and 44) diagnosed by
the rst author (J.L.F.-T.) during the period 19992002 at Cabuees
Hospital (Gijn, Asturias), a secondary hospital providing adult
neurophysiologic service to 350,000 habitants, were also included.
Eighteen of the patients included in this series have been
previously published in detail individually as case reports
(Fernndez-Torre, 2001; Fernndez-Torre and Daz-Castroverde,
2004; Fernndez-Torre and Martnez-Martnez, 2007; FernndezTorre and Leno, 2008; Fernndez-Torre and Rebollo, 2009;
Fernndez-Torre et al., 2000, 2003a,b, 2004, 2005, 2006a,b,c,
2007a,b, 2009). However, none has been analyzed regarding the
criteria and standpoint of this study. In addition, the full description of all patients may be found in Spanish as a Doctoral Thesis
elsewhere (Fernndez-Torre, 2009).
2.2. Denition and diagnostic criteria
NCSE was dened as a pleomorphic and heterogenous epileptic
condition, lasting more than 30 min, in which continuous or recurrent electrographic seizure activity was responsible for diverse
clinical symptoms including altered mental state, behavioral and
perception abnormalities, vegetative disturbances or reduced level
of consciousness (Drislane, 2000; Kaplan, 2002; Brenner, 2002;
Fernndez-Torre et al., 2003; Meierkord and Holtkamp, 2007;
Maganti et al., 2008; Bauer and Trinka, 2010). All these symptoms
occurred without major convulsive activity.
Differential diagnosis and conrmation of NCSE can be difcult
and depends to a large degree on electroencephalography
(Brenner, 2004). Electroencephalograms (EEGs) were performed
with 21 electrodes placed according to the International 1020
system. Continuous EEG or video-EEG was obtained for at least
30 min including photic, sensory and verbal stimulation in awake
and comatose subjects. All tracings were reviewed by one board-
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246
Table 1
Demographic, clinical characteristics, classication and neuroimaging features of patients with NCSE proper.
Patients
Sex/
age
Clinical presentation
Epilepsy
history
Precipitating factors
NCSE type
Neuroimaging
1 AAB
2 BDG
3 EAR
M/43
F/79
F/74
No
No
Yes
Cefepime
LZP withdrawal
De novo
De novo
Typical
4 FPR
M/76
Yes
Typical
CT normal
5 JGT
6 JTM
F/74
M/29
No
Yes
Cefepime
De novo
Atypical
CT: normal
ND
7 JTR
M/50
Yes
Typical
CT: normal
8 MCR
9 PCG
10 POO
11 RRA
F/39
M/57
F/27
M/33
Mutism/stupor
Confusion/incontinence
Somnolence/slowed
thinking
GTCS/slowed thinking/
stupor
Mutism/myoclonias
Slowed thinking/
myoclonias
Slowed thinking/
desorientation
Slowed thinking/stupor
GTCS/confusion
GTCS/mutism
GTCS/confusion
No
No
Yes
Yes
De novo
De novo
Typical
Typical
MR: normal
MR: white matter lesions
ND
CT: normal
12 RSV
13 USV
F/68
M/73
GTCS/slowed thinking
GTCS/slowed thinking
Yesa
No
Typical
De novo
14 YRG
15 PGR
F/19
M/44
GTCS/confusion/stupor
Posturing
Yes
Yes
Atypical
Frontal SPSE
16 ARL
17 CSV
M/69
F/67
Slowed thinking
Stupor
No
Yes
Parietal CPSE
Temporal CPSE
18
19
20
21
DPC
ESV
FOF
JCM
M/48
M/80
F/43
M/55
Stupor
Stupor
Slowed thinking
Confusion
Yes
Yes
Yes
No
22 JMG
23 LGD
24 LMF
F/53
F/47
M/66
Confusion/mutism
Slowed thinking
Confusion
Yes
Yes
No
25 MCA
26 MHM
M/67
F/89
Confusion, disphasia
Stupor
Yes
No
Cefepime
Alcohol
Levooxacin,
LZP, Morne
PME Lafora type
AED low levels;
sleep deprivation
GTCS
AED low levels;
GTCS
GTCS; infection
PB intoxication
GTCS
Alcohol
withdrawal;
GTCS
GTCS
None
Alcohol
withdrawal;
GTCS
AED low levels
Brain infarct
27 MVL
F/23
Yes
Brain infarct
28 PFM
F/75
Confusion,
metamorphosia
Confusion
Yes
CJD
29 SPP
M/50
Slowed thinking
Yes
30 TBM
31 TRD
32 VMS
M/74
F/20
F/81
Confusion
Slowed thinking
Confusion
No
Yes
No
Occipital CPSE
Occipital CPSE
Temporal CPSE
Frontal CPSE
Frontal CPSE
Temporal CPSE
Temporal CPSE
CT: normalb
MR: left hypocampal sclerosis
MR: hyperintense lesions in corona radiata/right
temporal lobe
Temporal CPSE
Fronto-temporal
CPSE
Parietal CPSE
Indeterminate
CPSE
Parieto-temporal
CPSE
Parietal CPSE
Frontal CPSE
Parietal CPSE
AED: antiepileptic drugs; CJD: CreutzfeldtJakob disease; CPSE: complex partial status epilepticus; CT: computerized tomography; GTCS: generalized tonicclonic seizures;
LZP: lorazepam. MR: magnetic resonance; ND: no done. PME: Progressive Myoclonus Epilepsy; SPSE: simple partial status epilepticus.
a
There was no previous diagnosis of epilepsy but there was history of seizures in infancy.
b
There was a previous history of left frontal hemorrhage.
epileptiform discharges (EDs) on the patients EEG until a followup EEG showed seizure resolution with or without changes in
the level of consciousness. The number of EEGs studies ranged
from one to 34 records.
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3. Results
In all, 50 patients were identied with both clinical and EEG evidence of NCSE. Thirty-two patients (64%) had NCSE proper and 18
patients (36%) comatose NCSE.
3.1. NCSE proper
Thirty-two patients were included in this group. All demographic, clinical characteristics, classication and neuroimaging
features are summarized in Table 1. There were 16 men and 16 women. The mean age was 56 years (range 1989 years). Five of these
patients (Cases 6, 14, 15, 20 and 31) had mental retardation. Five
patients (Cases 14, 16, 20, 22 and 29) were transferred to the ICU
by refractory NCSE. Two patients, one with Progressive Myoclonus
Epilepsy (PME) of Lafora type (Case 14) and other with sporadic
CreutzfeldtJakob disease (sCJD) (Case 28) died during the episode
of NCSE.
In 20 patients (62.5%), there was previous history of epilepsy. The
syndromic classication included: (a) six patients (Cases 3, 4, 7, 10,
11, and 14) with diagnosis of idiopathic generalized epilepsy (IGE);
(b) one (Case 6) with symptomatic generalized epilepsy (SGE); (c)
six (Cases 15, 17, 25, 27, 28 and 31) with probably symptomatic/
cryptogenic partial epilepsy and; (d) six (Cases 18, 19, 20, 22, 23,
and 29) with symptomatic partial epilepsy (SPE). In one patient
(Case 12), ASE occurred as late complication of an unrecognized picture of IGE (Fernndez-Torre and Rebollo, 2009). In the patient with
PME of Lafora disease, there was a previous misdiagnosis of Juvenile
Myoclonic Epilepsy (JME).
In all subjects except for one (Case 15), the clinical presentation
was an alteration in mental status. In 17 (53%), one or several generalized tonicclonic seizures (GTCSs) occurred at the onset of the
episode. Myoclonias were observed at onset or during the picture
of NCSE in three (Cases 5, 6 and 14).
All ictal EEG features, duration of the episode, treatment and
outcome are summarized in Supplementary Table S1. In 12
patients (37.5%), IVBZDs were administrated during the EEG
recording. The mean duration of NCSE was 49.1 h (range 12
20 h). The data from the patient with PME of Lafora type were
excluded for this statistical analysis because of the exceptional
long duration in this case (86 days). Fifteen patients (46.9%) were
elderly (age P 65 years). Recurrence of NCSE occurred in 10 patients (31%).
3.1.1. Absence status epilepticus (ASE)
Fourteen patients were included in this category. All
characteristics of these patients are summarized in Table 1 and
Supplementary Table S1. There were seven men and seven women.
The mean age was 52.9 years (range 1979 years). All patients were
mentally normal except for two (Cases 6 and 14).
All patients except for one (Case 14) with typical or atypical ASE
had a previous diagnosis of epilepsy. No of subjects with situationrelated ASE had history of previous seizures. The mean duration of
ASE was 33.2 h (range 2472 h; SD, 13.9). There was recurrence in
ve patients (Cases 3, 6, 7, 8 and 11).
Neuroimaging was normal in seven patients and revealed diverse
abnormalities in other ve (Cases 1, 9, 12, 13 and 14). In two (Cases 6
and 10) neuroimaging was not performed (Table 1).
Ictal EEG features are summarized in Supplementary Table S1.
An example of characteristic EEG is shown in Fig. 1a. In eight patients (Cases 2, 3, 4, 5, 8, 9, 10 and 14) accounting for 57%, IVBZDs
were administrated during the EEG. In all of them, a signicant
diminution of EDs was observed, and in ve (Cases 4, 8, 9, 10
and 14) there was clinical improvement (Supplementary Table
S1). In one patient (Case 14), generalized EDs were only abolished
Fig. 1. (A) EEG of patient 10 (POO). Note the presence of continuous polyspikewave (PSW) and spike-wave complexes (SW) in keeping with the diagnosis of
typical ASE. LF: 0.53 Hz, HF: 70 Hz; NF: 50 Hz; sensitivity: 150 lV/cm; speed:
15 mm/s; (B) EEG of patient 14 (LRG). Several years before the episode of atypical
ASE a diagnosis of JME has been established. However, she nally developed
Progressive Myoclonus Epilepsy (PME) of Lafora type. Observe as a tactile stimulus
(black arrow) elicited a burst of epileptiform discharges (EDs) in keeping with the
denition of stimulus-induced rhythmic, periodic, ictal discharges (SIRPIDs). LF:
0.53 Hz, HF: 70 Hz; NF: 50 Hz; sensitivity: 100 lV/cm; speed: 30 mm/s.
248
Table 2
Demographic, clinical antecedents, NCSE types and neuroimaging features in comatose NCSE.
Patients
Sex/age
Medical history
Precipitating factors
NCSE type
Neuroimaging
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
F/88
M/65
M/79
M/65
M/70
M/69
M/55
M/75
M/74
M/73
F/73
F/80
M/85
F/75
M/56
F/75
M/54
F/39
Hypertension
Lung tumor
Cardiopathy
Cardiopathy, OH
Hepatopathy, OH
Cardiopathy
Leukemia (CLL)
Aortic aneurysm
Hypertension, cardiopathy
Hypertension, CVD
Hypertension, cardiopathy
CVD, parkinsonism
CVD, leukoariosis
Hypertension, hepatopathy
Lung transplant
Hypertension, epilepsy
OH
None
ACVD
ACVD, GTCS
Anoxia
Anoxia
Subdural hematoma, GTCS
Anoxia
CNS infection
ACVD, PMS
Anoxia
ACVD
Subdural hematoma
GCSE
CNS infection, GTCS
Sepsis, hepatic failure
ACVD, PMS
ACVD
GCSE, alcohol deprivation
CNS infection
FSG
Focal
Generalized
Focal
Focal
Generalized
Generalized
Focal
FSG
Focal
Focal
Generalized
Generalized
Focal
Focal
FSG
Generalized
Generalized
ACG
CGC
EAM
EMP
JFG
JGL
JPJ
JRG
JRU
JSL
JTS
MGC
MGF
MRM
MTJ
PHE
SCR
YIS
ACVD: acute cerebrovascular disease; CNS: central nervous system; CLL: chronic lymphoid leukemia; CT: computerized tomography; CVD: cerebrovascular disease; FSG:
focal secondarily generalized; GCSE: generalized convulsive status epilepticus; GTCS: generalized tonicclonic seizures; ND: no done; NLE: necrotizing leukoencephalopathy;
OH: alcoholism; PMS: partial motor seizures.
a
Necropsy nding.
48, 49 and 50), abolition was only transient. None had signicant
changes in mental status.
The mean duration of NCSE was 153.3 h (range 24480 h; SD,
142.6). Antiepileptic treatment was varied, and patients were treated with an average of 2.7 drugs (range 16; SD, 1.3). The association between etiology and type of comatose NCSE, and number of
AEDs and etiology may be found in Supplementary Fig. S1.
Eleven patients (61%) died and seven (39%) survived to hospital
discharge. Of these seven patients, two had a favorable outcome.
However, ve out seven (Cases 33, 41, 43, 47 and 48) had signicant sequelae. None of the patients in this group had recurrence
on follow-up.
249
250
251