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[18F]FDG-PET Reveals Temporal Hypometabolism in Patients With Temporal Lobe Epilepsy Even When Quantitative MRI and Histopathological Analysis Show Only Mild Hippocampal Damage
Salla Lamusuo, MD;
Leena Jutila, MD;
Aarne Ylinen, MD, PhD;
Reetta Kälviäinen, MD, PhD;
Esa Mervaala, MD, PhD;
Merja Haaparanta, PhD;
Satu Jääskeläinen, MD, PhD;
Kaarina Partanen, MD, PhD;
Matti Vapalahti, MD, PhD;
Juha Rinne, MD, PhD
Arch Neurol. 2001;58:933-939.
ABSTRACT
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Background The relationship between reduced glucose metabolism in positron emission
tomography with fludeoxyglucose F 18 ([18F]FDG-PET) and hippocampal
damage (HD) in patients with temporal lobe epilepsy is still unclear.
Objective To determine whether the presence and severity of HD verified by quantitative
magnetic resonance imaging (QMRI) and histopathological analysis affect the
degree of hypometabolism.
Patients and Methods Sixteen patients with drug-resistant temporal lobe epilepsy underwent
[18F]FDG-PET and QMRI (hippocampal volumetry and T2 relaxometry)
before surgery. Histopathological analysis of the hippocampus included measurements
of neuronal loss, proliferation of glial cells, and mossy fiber sprouting.
The asymmetry in glucose metabolism described the degree of hypometabolism.
Results Temporal hypometabolism was not related to severity of HD as measured
by QMRI or histopathological analysis. The degree of hypometabolism did not
differ in patients with mild, moderate, or severe HD. In addition, [18F]FDG-PET revealed significant temporal hypometabolism even though
hippocampal QMRI findings were normal or showed only mild HD. Thus, glucose
consumption was reduced over and above the histopathological changes.
Conclusions [18F]FDG-PET is sensitive for localizing the epileptogenic
region in patients with temporal lobe epilepsy. However, it is insensitive
to reflect the severity of HD.
INTRODUCTION
POSITRON emission tomography (PET) with fludeoxyglucose F 18 ([18F]FDG) has shown the region of reduced interictal glucose metabolism
in the epileptogenic temporal lobe,1, 2, 3, 4
and high-resolution quantitative magnetic resonance imaging (QMRI)5, 6, 7 has reduced hippocampal
volume (HCV) and prolonged T2-weighted signal (HCT2) in the epileptic
hippocampus in patients with intractable temporal lobe epilepsy (TLE). Histopathologically,
hippocampal damage (HD) found in 60% to 70% of patients with TLE contains
neuronal loss in the hilus and CA1 subfield, gliosis, and synaptic reorganization.8, 9, 10
Reduced HCV in QMRI has been shown to be related to histopathologically
verified neuronal loss, whereas prolonged HCT2 is assumed to reflect
the increased proliferation of glial cells in the hippocampus.11, 12
However, the pathophysiological basis of the reduced glucose metabolism is
still unclear. At least the severity of HCV loss in QMRI has been assumed
to be unrelated to the temporal hypometabolism.13
Furthermore, a few studies have found no correlation between the histopathologically
verified HD and hypometabolism,14, 15, 16, 17
although the results have been contradictory.13, 14, 15, 16, 17, 18, 19
Therefore, we wanted to find out whether the relationship exists and whether
[18F]FDG-PET could lateralize the epileptogenic region in patients
with TLE even when hippocampal QMRI shows normal findings or only mild HD.
PATIENTS AND METHODS
PATIENTS
Sixteen patients (5 women and 11 men), all of whom underwent surgery
because of intractable TLE, were preoperatively investigated with [18F]FDG-PET in the Turku PET Centre, Turku, Finland. Their mean (SD) age
was 32.8 (10.9) years (median, 31.0 years); mean (SD) age at the onset of
epilepsy was 15.9 (11.8) years (range, 0.8-43.0 years; median, 14.0 years),
and mean (SD) duration of TLE was 17.0 (14.0) years (median, 13.0 years).
Clinical data are presented in Table 1.
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Table 1. Clinical Data for 16 Patients With Temporal Lobe Epilepsy
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The presurgical evaluation was performed by the Kuopio University Hospital,
Kuopio, Finland, epilepsy surgery team according to the method described previously.20, 21 Fifteen of 16 operations were preoperatively
evaluated as curative (unilateral TLE with a good outcome), and 1 was a palliative
procedure (only a reduction in seizure frequency expected). The palliative
operation was performed after careful patient counseling of the expected outcome
and in agreement with the patient. The histopathological analyses of resected
tissues were performed at the A.I. Virtanen Institute in Kuopio.
Written informed consent was obtained from all participants. The ethics
committees of Turku University Central Hospital and Kuopio University Hospital
approved the clinical and imaging parts of the protocol. The National Board
of Medical Legal Affairs approved the use of human tissue for histopathological
analysis.
PET PROCEDURES
The PET study was carried out with an 8-ring whole-body PET scanner
(ECAT 931/08-I2; Siemens/CTI, Knoxville, Tenn), and the [18F]FDG
was prepared according to methods described previously.20, 21, 22, 23
We used the values for the same healthy volunteers as in earlier studies.20, 21 Elliptical regions of interest, with
an average size of 0.5 x 2.0 cm, were placed individually in the lateral
temporal neocortical gyri (superior, middle, and inferior temporal) and in
the medial temporal lobe (covering the hippocampus and part of the amygdala)
in addition to the regions shown in Table
2. The locations of regions of interest in different brain areas
were defined using anatomical atlases and patients' MRI scans. Regional cerebral
glucose metabolic rates (rCMRgluc in micromoles per milliliter
per minute) were calculated according to the method of Patlak and Blasberg.24 The left-right asymmetry (asymmetry index [AI]) of
rCMRgluc was measured for all pairs of homologous regions of the
hemispheres using the widely used formula: AI = (L - R) x 100/([L
+ R]/2)%. The AI was used to indicate the region of hypometabolism and also
to describe the degree of hypometabolism. Regions of interest with the greatest
AIs showing the hypometabolic area ipsilaterally (ipsilateral referring to
the side of the surgical lobe) in each of the 3 lateral temporal neocortical
gyri and in the medial temporal lobe were selected when calculating comparisons
between the results of hippocampal QMRI and histopathological analyses. Also
the left-right ratio in glucose utilization in each temporal area was calculated,
as the HCV ratio is usually determined in the same way. Data from controls
were analyzed in the same manner by the investigator (S.L.) analyzing the
patient data. When calculating the mean AIs, the absolute AI ( = |AI|) was
used.
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Table 2. Mean Regional Glucose Metabolic Rates and AIs in Temporal
Areas in Patients With TLE and Controls*
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HISTOPATHOLOGICAL ANALYSIS
Results of histopathological analysis of resected hippocampus samples
were available for 15 of 16 patients. Hippocampal tissue was histologically
analyzed in patients and controls in the same manner as described previously.25, 26, 27, 28 In
each case, the sum score of the density of neurons and the severity of astrogliosis
can vary between 0 and 15 (the density of neurons: sum score 1-5 indicates
mild damage; 6-10, moderate damage; and 11-15, severe damage; and the severity
of astrogliosis: sum score 1-5, mild gliosis; 6-10, moderate gliosis; and
11-15, severe gliosis). The density of mossy fiber sprouting was scored from
0 to 5.29 If the score was lower than 2, the
severity of mossy fiber sprouting was considered mild; 2 to 3, moderate, and
4 to 5, severe.
Patients were divided into 3 groups based on the histopathological findings,
counting the sum scores of neuronal loss, astrogliosis, and mossy fiber sprouting
together. In patients with mild HD, the maximum total sum score was 11 (5
+ 5 + 1 = 11); in patients with moderate HD, the minimum total sum score was
14 (6 + 6 + 2) and the maximum was 23 (10 + 10 + 3); and in patients with
severe HD, the minimum total sum score was 26 (11 + 11 + 4).
QUANTITATIVE MRI OF THE HIPPOCAMPUS
Preoperative HCV and HCT2 were available for all patients.
The method used to measure HCV and HCT2 has been described previously.12, 30, 31 Briefly, the individuals
were scanned with a 1.5-T Magnetom SP63 (Siemens, Erlangen, Germany) using
a standard head coil and a tilted coronal 3-dimensional gradient-echo sequence
(MP-RAGE: repetition time, 10 milliseconds; echo time, 4 milliseconds; inversion
time, 250 milliseconds; flip angle, 12°; field of view, 250 mm; matrix,
256 x 192; and 1 acquisition). This gave 128 T1-weighted slices (thickness,
1.5-1.8 mm) oriented at right angles to the long axis of the hippocampus.
STATISTICS
To evaluate the significance of the asymmetry, the confidence interval
was calculated.20 Similar to earlier studies,3, 20, 32, 33 [18F]FDG-PET results with metabolic asymmetries exceeding 15% in at least
2 adjacent image planes in any region of the brain were considered significant.
In hippocampal QMRI, the reference range for all variables was defined as
2 SDs above and below the control mean (for normalized HCV [nHCV]: <2500
mm3 in the left side and <2717 mm3 in the right side;
for HCT2: >109 milliseconds34).
Statistical analysis was performed using Origin software (version 5.0; Microcal
Software Inc, Northampton, Mass). The Pearson correlation coefficient (r) and the Mann-Whitney U test
were used to determine the relationships between the results of [18F]FDG-PET,
hippocampal QMRI, and histopathological analyses. The t test was used to determine when results of [18F]FDG-PET
and hippocampal QMRI differed statistically from the values of the controls.
The Bonferroni correction for multiple comparisons was used when calculating
the comparisons shown in Table 3.
The level of significance was set at P<.05.
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Table 3. Comparison of the Mean Asymmetry Indexes in Temporal Areas
in [18F]FDG-PET and the Mean Sum Scores of the Histopathological
Analysis and the Results of QMRI in Patients With Varying Degrees of Hippocampal
Damage*
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RESULTS
ELECTROENCEPHALOGRAPHY
Electroencephalography with sphenoidal electrodes lateralized seizure
onsets unilaterally in the lateral temporal neocortical areas, the medial
temporal lobe, or both in 5 patients and with foramen ovale electrodes in
the medial temporal lobe in 1 patient (patient 5). In electroencephalography
with subdural electrodes, epileptiform activity originated from the lateral
temporal neocortical areas and the medial temporal lobe in 5 patients, only
from the medial temporal lobe in patient 2, and bitemporally in patient 4.
HISTOPATHOLOGICAL ANALYSIS
Mild HD (range of the total sum scores of the histopathological analysis,
7-11) was found in 3 patients (patients 2, 10, and 13), moderate HD (range,
14-21) in 4 patients (patients 1, 8, 11, and 15), and severe HD (range, 27-34)
in 8 patients. The differences in the mean sum scores of the histopathological
analyses between these groups were significant except the difference in the
mean sum score of the severity of mossy fiber sprouting between patients with
mild or moderate HD (Table 3).
[18F]FDG-PET ANALYSIS
Table 2 summarizes separately
the mean rCMRgluc and AIs in all determined brain regions in patients
and controls. In controls, there were no significant differences in the mean
left and right rCMRgluc values in any temporal areas or in other
brain areas. In patients, the mean rCMRgluc was reduced by 4% to
33% from the control mean in all brain regions. However, the mean AIs in brain
regions other than the temporal areas did not differ from those of the controls
(Table 2).
[18F]FDG-PET lateralized the epileptogenic zone in agreement
with the surgical lobe in 88% (14/16) of the patients. Patient 10 had visually
reduced uptake of [18F]FDG in the ipsilateral temporal area but,
quantitatively, the AI (12%) did not reach the cutoff threshold of 15%. In
patient 16, [18F]FDG-PET revealed a wide hypometabolic area covering
all the right temporal areas and the right parietal lobe (Table 4).
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Table 4. Asymmetry Indexes of Temporal Areas in [18F]FDG-PET
and Normalized Values of Hippocampal Volumetry and T2 Relaxometry in QMRI*
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In 3 patient groups with differing severity of HD, the mean AIs were
significantly different from the control mean in all temporal areas except
in the inferior temporal gyrus in patients with mild HD (P = .09) and in the superior temporal gyrus in patients with moderate
HD (P = .12) (Table 3).
QUANTITATIVE MRI
In 8 of 16 patients, the ipsilateral, and in 2 of the 8 patients also
the contralateral, nHCV was reduced significantly. Patient 15 had contralaterally
reduced nHCV. In 10 (62%) of 16 patients, the ipsilateral, and in 2 of these
10 the contralateral, HCT2 was also prolonged significantly (Table 4).
In 7 of 16 patients, the ipsilateral nHCV and HCT2 were at
least 2 SDs from the control mean, whereas in 4 patients, either ipsilateral
nHCV or HCT2 was normal, indicating only a mild HD according to
QMRI. Thus, hippocampal QMRI was congruent with the surgical lobe in 69% (11/16)
of the patients. In patient 2, HCT2 was prolonged, and a tumor
was found in the medial temporal lobe. In addition to bilateral HD, patient
7 had focal cortical dysplasia in the lateral temporal neocortex. In 5 (31%)
of 16 patients, nHCV and HCT2 were referred normal. One of these
5 patients (patient 13) had focal cortical dysplasia in the lateral temporal
cortex (Table 4).
Three patients with histopathologically verified mild HD also had significantly
milder changes in the mean nHCV and HCT2 than the 2 other groups
(Table 3). The mean HCT2 in patients with moderate or severe HD and the mean nHCV in patients
with severe HD differed significantly from the control means (P<.001 for HCT2 and nHCV in patients with severe HD; P<.01 for HCT2 in patients with moderate
HD). The mean nHCV has been compared with the left HCV of controls (Table 3).
COMPARISON OF [18F]FDG-PET AND HIPPOCAMPAL QMRI
All patients with abnormal and 3 of 5 patients with normal hippocampal
QMRI results had ipsilateral temporal hypometabolism. Figure 1 shows patient 8 with normal findings of QMRI but abnormal
findings of [18F]FDG-PET.
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Transaxial positron emission tomography with fludeoxyglucose F 18
image (A) and coronal T1-weighted magnetic resonance image (B) of patient
8, with left temporal hypometabolism (arrows) and normal hippocampal quantitative
magnetic resonance imaging results.
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[18F]FDG-PET and HCV
The left-right ratio and AI in [18F]FDG-PET correlated significantly
with the left-right ratio in nHCVs in all temporal areas except the superior
temporal gyrus (Table 5). However,
the AI in any temporal area was not significantly related to the ipsilateral
nHCV even though the relation was studied only in the 11 patients with preoperatively
well-established HD in QMRI (data not shown).
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Table 5. Relationships of Asymmetry Indexes and Left-Right Ratios in
[18F]FDG-PET and Left-Right Ratios in Hippocampal Volumetry and
in T2 Relaxometry in QMRI*
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[18F]FDG-PET and T2 Relaxometry
The left-right ratio and AI in [18F]FDG-PET and the left-right
ratio in HCT2 were significantly inversely related in all temporal
areas (Table 5). However, the
AI in any temporal area was not associated with ipsilateral HCT2
even when the relation in patients with abnormal hippocampal QMRI findings
was studied separately (data not shown).
COMPARISON OF [18F]FDG-PET AND HISTOPATHOLOGY
In no patients was the AI in either lateral temporal neocortical gyri
or the medial temporal lobe related significantly to any aspects of the histopathologically
verified HD: severity of neuronal loss, proliferation of glial cells, or sprouting
of mossy fiber (data not shown). In addition, AIs between patients with differing
severity of HD did not differ significantly in any of the temporal areas (Table 3).
OUTCOME OF SURGERY
The surgical outcome after at least a 1-year follow-up was evaluated
according to Engel.35 In patients with a preoperatively
assumed good outcome, 12 of 15 became seizure free (9 patients were totally
seizure free, class Ia, and 3 patients experienced auras only after surgery,
class Ib). One patient was initially seizure free but now has rare seizures
(class IIa, <3 seizures per year). The seizure reduction was worthwhile
(class IIIa, at least 80% seizure reduction) in 2 patients (patients 4 and
11). Patient 16 had no worthwhile seizure reduction (class IVa) (Table 4).
Because of the bilateral seizure onsets in patient 4, surgery was considered
to be palliative. The patient still benefited from surgery (class IIIa) (Table 4).
COMMENT
In this study, temporal hypometabolism even in the medial temporal lobe
was shown not to reflect the severity of HD verified by QMRI (volumetry and
T2 relaxometry) or histopathological analysis. However, [18F]FDG-PET
was lateralizing, even when hippocampal QMRI findings were normal or showed
only mild HD in patients with drug-resistant TLE.
All the earlier studies13, 18, 19
have relied solely on the reduced HCV in MRI to discover the relationship
between HD and temporal hypometabolism. However, reduced HCV is not the only
feature of HD, and normal volumetry does not rule out the possibility of histopathological
changes in the hippocampus,36 but the results
of HCT2 must also be taken into account. In this study, the AI
in the medial temporal lobe covering, for instance, the hippocampus or in
the lateral neocortical temporal gyri were not related either to ipsilateral
reduction in HCV or to prolongation in HCT2. In agreement with
the results of a previous study,13 this suggested
that HD would not be a determining factor for reduced glucose consumption.
The significant correlations between the left-right ratio and AI in [18F]FDG-PET and the left-right ratios in HCV and HCT2 merely
indicated that these methods were in agreement with lateralizing the side
of the epileptogenic region in most patients.13
However, because hippocampal QMRI might be normal even though a patient
had histopathological changes in the hippocampus, the relation between the
results of [18F]FDG-PET and the aspects of histopathologically
verified HD was also examined. The AI was unrelated to the severity of neuronal
loss, proliferation of glial cells, or sprouting of mossy fiber, even in the
medial temporal lobe. Moreover, the mean AIs in temporal areas did not differ
significantly in patients with significant differences in HD. Thus, it seemed
that even though the hippocampus was only mildly damaged, glucose consumption
was reduced over and above histopathological changes. Therefore, [18F]FDG-PET was considered to be insensitive to reflect the severity of
HD and, according to the general assumption, reflects only synaptic reorganization
and especially decreased synaptic activity in the whole epileptogenic zone.13, 16, 37, 38
The greatest utility of PET is in patients with normal or uncertain
findings in QMRI. In the present study, 31% of patients had normally defined
HCV or HCT2. However, [18F]FDG-PET lateralized the epileptogenic
zone in 60% of these patients when the generally applied cutoff threshold
(15%) in asymmetry was used, thus suggesting the usefulness of [18F]FDG-PET
in these patients. In addition, 4 patients with only mild changes in hippocampal
QMRI still showed clear reduction in glucose metabolism. An AI of more than
15% was chosen to avoid false-positive findings32
and to predict good surgical outcome.33 If
based solely on the results of our controls, a cutoff threshold of 10% was
used, 1 patient with normal hippocampal QMRI findings and visibly reduced
uptake of [18F]FDG would also have had a quantitatively significant
result.
There were some limitations to our study. The spatial resolution of
our PET camera did not allow detection of the hippocampus as well as a scanner
with better resolution would have done. The partial volume effect or spillover
activity of surrounding tissues might have affected the values of glucose
consumption, at least in the medial temporal lobe ipsilateral to the epileptic
hippocampus with reduced volume. In addition, the PET studies were oriented
in the orbitomeatal line, which might not be optimal for studying the medial
temporal lobe. Patients also had diverse etiologies and electroencephalographic
findings. However, the hippocampus was carefully analyzed after surgery. Because
2 patients with histopathologically moderate HD had normal hippocampal QMRI
findings, the question of the ability of QMRI to detect mild to moderate damage
is also raised.
Our study provides a detailed analysis of the presence and severity
of HD and its relationship to the degree of hypometabolism in patients with
TLE.
AUTHOR INFORMATION
Accepted for publication December 4, 2000.
This study was financially supported by the Finnish Neurological Association,
the Finnish Instrumentarium Foundation, the Turku University Foundation, the
Research Foundation of Orion Corporation (Espoo, Finland), and the Päivikki
and Sakari Sohlberg Foundation (Helsinki, Finland).
We are grateful to Prof Asla Pitkänen for data on the histopathological
analysis of resected tissue and to the staff of the Turku PET Centre for their
assistance.
From the Departments of Neurology (Drs Lamusuo and Rinne) and Neurophysiology
(Dr Jääskeläinen) and the Turku PET Centre, Radiopharmaceutical
Chemistry Laboratory (Dr Haaparanta) and PET Unit (Dr Rinne), University of
Turku, Turku, Finland; the Departments of Neurology (Drs Jutila, Ylinen, and
Kälviäinen), Neurophysiology (Dr Mervaala), and Radiology, MRI Unit
(Dr Partanen), Kuopio University Hospital, Kuopio, Finland; and the Departments
of Neuroscience and Neurology (Dr Ylinen) and Neurosurgery (Dr Vapalahti),
University of Kuopio.
Corresponding author and reprints: Juha Rinne, MD, PhD, Department
of Neurology, University of Turku, PO Box 52, FIN-20521 Turku, Finland (e-mail:
juha.rinne{at}pet.tyks.fi).
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