doi:10.1093/brain/awp027
Brain 2009: 132; 2102–2113
| 2102
BRAIN
A JOURNAL OF NEUROLOGY
Clinical use of ictal SPECT in secondarily
generalized tonic–clonic seizures
G. I. Varghese,1 M. J. Purcaro,1 J. E. Motelow,1 M. Enev,1 K. A. McNally,1 A. R. Levin,1
L. J. Hirsch,2 R. Tikofsky,3 A. L. Paige,4 I. G. Zubal,5 S. S. Spencer1,6 and H. Blumenfeld1,6,7
1
2
3
4
5
6
7
Department
Department
Department
Department
Department
Department
Department
of
of
of
of
of
of
of
Neurology, Yale University School of Medicine, New Haven, Connecticut, USA
Neurology, Columbia University College of Physicians & Surgeons, New York, USA
Nuclear Medicine, Columbia University College of Physicians & Surgeons, New York, USA
Neurology, University of Alabama School of Medicine, Birmingham, Alabama, USA
Nuclear Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA
Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA
Correspondence to: Hal Blumenfeld,
Yale Departments of Neurology, Neurobiology,
Neurosurgery 333 Cedar Street,
New Haven,
CT 06520-8018,
USA
E-mail: [email protected]
Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow
increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for
seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since
propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been
thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic–clonic seizures obtained during epilepsy
surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://
spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT
showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization.
This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in
secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left
versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase
was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures
without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during
or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion
during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of
patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures
can help localize the region of seizure onset.
Keywords: epilepsy; cerebral blood flow; grand mal; surgery; nuclear medicine
Received August 28, 2008. Revised and Accepted January 26, 2009 . Advance Access publication April 1, 2009
ß The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
Localization of ictal SPECT in tonic–clonic seizures
Introduction
Patients with medically refractory epilepsy face many challenges.
In selected cases, surgical treatment can offer the hope for permanent control of seizures. However, surgical treatment of epilepsy depends on precise knowledge of the region of seizure
onset. It has long been recognized that focal seizure activity
is associated with increased cerebral blood flow (CBF) in the
involved region of cerebral cortex (Horsley, 1892; Penfield,
1933). Advances in neuroimaging now allow the non-invasive
visualization of CBF changes in patients with epilepsy, which can
be used as a clinical tool to identify the region of seizure onset.
Although surgical treatment is aimed at the focal region of seizure
onset, some seizures can secondarily generalize, which complicates
the interpretation of CBF changes. The aim of the present study
was to determine whether useful clinical information could be
gleaned from CBF imaging performed in patients during partial
seizures with secondary generalization.
Single photon emission computed tomography (SPECT) is currently the only practical method for imaging CBF during seizures.
The advantage of SPECT is that the tracer is injected during the
seizure (ictal SPECT), however, imaging can be done an hour or
more later, when seizure motor activity has ended, thus avoiding
movement artifact. This approach is possible because the tracer is
rapidly taken up by the brain at the time of injection and does not
significantly redistribute (Andersen, 1989; Devous et al., 1990).
Since it was first introduced, ictal SPECT has come into widespread
use in epilepsy centres performing pre-surgical evaluation for medically refractory epilepsy (O’Brien et al., 1998; Lee et al., 2000c,
2001; Knowlton, 2006; Kim et al., 2009). To improve sensitivity
and specificity, ictal SPECT images are typically compared with a
baseline SPECT scan in the same patient without seizures (interictal
SPECT). Since the mid 1990s (Zubal et al., 1995; McNally et al.,
2005), several methods have been developed to digitally coregister
and subtract ictal–interictal SPECT images to obtain maps of ictal
increases and decreases in CBF (Zubal et al., 1995; O’Brien et al.,
1998; Spanaki et al., 1999; Lee et al., 2000a, b; Chang et al.,
2002; McNally et al., 2005).
Many studies have been done to examine the clinical usefulness
of ictal–interictal SPECT [reviewed in Kim et al. (2009)]. It has
been shown that ictal SPECT is far more useful for correctly localizing seizure onset than interictal SPECT (Spencer et al., 1995;
Devous et al., 1998; Kim et al., 2009). In addition, ictal–interictal
SPECT difference imaging analysis yields better results than visual
read of ictal SPECT alone (Zubal et al., 1995; O’Brien et al., 1998;
Spanaki et al., 1999; Lee et al., 2000b; Koo et al., 2003). Another
important determinant of the sensitivity and specificity of ictal
SPECT is the time of tracer injection. Although at early injection
times CBF increases are often confined to the region of seizure
onset, later changes can be complicated, especially in the post-ictal
period when both increases and decreases occur in different brain
regions from seizure onset. When SPECT injection comes late,
and especially when it occurs in the post-ictal period, the diagnostic yield of CBF increases for localizing seizure onset is very low
(Rowe et al., 1991; Newton et al., 1994; Spencer, 1994; O’Brien
et al., 1998; Avery et al., 1999; McNally et al., 2005). In addition,
efforts to localize seizure onset based on SPECT CBF decreases,
Brain 2009: 132; 2102–2113
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whether early or late, have not been very successful compared to
ictal CBF increases (McNally et al., 2005; Kim et al., 2009),
although some have reported good results in the post-ictal
period (O’Brien et al., 1999).
Thus, ictal SPECT has emerged as a useful tool for pre-surgical
localization of partial seizures, as long as the SPECT injection is
performed during the seizure, and not post-ictally. One important
unresolved question is how to interpret ictal SPECT in seizures that
secondarily generalize. In secondarily generalized seizures, patients
initially exhibit localized seizure manifestations such as focal limb
movement, staring or automatisms, which is then followed
by generalized tonic–clonic activity (Theodore et al., 1994; Jobst
et al., 2001). On electroencephalography, localized changes are
seen at onset, followed by propagation to involve widespread
regions of cerebral cortex in secondarily generalized seizures
(Rodin et al., 1969; Schindler et al., 2007). Over 70% of patients
with localization-related epilepsy have occasional secondarily generalized seizures (Forsgren et al., 1996). Therefore, it is not
uncommon for ictal SPECT injections to occur during partial seizures that secondarily generalize. A few studies have reported that
ictal SPECT may still be useful in secondarily generalized seizures
(Lee et al., 1987; O’Brien et al., 1998; Shin et al., 2002).
However, this has not been rigorously investigated.
In the present study, we investigated the localizing value of ictal
SPECT in a group of patients injected during or shortly after partial
seizures with secondary generalization. In all cases, we evaluated
whether a single region of increased CBF could be identified, and
whether this agreed with overall seizure localization based on surgical outcome and other diagnostic tests. We found that ictal
SPECT in secondarily generalized seizures often shows multiple
regions of CBF increases. This makes the identification of a
single unambiguous region of seizure onset more difficult than
in partial seizures without secondary generalization. Nevertheless,
we found that with careful interpretation, ictal SPECT in secondarily generalized seizures could be used to at least narrow down
the region of seizure onset to a few regions or to one hemisphere.
Thus, although it is preferable to obtain ictal SPECT in partial
seizures without secondary generalization, if a secondarily generalized seizure occurs during ictal SPECT, the present work still
enables clinically useful information to be obtained.
Methods
Patients
All procedures were in accordance with the Institutional Review Boards
and NIH guidelines for human research. Inclusion and exclusion criteria
were chosen to identify patients who had SPECT imaging during secondarily generalized tonic–clonic seizures. To obtain a sufficiently large
sample, data were combined from three academic epilepsy centres
(Yale New Haven Hospital, Columbia-Presbyterian Medical Center
and University of Alabama, Birmingham). Inclusion criteria were ictal
SPECT performed during video-EEG monitoring; SPECT injection
performed during or immediately after a secondarily generalized
tonic–clonic seizure based on video-EEG monitoring; and interictal
SPECT performed at least 24 h after the most recent seizure.
Exclusion criteria were diagnosis of primary generalized epilepsy;
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unavailable SPECT images; and inconclusive SPECT injection timing
(e.g. poor video quality). We analysed a total of 59 interictal–ictal
scan pairs in 53 patients (30 males, 23 females) with a mean age at
time of SPECT injection of 33 years (age range 11–65 years).
Clinical data were obtained from patient records, and included
results of magnetic resonance imaging (MRI), fluorodeoxyglucose
positron emission tomography (FDG-PET), scalp and intracranial EEG
seizure onset, site of surgical resection (when applicable), surgical
pathology and seizure outcome after surgery. Overall seizure localization (see Supplementary Tables 1–3) was determined based on concordance of these data, not including SPECT imaging.
Behavioural and EEG review
Video and EEG of seizures for all SPECT injections were reviewed by
two readers, blinded to the results of the imaging studies. Seizure
onset was defined as the earliest EEG or clinical evidence of seizure
activity. Seizure offset was defined as the last EEG or clinical evidence
of seizure activity; usually this coincided with the last clonic jerk exhibited by the patient. Onset of generalization was defined based on
head or eye version, vocalization or asymmetric tonic facial contraction, as in previous behavioural studies of generalized tonic–clonic
seizures (Theodore et al., 1994; Jobst et al., 2001). SPECT injection
time was defined as when the plunger of the syringe containing the
radiopharmaceutical was fully depressed.
SPECT image acquisition
Ictal SPECT injections were performed during continuous scalp EEG
and video recordings. Upon noting seizure onset, a nurse or technologist injected 20–40 mCi of Tc-99m labelled hexamethylpropyleneamine-oxime (HMPAO) (Amersham Healthcare, Arlington Heights,
IL). Patients were asked to close their eyes during the injection.
Inter-ictal injections were performed in these same patients after
524 h of no seizure activity, in a quiet room, while patients were at
rest, awake, but with their eyes closed.
SPECT images were acquired within 90 min after injection. Projection
data were obtained on a Picker PRISM 3000, 3000XP or Marconi/
Philips IRIX three-headed scanner (Philips Medical Systems, Best,
Netherlands) mounted with high resolution fan beam collimators.
Transverse slices were reconstructed using standard low pass
Butterworth filter and Chang attenuation correction as previously
described (Zubal et al., 1995). SPECT image data were transferred
to personal computer, and saved in Analyse format using ImageJ
(http://rsb.info.nih.gov/ij/).
Image analysis
Ictal–interictal SPECT difference analysis was performed for each
patient using methods described in detail previously (McNally et al.,
2005) (http://spect.yale.edu/). This approach, referred to as ictal–
interictal SPECT analysed by SPM (ISAS), calculates differences
between ictal and interictal SPECT image pairs, and then determines
which changes are statistically significant by comparison with image
pairs in a normal database. Results are similar to conventional ictal–
interictal difference imaging analysis (Zubal et al., 1995; O’Brien et al.,
1998; Spanaki et al., 1999), but have the advantage of being more
objective and providing a statistical significance level (Chang et al.,
2002; McNally et al., 2005). Full details of the ISAS method, including
free downloads of the software and normal database, are available at
http://spect.yale.edu/. Briefly, each ictal–interictal scan pair was analysed using statistical parametric mapping (SPM2, Wellcome Department of Cognitive Neurology, London, UK http://fil.ion.ucl.ac.uk/
spm/) on a MATLAB (The MathWorks, Inc. Natick, MA) platform.
G. I. Varghese et al.
The patient scan pairs were compared with a group of 14 healthy
normal scan pairs using a multi-group conditions and covariates
design (McNally et al., 2005), (http://spect.yale.edu). Images were
realigned, spatially normalized, masked and smoothed using a
16 16 16 mm Gaussian kernel. Global intensity normalization at
an analysis threshold of 0.8 was performed to correct for differences
in total brain counts among scan pairs (Friston et al., 1996; Acton and
Friston, 1998). As a double check for problems in the spatial warping,
smoothing or masking steps, especially due to extraneous signal from
outside the brain, we also analysed images without these pre-processing steps using rview freeware (http://www.colin-studholme.net/software/software.html). Contrasts were set up in SPM looking at
hyperperfusion and hypoperfusion throughout the entire brain for
ictal minus interictal images. We used an extent threshold (k) of 125
voxels or 1 cc (voxel size 2 2 2 mm) because this is the approximate spatial resolution of SPECT in tissue. Height threshold (individual
voxel-level significance) was set at P = 0.01 (Z-score 2.33), as determined by prior receiver operating characteristic analysis (McNally
et al., 2005).
SPM identifies clusters of voxels with changes that exceed the previously defined thresholds. We further considered only clusters of
voxels with significance level P50.05 (corrected cluster-level significance), which effectively corrects for multiple comparisons for the
entire brain (Friston et al., 1996). ISAS results were interpreted as
described previously (McNally et al., 2005). Briefly, SPECT ISAS localization was determined for each patient by the location of the most
significant cluster of hyperperfusion voxels in the ictal–interictal comparison. If two or more lobes are equally involved, then localization is
ambiguous and all involved lobes are listed. In partial seizures that do
not secondarily generalize, this approach for localizing CBF increases
has been shown to correctly and unambiguously identify a single
region of seizure onset in most patients (McNally et al., 2005).
In addition to CBF increases, we also identified regions of CBF
decreases using the same approach in ISAS. As reported previously
for partial seizures, perfusion decreases may not be useful for detecting the lobe of seizure onset, but can help lateralize the hemisphere
(left or right) of seizure onset (McNally et al., 2005). Therefore, we
also calculated a hypoperfusion asymmetry index to determine which
hemisphere had more extensive CBF decreases. The hypoperfusion
asymmetry index was calculated based on the volume of significant
voxels (at a voxel-level significance threshold P = 0.01, and clusterlevel significance k = 125 as before) showing decreased perfusion in
each hemisphere (McNally et al., 2005). Thus, we took the number
of hypoperfusion voxels in the left hemisphere minus number of hypoperfusion voxels in the right hemisphere divided by the total number
of hypoperfusion voxels [(kleft-kright)/(kleft+kright)]. Binary images corresponding to each hemisphere were created in MRIcro (for detailed
methods and downloadable binary masks, see http://spect.yale.edu/)
and were used to determine kleft and kright using the small volume
correction function in SPM.
Results
Although seizures were generalized, we observed focal CBF
changes in all cases. Unlike partial seizures however, CBF increases
during secondarily generalized seizures often involved several
lobes. We studied a total of 59 secondarily generalized tonic–
clonic seizures in 53 patients (six patients were injected twice on
different days). Mean seizure duration was 126 12 s (mean SEM), with mean duration of the partial phase prior to
Localization of ictal SPECT in tonic–clonic seizures
Brain 2009: 132; 2102–2113
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Table 1 Ictal SPECT increases: localization and lateralization of seizure onset
Inj t (s) relative to
Patienta
Seizure duration (s)
Onset
Gen
End
Pre-generalization
1
83
2
171
3
110
4
154
5
101
6
98
7
95
8
161
9
129
10
210
11
230
12
444
9
10
11
16
18
20
28
36
40
55
85
241
42
33
50
19
20
23
33
57
12
64
65
139
74
161
99
138
83
78
67
125
89
155
145
203
Generalization
13
80
14
43
15
83
16
194
17
91
18
133
19
80
20
68
21
72
22
76
23
150
24
103
4
11
12
128
24
81
64
57
58
72
118
40
0
3
4
10
20
31
37
47
53
70
78
NA
76
32
71
66
67
52
16
15
14
4
32
63
Overall localizationb
ISAS hyper-perfusion
Correct side?
LH
LH
RT NC
Unlocalized
LT versus RT NC
LT
LT
RH
LT
RH
Multifocal
RT NC
LT
LT, P, F
R P
BiF, Bi T
BiF, BiT, BiP
LT
Bi T
RT
LT
RO, T, P
LT
RT, O
Y
Y
Y
NA
NA
Y
N
Y
Y
Y
NA
Y
LC (C3, P3)
LH
RH
L mesial T
RH
LH
Unlocalized
LH multifocal
Unlocalized
RH
RH
LH
LC
LF, T
RF, T, P
LT
RP
LT
LT, P
RF, P
RC
BiT
RO
LF, P
Y
Y
Y
Y
Y
Y
NA
N
NA
N
Y
Y
a Patients are listed in order of injection time relative to seizure onset (Pre-generalization group) or generalization (Generalization group; see Methods section for
definitions of seizure onset, generalization and end). The following six patients were injected twice on different days, so appear in the Tables twice: Pt 12 = 25, 19 = 50,
20 = 33, 32 = 34, 37 = 41, 51 = 57. See also Table 2.
b Overall localization was based on concordance of MRI, PET, EEG, surgical pathology and outcome (see Supplementary Tables 1 and 2 online for details), and did not
include SPECT results.
Inj = injection; ISAS = ictal–interictal SPECT analyzed by SPM; R = right; L = left; C = central; T = temporal; P = parietal; F = frontal; O = occipital; H = hemisphere;
Bi = bilateral; NC = neocortical.
generalization 51 11 s. Seizures were divided into three groups,
based on SPECT injection time (see Methods section for definitions): (i) Pre-generalization: 12 seizures were injected during the
partial phase prior to generalization; (ii) generalization: 12 seizures
were injected after onset of generalization but prior to seizure end;
and (iii) post-ictal: 35 seizures were injected after termination
(Tables 1 and 2).
Ictal CBF increases can help localize
seizure onset
The goal of ictal SPECT is to unambiguously localize a single lobe
of seizure onset for surgical planning. When ictal SPECT shows
equal involvement of multiple lobes, localization is ambiguous.
We were interested in determining whether increases in CBF
during secondarily generalized seizures would be useful to localize
a single lobe of seizure onset. In addition, if multiple lobes were
involved, we were interested in determining if this could at least
help narrow down the possible side or lobes of seizure onset. We
found that multiple lobes were involved in SPECT increases for
50% (12/24) of patients injected during seizures (Table 1). This
was true, regardless of whether patients were injected pregeneralization (6/12), or during the generalization phase (6/12).
By comparison, our recent study of partial seizures without
generalization (McNally et al., 2005) found that CBF increases
involved multiple lobes in only 15% (2/13) of patients injected
during seizures. While comparisons between these studies should
be interpreted cautiously since the patient composition could have
differed in important ways, including of note the lower incidence
of confirmed temporal lobe epilepsy in the present cohort, we did
find significantly more involvement of multiple lobes in the present
study (2 = 4.30; P = 0.04).
Although increases in multiple lobes cannot provide a single
unambiguous region for epilepsy surgery, do they still provide
some helpful localizing information? Comparison of ictal SPECT
ISAS hyperperfusion regions to overall localization (Table 1)
demonstrated that CBF increases during seizures correctly identified the side of seizure onset (left versus right hemisphere) in
84% of cases (16/19). Thus, for patients injected during the
pre-generalization phase, regions of ISAS hyperperfusion correctly
identified the side of seizure onset in nearly all cases (8/9) in
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G. I. Varghese et al.
Table 2 Post-ictal SPECT increases: localization and lateralization of seizure onset
Inj t (s) relative to
Patienta
Seizure duration (s)
Onset
Gen
End
Overall localizationb
ISAS hyper-perfusion
Correct side?
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
128
97
90
113
475
72
101
108
95
92
89
81
82
155
90
75
61
486
107
337
94
84
105
179
93
93
72
61
99
75
85
40
81
76
107
129
99
93
119
484
81
103
120
106
113
103
111
113
187
129
104
101
530
151
384
142
134
155
233
153
140
109
135
188
187
198
177
248
352
399
69
88
63
84
98
68
75
87
63
95
88
91
NA
101
110
110
NA
110
110
178
105
113
123
113
133
115
97
141
150
162
168
177
233
342
359
1
2
3
6
9
9
12
12
21
21
24
30
31
32
39
39
40
44
44
47
48
50
50
54
60
67
72
74
89
112
113
137
167
276
292
RT neocortical
LO
RH multifocal
BiO
Bi R4L T
LH
L mesial T
LT
LH multifocal
LT
LH multifocal
Unlocalized
R H
Unlocalized
L T-P
R T-O
RH
BiO
LH
RH
RT versus LT
L mesial T
RH
L P-O
L medial P
Unlocalized
Unlocalized
Unlocalized
R mesial T
RH
Unlocalized
RF
Unlocalized
Bi mesial T
LH
RP, T, O
LF
RP
RT, O
RF
BiO
LT, P, F
None
RO, T, F
None
RT, O
RT
None
LT
BiT
RF, T
None
RP
LF, T
RH
RF, T
LO
RO, T
LT, P
RT
LP, O
None
LP
None
RT
LH
LF
None
None
BiT
Y
Y
Y
NA
Y
N
Y
N
N
N
N
NA
N
NA
N
Y
N
NA
Y
Y
NA
Y
Y
Y
N
NA
NA
NA
N
Y
NA
N
NA
NA
N
a Patients are listed in order of injection time relative to seizure end. Six patients in Tables 1 and 2 were injected twice (see Table 1 for details).
b Overall localization was based on concordance of MRI, PET, EEG, surgical pathology and outcome (see Supplementary Table 3 online for details), and did not include
SPECT results.
Inj = injection; ISAS = ictal–interictal SPECT analysed by SPM; R = right; L = left; C = central; T = temporal; P = parietal; F = frontal; O = occipital; H = hemisphere;
Bi = bilateral; NC = neocortical.
which the side of onset was known based on other data (Table 1,
see also Supplementary Tables). Even for patients injected during
the generalization phase, the regions of CBF increases still correctly
lateralized the side of seizure onset in most cases (8/10) (Table 1).
In two of the cases where correct lateralization was not possible
(Patients 7 and 22), this was because CBF increases were bilateral.
These finding suggest that ictal SPECT during generalized tonic–
clonic seizures often shows multiple areas of CBF increases, however, these can still be useful to at least narrow down the probable
regions or side of seizure onset.
Only half (12/24) of the seizures showed a single unambiguous
region of ictal CBF increase. Of these, an even smaller subset
(5/12) had known localization to a single lobe based on other
data (Patients 3, 6, 9, 13 and 16). However, in 80% (4/5) of
these cases the single region of ictal CBF increase correctly localized seizure onset (Table 1). This compares favourably with partial
seizures, where we recently found using the same methods that if
a single unambiguous region of ictal CBF increase was found, it
was correct in 10/10 patients (100%) meeting these criteria
(McNally et al., 2005). In the other six patients with a single
unambiguous CBF increase (Patients 8, 11, 17, 18, 21, 23), the
precise localization was not known. However, as already discussed, the CBF increases correctly identified at least the hemisphere of onset in all of these patients in which the side of onset
was known (Patients 8, 17, 18, 23).
An example of an ictal SPECT injected during the pregeneralization period is shown in Fig. 1. In this patient
(Patient 12, Table 1), ictal–interictal SPECT analysed using ISAS
Localization of ictal SPECT in tonic–clonic seizures
Brain 2009: 132; 2102–2113
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Figure 1 Ictal SPECT injected during the pre-generalization period, with CBF increases including but not limited to the correct
localization. Patient had right temporal neocortical epilepsy confirmed by intracranial EEG (Patient 12, Table 1, see also Supplementary
Table 1). (A) Three dimensional rendering. (B) Coronal views with results superimposed on the SPM MRI template. Ictal SPECT scan
was background subtracted using the patient’s interictal SPECT, and the difference was then compared with a database of normal
SPECT pairs using ISAS (see Methods section). CBF increases are shown as warm colours, and decreases are shown as cool colours;
colour bars indicate t-values. The most significant hyperperfusion cluster was localized to the right temporal and occipital lobes
(cluster-level significance P50.0001 corrected for multiple comparisons, Z-score of most significant voxel = 6.48, cluster size,
k = 29 663 voxels). Extent threshold, k = 125 voxels (voxel dimensions 2 2 2 mm), voxel-level height threshold, P = 0.01.
revealed CBF increases involving the right temporal and occipital
lobes to an equal extent (with some lesser involvement of the
right parietal lobe as well). It was, therefore, not possible to unambiguously localize the lobe of seizure onset based on the ictal
SPECT in this patient. The increases in this patient did, however,
include the right temporal lobe, which ultimately was confirmed
by other data to be the region of seizure onset (Patient 12,
Table 1, see also Supplementary Table 1). Thus, ictal SPECT
correctly lateralized the seizure onset to the right hemisphere,
and correctly identified a set of ‘candidate regions’ in this
patient, but did not unambiguously identify a single lobe of seizure
onset.
An example of an ictal SPECT injected during the generalization
phase is shown in Fig. 2. This patient (Patient 15, Table 1) had
equal involvement of the right frontal, parietal and temporal lobes
based on CBF increases (with some lesser involvement of the right
occipital lobe as well). Therefore, it was once again not possible to
unambiguously identify a single lobe of seizure onset based on the
ictal SPECT data in this patient. However, the ictal SPECT did
lateralize the side of seizure onset correctly to the right hemisphere (Table 1, see also Supplementary Table 2).
Post-ictal CBF increases are
not helpful for localization
For injections in the post-ictal period, SPECT increases were
not helpful for localizing or for lateralizing seizure onset.
SPECT hyperperfusion regions agreed with the side of overall
localization in 50% (12 of 24) of patients injected post-ictally
in which side of onset was known (Table 2). Thus, for post-ictal
injections, CBF increases lateralized to the correct side of seizure
onset at chance levels. Interestingly, the lobe of seizure onset was
usually not included in the regions of CBF increases for post-ictal
injections. Thus, for patients with a single known lobe of seizure
onset, this lobe was involved in only two (of nine) patients and
these two occurred at relatively early post-ictal injection times
(Patients 25, 31 in Table 2). Lobe of known seizure onset was
not involved for other patients injected post-ictally (Patients 26,
32, 34, 46, 49, 53, 56 in Table 2).
For post-ictal injections, only 11 of 35 seizures showed a single
unambiguous region of CBF increase (Patients 26, 27, 29, 36, 38,
42, 46, 49, 52, 54, 56 in Table 2). Of the remaining seizures, 16
showed CBF increases in multiple lobes, and eight showed no
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G. I. Varghese et al.
Figure 2 Ictal SPECT injected during the generalization period, with CBF increases involving multiple lobes in the hemisphere of seizure
onset, and CBF decreases in the contralateral hemisphere. Patient had right hemisphere seizure onset (Patient 15, Table 1, see also
Supplementary Table 2). (A) Three-dimensional rendering. (B) Coronal views with results superimposed on the SPM MRI template.
The most significant hyperperfusion cluster was localized to the right frontal, temporal and parietal lobes (cluster-level significance
P50.0001 corrected for multiple comparisons, Z-score of most significant voxel = 5.09, cluster size, k = 27 513 voxels). Hypoperfusion
was greatest in the left hemisphere, contralateral to seizure onset (hypoperfusion asymmetry index = 0.91, Patient 15, Table 3).
Ictal–interictal SPECT difference images were analysed using ISAS (see Methods section). CBF increases are shown as warm colours, and
decreases are shown as cool colours; colour bars indicate t-values. Extent threshold, k = 125 voxels (voxel dimensions 2 2 2 mm),
voxel-level height threshold, P = 0.01.
significant CBF increases in the post-ictal period (Table 2). Of the
patients with a single unambiguous region of CBF increase, only
six had known localization based on other data (Patients 26, 29,
42, 46, 49, 56 in Table 2, see also Supplementary Table 3). The
single region of CBF increase correctly localized the lobe of seizure
onset in none (0/6) of these cases. This was in agreement with our
previous SPECT findings from partial seizures that did not secondarily generalize, which also showed very poor localization based on
CBF increases in the post-ictal period (McNally et al., 2005).
An example of a SPECT injection from the post-ictal period is
shown in Fig. 3. In this patient (Patient 49, Table 2), ISAS analysis
of CBF increases demonstrated that the most significant voxel
cluster was located in the right temporal lobe. Of note, a
second slightly less significant region of CBF increase was
seen in the left temporal lobe as well (Fig. 3). However, the
known region of seizure onset based on MRI, PET and surgical
pathology was the left medial parietal cortex (Table 2, see also
Supplementary Table 3). Thus, regions of CBF increase did not
agree with the known region of seizure onset in this patient
injected in the post-ictal period. Interestingly, bilateral CBF
increases were also seen in the cerebellum in this patient injected
in the post-ictal period (Fig. 3). Cerebellar changes in tonic–clonic
seizures were analysed in greater detail in another recent study
(Blumenfeld et al., 2009).
CBF decreases during generalization
are contralateral to side of seizure
onset
In addition to CBF increases, we also analysed the localizing and
lateralizing value of CBF decreases during secondarily generalized
tonic–clonic seizures (Tables 3 and 4). We found that CBF
decreases during and after secondarily generalized tonic–clonic
seizures were not useful for localizing the lobe of seizure onset.
Thus, the regions of CBF decreases included the lobe of known
seizure onset in none of the patients injected during seizures
(Table 3), and in only four patients (Patients 46, 49, 53 and 56)
injected post-ictally (Table 4). In agreement with this, a recent
study of partial seizures (without secondary generalization),
found that ictal and post-ical CBF decreases have poor localizing
value for the specific lobe of seizure onset (McNally et al., 2005).
Localization of ictal SPECT in tonic–clonic seizures
Brain 2009: 132; 2102–2113
| 2109
Figure 3 Ictal SPECT injected during the post-ictal period was not useful for seizure localization. Patient had a left medial parietal
localization based on MRI, PET and surgical pathology (Patient 49, Table 2, see also Supplementary Table 2). (A) Three-dimensional
rendering. (B) Coronal views with results superimposed on the SPM MRI template. The most significant hyperperfusion cluster was
localized to the right temporal lobe (cluster-level significance P50.0001 corrected for multiple comparisons, Z-score of most significant
voxel = 4.32 cluster size, k = 6298 voxels), and a second large hyperperfusion cluster was present in the left temporal lobe (cluster-level
significance P = 0.002 corrected for multiple comparisons, Z-score of most significant voxel = 4.80 cluster size, k = 2958 voxels).
Hypoperfusion changes were also bilateral (hypoperfusion assymetery index = 0.03, Patient 49, Table 4). Ictal–interictal SPECT
difference images were analysed using ISAS (see Methods section). CBF increases are shown as warm colours, and decreases are shown
as cool colours; colour bars indicate t-values. Extent threshold, k = 125 voxels (voxel dimensions 2 2 2 mm), voxel-level height
threshold, P = 0.01.
It should be noted that some studies reported good localization of
seizure onset based on post-ictal CBF decreases (Devous et al.,
1998; O’Brien et al., 1999), which could reflect differences in
analysis methods.
Although post-ictal CBF decreases may have questionable value
for localizing the lobe of seizure onset, we recently found that the
hemisphere with greatest overall post-ictal CBF decreases usually
corresponds to the side of seizure onset (McNally et al., 2005).
Post-ictal CBF decreases in partial seizures without secondary generalization can thus be useful to at least lateralize the side of
seizures onset. We were therefore interested in whether the side
of overall greatest hypoperfusion would be useful for lateralizing
the side of onset of partial seizures with secondary generalization.
We found that for SPECT injections in the pre-generalization
phase, the side of greater hypoperfusion was ipsilateral or contralateral to the side of onset with about equal frequency, and was
therefore not clinically useful for lateralization (five ipsilateral and
four contralateral, Table 3). Interestingly, for seizures injected
during the generalization phase, hypoperfusion was greater in
the hemisphere contralateral to seizure onset in 90% (9 of 10)
of patients with known side of seizure onset (Table 3). For postictal injections, hypoperfusion remained greater in the hemisphere
contralateral to onset in most cases (71%; 17 of 24 patients,
Table 4). This was especially true for patients injected within
15 s of seizure end, where 100% (seven of seven) showed greater
hypoperfusion contralateral to onset (Patients 25–32 in Tables 2
and 4). These findings suggest that while CBF decreases are not
useful for localizing the lobe of seizure onset, CBF decreases
during and shortly after generalization are usually greatest in the
hemisphere contralateral to the side of onset. It is of interest that
this is opposite to the pattern seen following partial seizures without generalization, where overall hypoperfusion is usually greatest
in the hemisphere ipsilateral to side of onset (McNally et al.,
2005).
Examples of CBF decreases during partial seizures with secondary generalization are shown in Figs 1–3. In the example shown
during the pre-generalization period, CBF decreases were seen in
multiple bilateral brain regions (Fig. 1), similar to those reported
previously for temporal lobe seizures without generalization (Van
Paesschen et al., 2003; Blumenfeld et al., 2004). In the example
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| Brain 2009: 132; 2102–2113
G. I. Varghese et al.
Table 3 Ictal SPECT decreases: localization and lateralization of seizure onset
Patienta
Overall
Localizationb
ISAS
Hypoperfusion
L hemisphere
hypoperfusion
volumec
R hemisphere
hypoperfusion
volumec
Pre-generalization
1
LH
2
LH
3
RT NC
4
Unlocalized
5
LT versus RT NC
6
LT
7
LT
8
RH
9
LT
10
RH
11
Multifocal
12
RT NC
LF
RO
RP, O
RF, P
LF
LP
BiF
RP
RF, P, T
LT, P
BiO
RF, LO
7367
10 772
2031
10 075
4690
2235
12 890
1348
4956
7370
20 647
17 519
1342
23 805
3530
15 218
1734
1940
11 280
4438
23 453
6358
17 345
10 538
Generalization
13
LRo (C3, P3)
14
LH
15
RH
16
L mesial T
17
RH
18
LH
19
Unlocalized
20
LH multifocal
21
Unlocalized
22
RH
23
RH
24
LH
BiP, O
RP
LF, O
BiF
LF
BiF
BiF,P
LF
RF, T
BiF,P
LF, T, P
RP, O
4871
1110
14 753
18211
15 332
1560
13741
10 136
3489
26 728
21 020
6594
15 641
17 331
674
15 521
1850
2194
15 584
10 726
6286
22 833
4649
14631
Asymmetry
Indexd
Side of greater
hypoperfusion
Ipsi- or contralateral to
localization
0.69
0.38
0.27
0.20
0.46
0.07
0.07
0.53
0.65
0.07
0.09
0.25
L
R
R
R
L
L
L
R
R
L
L
L
I
C
I
NA
NA
I
I
I
C
C
NA
C
0.53
0.88
0.91
0.08
0.78
0.17
0.06
0.03
0.29
0.08
0.64
0.38
R
R
L
L
L
R
R
R
R
L
L
R
C
C
C
I
C
C
NA
C
NA
C
C
C
a Patients listed in order of injection time from seizure onset (Pre-generalization group), or generalization (Generalization group), as in Table 1.
b See Supplementary Tables 1 and 2 online for details.
c Volume expressed as number of significant voxels; voxel dimensions 2 2 2 mm (see Methods section).
d (L R)/(L+R) See Methods section.
R = right; L = left; T = temporal; P = parietal; F = frontal; O = occipital; Ro = Rolandic; H = hemisphere; Bi = bilateral; NC = neocortical; I = ipsilateral to overall localization;
C = contralateral.
shown during generalization, CBF decreases were most prominent
in the hemisphere contralateral to seizure onset (Fig. 2). During
the late post-ictal period, in the example shown, CBF decreases
were present bilaterally (Fig. 3).
Discussion
We found that ictal SPECT can provide clinically useful localizing
information even when obtained during partial seizures with secondary generalization. Caution is necessary in interpreting ictal
SPECT in secondarily generalized seizures, since multiple lobes
are often involved in CBF increases. However, the side of ictal
CBF increases correctly lateralizes the side of seizure onset 84%
of the time. In addition, when focal CBF increases occur involving
a single lobe this usually is the region of seizure onset, even in
partial seizures with secondary generalization. These finding suggest that partial seizures with secondary generalization do not
homogenously involve the whole brain, but rather affect some
regions most intensely, while other areas are relatively spared
even in so-called ‘generalized’ seizures.
A growing body of evidence supports the notion that ‘generalized’ seizures are not truly generalized. Even in primary generalized epilepsy where bilateral spike-wave discharges are seen,
electrical mapping and neuroimaging studies show focal bilateral
involvement of frontal and parietal cortex, while other regions are
spared (Meeren et al., 2002; Archer et al., 2003; Salek-Haddadi
et al., 2003; Aghakhani et al., 2004; Holmes et al., 2004;
Nersesyan et al., 2004a,b; Berman et al., 2005; Berman et al.,
submitted for publication). In partial seizures with secondary generalization, there is also evidence that localized regions are most
intensely involved, and that these regions are related to the site of
seizure onset. For example, post-ictal Todd’s paresis and other
deficits are often localized to the region of seizure onset even
following partial seizures with secondary generalization (Rolak
et al., 1992; Blumenfeld et al., 2003b). Focal regional involvement
with sparing of other areas in secondarily generalized seizures is
also supported by intracranial EEG (Schindler et al., 2007) and by
previous SPECT imaging studies in spontaneous and induced seizures (Lee et al., 1987; Green and Buchhalter, 1993; Koc et al.,
1997; Shin et al., 2002; Blumenfeld et al., 2003a,b; Enev et al.,
2007).
Localization of ictal SPECT in tonic–clonic seizures
Brain 2009: 132; 2102–2113
| 2111
Table 4 Postictal SPECT decreases: Localization and lateralization of seizure onset
Patienta
Overall
Localizationb
ISAS
Hypoperfusion
L hemisphere
hypoperfusion
volumec
R hemisphere
hypoperfusion
volumec
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
RT NC
LO
RH multifocal
BiO
Bi R4L T
LH
L mesial T
LT
LH multifocal
LT
LH multifocal
Unlocalized
RH
Unlocalized
L T-P
R T-O
RH
BiO
LH
RH
R versus L T
L mesial T
RH
L P-O
L medial P
Unlocalized
Unlocalized
Unlocalized
R mesial T
RH
Unlocalized
RF
Unlocalized
Bi mesial T
LH
BiF
RF, T, P
NA
NA
RP, T
RF, T, P
RP, T
BiF
BiP
BiF
RF
BiF, P
RP
NA
BiF, RP
R P
RT
LO
RP, O
LF, T, P
BiP
LT
BiF
BiF
BiP
RT
RF
BiF
BiF, T, P
BiF
RP, F, T
RF
RF, T
RF, P, O
BiF, P, O
10 895
5240
2482
1086
17 215
2603
1958
5811
3148
9214
3994
34 579
4120
1588
10 004
5764
2497
4132
3265
36 536
3228
1943
5127
1671
2709
1048
1459
5647
11 540
17 866
2351
2893
14 034
20 656
13 106
6855
6712
1386
329
2235
16 448
4521
7114
3112
12 258
4300
31 058
9540
827
14 593
8019
9570
3089
5083
3873
3768
2307
1617
771
2851
7402
7912
4304
19 173
10 841
32 534
5041
14 815
31 990
16 592
Asymmetry
Indexd
0.23
0.12
0.28
0.53
0.77
0.73
0.40
0.10
0.01
0.14
0.04
0.05
0.40
0.32
0.19
0.16
0.59
0.14
0.22
0.81
0.08
0.09
0.52
0.37
0.03
0.75
0.69
0.13
0.25
0.24
0.87
0.27
0.03
0.22
0.12
Side of greater
hypoperfusion
Ipsi- or contralateral to
localization
L
R
L
L
L
R
R
R
L
R
R
L
R
L
R
R
R
L
R
L
R
R
L
L
R
R
R
L
R
L
R
R
R
R
R
C
C
C
NA
C
C
C
C
I
C
C
NA
I
NA
C
I
I
NA
C
C
NA
C
C
I
C
NA
NA
NA
I
C
NA
I
NA
NA
C
a Patients listed in order of injection time from seizure end, as in Table 2.
b See Supplementary Table 3 online for details.
c Volume expressed as number of significant voxels; voxel dimensions 2 2 2 mm (see Methods section).
d (L R)/(L+R) See Methods section. R = right; L = left; T = temporal; P = parietal; F = frontal; O = occipital; Ro = Rolandic; H = hemisphere; Bi = bilateral; NC = neocortical;
I = ipsilateral to overall localization; C = contralateral.
Prior investigations have also suggested that CBF increases
during secondarily generalized seizures may be useful for localizing
seizure onset (Lee et al., 1987; O’Brien et al., 1998; Shin et al.,
2002). However, these studies were based on relatively few secondarily generalized seizures, and did not examine in detail how
SPECT images during generalized seizures can be interpreted to
yield clinically useful results. We found that SPECT increases
during secondarily generalized seizures often involved multiple
lobes, making it impossible to identify a single unambiguous
lobe of seizure onset. However, our results enable the use of
ictal SPECT increases in multiple lobes to at least narrow down
the most likely hemisphere or group of regions for seizure onset,
which can be helpful for planning additional presurgical studies. In
addition, our results suggest that when a single lobe shows the
greatest CBF increases even during secondarily generalized seizures, this lobe is often the correct localization for seizure onset.
Injections during both the pre-generalization and generalization
periods were helpful for localization. However, injections during
the post-ical period did not yield CBF increases that were helpful
for seizure localization. This is in agreement with prior work from
partial seizures, in which post-ictal CBF increases were very poor
at correctly localizing seizure onset (McNally et al., 2005; Kim
et al., 2009).
We found that CBF decreases during the generalization period
and early post-ictal periods were usually greatest in the hemisphere contralateral to seizure onset. This was quantified using a
hypoperfusion asymmetry index, and provides another useful
method for interpreting ictal SPECT during secondarily generalized
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| Brain 2009: 132; 2102–2113
seizures to glean clinically useful information. It is interesting that
in partial seizures without generalization, we found that post-ictal
CBF decreases were greatest in the hemisphere ipsilateral to onset
(McNally et al., 2005), whereas during and shortly following generalized seizures the present study shows greater CBF decreases
contralateral to seizure onset. It is likely that the CBF decreases
occur through different mechanisms in these two situations. It is
known that partial seizures often cause post-ictal CBF decreases
both in the region of seizures (Newton et al., 1992; Zubal et al.,
1999) and in surrounding regions (Avery et al., 2000; Blumenfeld
et al., 2004; Englot et al., 2008), which together may explain the
larger post-ictal CBF decreases on the side of seizure onset with
partial seizures (McNally et al., 2005). In contrast, secondarily
generalized seizures, often show large CBF increases involving
multiple lobes on the side of seizure onset (e.g. see Fig. 2),
which may cause a relative decrease in CBF in the contralateral
hemisphere either through long-range neuronal network mechanisms (Blumenfeld et al., 2004; Englot et al., 2008) or vascular
mechanisms. We also cannot exclude the possibility that the intensity normalization used in image processing to correct for differences in total brain counts between ictal and interictal scans may
artificially depress the relative SPECT signal in the contralateral
hemisphere when increases in the ipsilateral hemisphere are
large. Further investigation will be needed to determine the
mechanisms, but in any case, contralateral SPECT signal decreases
remain a useful clinical sign for lateralizing the side of onset of
secondarily generalized tonic–clonic seizures.
Additional investigation of the cortical and subcortical changes
in secondarily generalized tonic–clonic seizures may also provide
important insights into pathophysiology of this seizure type. For
example, regions showing the most intense changes could be
related to pathological damage caused by extreme increases in
neuronal electrical activity and metabolism (Schridde et al.,
2008). Regions of CBF decreases may also contribute to impaired
cerebral function during and following seizures (Blumenfeld et al.,
2004; Englot et al., 2008). In addition, late increases in cerebellar
activity, which we often observed during and following generalized tonic–clonic seizures (e.g. Fig. 3) could be important for
mechanisms of seizure termination or post-ictal suppression
(Salgado-Benitez et al., 1982). Group analysis of neuroimaging
data, to determine the regions most commonly affected before,
during, and after secondarily generalized tonic-seizures may help
elucidate some of these fundamental questions, and were the
subject of another recent study (Blumenfeld et al., 2009).
Conclusions
We found that ictal and post-ictal SPECT from secondarily generalized tonic–clonic seizures demonstrate regional CBF changes that
are clinically useful for localizing seizure onset. Although partial
seizures without generalization provide more focal changes, even
secondarily generalized seizures do not involve the whole brain
homogeneously. When CBF increases are observed in multiple
regions during the pre-generalization and generalization periods,
these regions usually include the correct lobe and are greatest in
the hemisphere of seizure onset. In addition, when a single region
G. I. Varghese et al.
shows the greatest CBF increase, even during generalized tonic–
clonic seizures, this is most often the correct lobe of seizure onset.
CBF decreases do not identify the specific lobe of seizure onset,
but are usually greatest in the hemisphere contralateral to onset
during the generalization period and shortly afterwards. These
patterns of CBF changes allow SPECT obtained from secondarily
generalized tonic–clonic seizures to be used for presurgical localization in patients with medically refractory epilepsy. Therefore,
although partial seizures are preferred, if secondarily generalized
seizures occur during ictal SPECT, careful interpretation can provide clinically useful results.
Acknowledgements
We thank Sarah Doernberg and Kathryn Davis for initial patient
identification and video/EEG review, and Matthew DeSalvo for
helpful comments on the manuscript.
Funding
National Institutes of Health (R01 NS055829); Donaghue
Investigator Award; Betsy and Jonathan Blattmachr family.
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