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Ictal Fear in Temporal Lobe Epilepsy
Surgical Outcome and Focal Hippocampal Changes Revealed by Proton Magnetic Resonance Spectroscopy Imaging
Michael Feichtinger, MD;
Elisabeth Pauli, PhD;
Iris Schäfer;
Knut W. Eberhardt, MD;
Bernd Tomandl, MD;
Johannes Huk, MD;
Hermann Stefan, MD
Arch Neurol. 2001;58:771-777.
ABSTRACT
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Background Ictal fear (IF) is most frequently associated with epileptic discharges
from mesial temporal areas.
Objectives To determine whether patients with IF were more likely to become seizure
free after anteromesial temporal lobe resection compared with those without
IF and whether they show more anteriorly pronounced metabolic changes assessed
by means of multivoxel magnetic resonance spectroscopy (MRS) along the hippocampal
axis.
Methods Surgical outcome was assessed in 33 consecutive patients with temporal
lobe epilepsy after a mean follow-up of 25 months (range, 12-38 months). Proton
multivoxel MRS of the hippocampal formation was applied to detect regional
differences along the axis of the hippocampus in patients with and without
IF. Magnetic resonance tomography showed typical features of hippocampal sclerosis
in all patients.
Results Twelve (36%) of the 33 patients reported fear at the beginning of their
habitual seizures. Eleven of these patients were seizure free postoperatively.
In contrast, only 11 of 21 patients without IF had a favorable outcome. Results
of MRS revealed significantly higher pathologic N-acetylaspartate–choline
ratios in the anterior portion of the hippocampal formation in patients with
than in those without IF, indicating focal metabolic and/or morphologic changes
in the head of the hippocampus.
Conclusions These results indicate the importance of diagnosing auras with IF to
provide a more detailed prognosis of the surgical outcome. In addition, our
data emphasize that multivoxel MRS is a valuable tool in the presurgical evaluation,
as it may reveal different topographical patterns of hippocampal sclerosis.
INTRODUCTION
FEAR IS AMONG the most common experiential phenomena elicited by temporal
lobe epileptic discharge.1, 2, 3, 4, 5, 6, 7
The leading role of the amygdala, as well as that of the hippocampus and the
parahippocampal gyrus, in the mechanisms of inducing a fearful perception
is well established by studies of electrical stimulation performed intraoperatively8 or during presurgical evaluation using intracranial
depth electrodes.2, 9, 10, 11, 12
Surgical resection of the temporal lobe became a widely accepted therapeutic
approach to control complex partial seizures.13
In patients with fear as an initial manifestation of their epileptic seizures
(IF patients), ictal discharges were reported to originate from the amygdala,
the hippocampus, or its near vicinity,2, 14
ie, regions that are removed by temporal lobectomy. We therefore investigated
whether the presence of IF may predict a favorable outcome of surgical therapy.
Proton (1H) magnetic resonance spectra obtained by magnetic
resonance spectroscopic imaging (MRSI) provide detailed information about
metabolic changes of the mesial temporal region using signals from N-acetylaspartate (NAA)-, choline (Cho)-, and creatine (Cr)-containing
compounds.15, 16, 17, 18, 19, 20
Because NAA is primarily located in mature neurons, a reduced NAA signal is
generally interpreted as neuronal loss or dysfunction.21, 22, 23
Concentrations of Cho and Cr are reported to be higher in the glia22, 23; thus, a decrease of levels of Cho
and, to a lesser extent, Cr24 may indicate
astrocytosis. Unilateral changes (a reduced NAA/Cho ratio) have been shown
to be of value for preoperative focus localization in epilepsy surgery.16, 17, 20, 24, 25
Because atrophy of the amygdala and the hippocampus correlates with
the presence of IF,26 analysis of these structures
by means of MRS could confirm the involvement of these regions in the perception
of IF. Unfortunately, MRS of the amygdala is not applicable because of its
small size, its difficult differentiation to adjacent structures,27, 28 and the interference of neighboring
cerebral and extracerebral tissue.29 Thus,
we focused on the hippocampal formation. Since sclerosis of amygdala and hippocampus
was observed more often in IF patients,26 we
hypothesized that in these patients, neuronal loss and astrogliosis could
be more pronounced in the head of the hippocampus. In other words, MRSI analysis
aimed to detect regional differences in hippocampal metabolism.
PATIENTS AND METHODS
PATIENTS
We included 33 consecutive patients with unilateral medically intractable
temporal lobe epilepsy (TLE) (19 male and 14 female) considered for surgical
treatment at the Epilepsy Center of the Department of Neurology, University
Erlangen–Nuremberg, Erlangen, Germany. The mean age was 34 years (range,
20-48 years). The epileptogenic temporal lobe was identified by means of a
comprehensive evaluation, including a detailed history and neurologic examination,
prolonged electroencephalographic and video monitoring with scalp and sphenoidal
electrodes for ictal analysis, neuropsychological assessment, and MRI. In
5 patients, electrodes for recording intracranially ictal activity were implanted.
Only patients with distinct unilateral focus within the temporal lobe
were scheduled for epilepsy surgery. These patients were also included in
the current study, since they fulfilled the following inclusion criteria:
(1) typical seizure symptoms for TLE, (2) all seizures arising from a single
temporal lobe, and (3) typical findings of mesial temporal sclerosis on MRI
(ie, atrophy and/or decreased signal on T1- and/or increased signal on T2-weighted
images of the hippocampus and/or amygdala). Thus, these patients represented
a homogeneous group of good candidates for temporal lobectomy. This homogeneity
is crucial for determination of whether IF is a prognostic variable independent
from already established predicting factors.
SURGICAL PROCEDURE
All 33 patients underwent anteromesial temporal resection performed
by the same neurosurgeon. All patients received at least a selective amygdalohippocampectomy,
including the parahippocampal gyrus. Additional neocortical resection was
individually tailored, guided by intraoperative electrocorticography to keep
resected brain volume restricted to epileptogenic tissue.30
The mean extent of the resected hippocampus was 24 mm (range, 16-40 mm).
Postoperative seizure control outcome was assessed 3 and 6 months and
each year after the operation, using the classification according to Engel.13 Only patients with a follow-up of at least 12 months
were included in the study. For further statistical analysis, outcome was
divided into a seizure-free group (Engel class 1) and a non–seizure-free
group (Engel classes 2-4).
PATHOLOGICAL FINDINGS
All available brain specimens were prepared and stained for histopathological
examination performed by a pathologist blinded to the results of MRSI. Hippocampal sclerosis (HS) was defined as neuronal loss
and marked proliferation of astrocytes involving the hippocampus, preferentially
the sectors CA1 and CA3/4. In 3 cases, hippocampal sections did not allow
a proper diagnosis of an HS owing to fragmentation of the specimen. Histopathological
analysis of the amygdala was not available.
CHARACTERIZATION AND CLASSIFICATION OF IF AND AURAS
Assessment of the presence of IF included a detailed review of available
medical records and an accurate inquiry about the type of auras. A standardized
interview was used, including the assessment of fear and fear-related emotional,
cognitive, and autonomous signs as part of an aura or in the course of a habitual
seizure. Care was taken to avoid suggestive questioning. For further investigation,
the term ictal fear was accepted only (1) if it was
reported as being concomitant with an epileptic seizure; (2) if it arose spontaneously,
out of context; and (3) if it could be clearly distinguished from the fear
of a seizure. Type and presence of any other sensations or phenomena associated
with seizures were assessed in a similar manner.
ROUTINE MRI
Routine MRI examinations were performed on a 1.5-T whole-body MR system
(Siemens Magnetom Vision; Siemens, Erlangen, Germany) according to a standard
protocol, including transversal and coronal T2-weighted targeted systemic
exposure, coronal fluid-attenuated inversion recovery, coronal T1-weighted
3-dimensional–magnetization-prepared rapid acquisition gradient echo,
and coronal inversion recovery. Atrophy of the hippocampus and/or amygdala
seen by means of visual inspection and/or as hyperintensity inside the hippocampus
on T2-weighted images was taken as criterion for mesial temporal sclerosis.
MULTIVOXEL 1H-MRSI
During presurgical evaluation, 27 patients underwent multivoxel 1H-MRSI of the hippocampal formation after written informed consent
was obtained.
We acquired MRSI using a 1.5-T whole-body MR system (Siemens Magnetom
Vision). To establish normative data, an additional 30 healthy volunteers
(17 male and 13 female subjects; age range, 16-47 years; mean age, 31 years)
underwent MRSI examinations.
Acquisition of MR spectra was performed using a 2-dimensional (2-D)
hybrid chemical shift imaging (CSI) technique. Three orthogonal slice-selective
high-frequency pulses were applied for preselection of a region of excitation,
avoiding the intensive signal of subcutaneous fat. Phase encoding (16 x
16 matrix) was used for in-plane spatial resolution and chemical shift-selective
gaussian pulses for water suppression. To optimize the homogeneity of the
magnetic field, an automatic multiangle-projection shim was applied.
A series of orthogonal T1-weighted images for localization were obtained,
with the transaxial plane approximately parallel to the long axis of the hippocampus.
The preselected region of excitation was positioned on 3 orthogonal base images
in the left and right temporal lobe. The volume of interest was chosen, including
a column of 3 voxels (voxels 1-3) in the transversal plane placed in the hippocampal
formation. As shown in Figure 1, this column was chosen to obtain data mainly from the hippocampus with little
or no interference from adjacent regions. The position was carefully checked
and meticulously adjusted in all 3 orthogonal sections to ensure identical
placement in all subjects. After interactive volume-selective shimming and
water suppression (frequency-selective 90° Gauss pulse), a 2-D 1H CSI spin-echo protocol was selected (acquisition variables: repetition
time, 1500 milliseconds; echo time, 135 milliseconds; field of view, 200 mm2; matrix, 16 x 16). The nominal resultant size of individual
voxels was 1.2 x 1.2 cm in the sagittal and coronal planes and 1.5 cm
in the transversal plane (2.16 cm3). The acquisition time for each
hippocampus was 6 minutes 31 seconds. The total time required for MRS measurement
was about 45 minutes.
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Figure 1. A, Proton magnetic resonance spectroscopic
imaging (1H-MRSI) regions of interest in patient 2 with ictal fear
and an epileptic focus within the right mesiotemporal region. Transversal
T1-weighted MRI scan with the original phase-encoding grid superimposed is
seen. The volume of interest was outlined (black line). Spectra of voxels
1 to 3 (v1, v2, and v3) placed exactly in the hippocampal formation are displayed.
In the 2 anterior voxels (v1 and v2), the peak level of N-acetylaspartate (NAA) is clearly reduced compared with that of choline
(Cho), leading to a lower NAA/Cho ratio. This indicates focal accentuated
neuronal loss (or dysfunction) and/or reactive gliosis in the anterior portion
of the hippocampus. B, Demonstration of a normal vs a pathologic spectrum.
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MRS DATA PROCESSING
The CSI raw data were evaluated using a standard automatic CSI postprocessing
program (Siemens Magnetom Vision). Spectra were displayed on transversal T1-weighted
MRI scans with an overlaid grid indicating the anatomic location from where
the data were derived. The postprocessing protocol used k-space filtering, 2-D fast Fourier transformation to real space, gaussian
filtering of the time-domain data in each voxel, fast Fourier transformation
to the frequency domain, baseline and phase correction, and curve fitting
for the peaks of NAA and Cho. The ratios of the fitted peak integrals for
NAA and Cho were evaluated and integration of the Cr peak was omitted. Although
many studies included Cr for assessment, we preferred the NAA/Cho ratio, as
this ratio is reported to be highly reliable in detecting HS in TLE.16, 20, 24 Spectra of poor quality
were excluded from the analyses, for instance, when Cr and Cho peaks were
not resolved.
The NAA/Cho ratios of each voxel were compared with the average ratio
of the corresponding, homotopically located voxel in the control subjects.
Pathologic voxel values (PX patient) in patients were defined as differences between the patient's NAA/Cho
ratio (R) of the specific voxel (X =
1-3) and the 2-SD threshold of the corresponding voxel (X = 1-3) in controls,20, 31
as seen in the following equation:
where M indicates the mean voxel value of the
controls.
Deviation from the healthy controls is more pronounced as the negative
pathologic value (PX patient)
increases. The value 0 was assigned when no abnormality was found.
A CSI score representing the mean pathologic values of voxels 1, 2,
and 3 (v1, v2, and v3) was calculated using the following equation20, 31, 32:
To determine ipsilateral, contralateral, and bilateral abnormalities,
we computed the laterality ratio (r) using the following
equation:
where ipsi and contra
refer to the ipsilateral and contralateral sides of resection. Thus, a CSI
laterality ratio of r = 1 reflects ipsilateral CSI
changes, and a ratio of r = -1 reflects exclusively
contralateral CSI changes. A ratio of r = 0 corresponds
to bilateral CSI changes but would also be seen in cases of no abnormality.
For practical reasons, results were classified as strictly ipsilateral (0.25
< r  1), strictly contralateral (-0.25
> r  -1), and bilateral (-0.25 < r < 0.25).
To evaluate whether anterior parts of the hippocampus (predominantly
the head) show metabolic changes different from those of the posterior parts,
separate comparison of single-voxel data (Pv1, Pv2, and Pv3) in patients with and without IF was performed. To assess
the prevalence of different distribution patterns, we used the following equation
to compute difference score (Iap) of the
pathologic values of the anterior (Pv1
and Pv2) and posterior voxels
(Pv3):
STATISTICAL ANALYSIS
Statistical analysis was performed using commercially available software
(SPSS E 8.0 for Windows 95; SPSS Inc, Chicago, Ill). Inference statistical
decisions were based on a significance level of  .05.
We performed  2 tests (Fisher exact test) to evaluate
the relation between the presence or absence of IF with seizure outcome and
the prevalence of different spectroscopic results.
For evaluation of the severity of abnormality ipsilateral to the side
undergoing operation in IF and non-IF patients, 1-way analysis of variance
(ANOVA) with IF as between-subject factor was computed separately for the
following dependent variables: CSI score; pathologic values of voxels 1, 2,
and 3; and the NAA/Cho ratio of voxels 1, 2, and 3.
RESULTS
Twelve patients (36%) reported fear as an initial manifestation of their
habitual seizures. Five of these patients described an accompanying epigastric
sensation; 2 patients, a cephalic aura; and 3 patients, fear as a single phenomenon.
The remaining symptoms included déja vu and autonomous signs in 1 case
each. Between IF and non-IF patients, there was no difference in age at operation,
duration of epilepsy, or age at onset of epilepsy. The extent of resected
hippocampus did not differ between patient groups. There was no significant
difference between IF and non-IF patients with regard to results of histopathological
examination (ie, presence or absence of HS).
IF AND OUTCOME
Postoperative outcome assessment was possible in all 33 patients (average
postoperative period, 25 months [range, 12-38 months]). According to the Engel
classification, 22 patients became seizure free (Engel class 1), 8 patients
had rare disabling seizures (Engel class 2), 1 patient had an improvement
in seizure frequency of greater than 80% (Engel class 3), and 2 patients reported
no improvement (Engel class 4).
Eleven of 12 IF patients had an excellent outcome, whereas only 11 of
21 non-IF patients were classified as seizure free (Engel class 1) (2-sided
Fisher exact test, P = .03) (Figure 2). No other aura showed a clear relation to postoperative
outcome.
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Figure 2. Relationship between ictal fear
(IF) and seizure outcome.
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PATHOLOGIC CSI SCORES AND THEIR RELATION TO HS AND IF
In 24 patients, comparison of ipsilateral CSI scores with the histopathological
diagnosis of an HS was possible. Pathologic CSI scores were measured in 10
(59%) of 17 cases with histologically proven HS; normal CSI scores were found
in 6 of 7 patients without HS. Two of 3 cases with insufficient specimen for
histological analysis also showed pathologic CSI scores ipsilaterally.
Concerning the frequency of bilateral or contralateral CSI score changes,
no significant difference could be found between the IF and the non-IF patient
groups.
IPSILATERAL NAA/Cho RATIOS AND IF
Separate comparison of the ipsilateral NAA/Cho ratio in voxels 1, 2,
and 3 revealed marked differences between IF and non-IF patients; results
of 1-way ANOVA showed significantly lower ratios in the anterior part of the
hippocampus (voxels 1 and 2) in IF patients (voxel 1, F1,25 = 4.78
[P = .04]; voxel 2, F1,26 = 9.29 [P = .005]) (Figure 3
and Table 1).
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Figure 3. Box and whisker plot of the N-acetylaspartate–choline (NAA/Cho) ratio of each
voxel (v1, v2, and v3) in patients with and without ictal fear (IF) compared
with healthy control subjects. White boxes represent the 1-SD range; the whiskers,
the 2-SD range of NAA/Cho ratios of controls. The black line is positioned
at the median. Shaded boxes extend from the 25th to the 75th percentile with
a horizontal black line at the median in the IF and non-IF patient groups.
The whiskers represent the range of the data; small black squares, extremes.
Lower NAA/Cho ratios in voxels 1 and 2 are seen in the IF group compared with
the non-IF group, reflecting a higher degree of neuron loss and/or reactive
gliosis in the anterior part of the hippocampus of these patients.
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Table 1. NAA/Cho Ratio, Pathologic Values for Voxels, and CSI Score
in Relation to Ictal Fear*
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IPSILATERAL PATHOLOGIC CSI VALUES AND IF
A similar relation was found when ipsilateral pathologic values for
each voxel (Pv1, Pv2, and Pv3) were compared between
groups (voxel 1, F1,25 = 5.93 [P = .02];
voxel 2, F1,26 = 14.98 [P = .001]) (Table 1). Pathologic values of voxel 3
did not differ significantly between IF and non-IF patients.
The mean pathologic value of all 3 voxels (CSI score) also showed significantly
lower scores (ie, more abnormal compared with the controls' 2-SD threshold)
in IF patients compared with non-IF patients (1-way ANOVA, F1,26
= 5.41 [P = .03]) (Table 1).
In all 6 IF patients with a pathologic CSI score, changes in the anterior
hippocampus (Iap < 0) were more pronounced,
whereas in 6 of 7 non-IF patients, abnormality was predominantly located posteriorly
(Iap > 0). One non-IF patient had higher pathologic values in the
anterior hippocampus (2-sided Fisher exact test, P
= .005) (Table 2).
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Table 2. Frequencies of Different Distribution Patterns in Patients
With and Without Ictal Fear*
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COMMENT
There is no doubt that the mesial temporal regions and especially the
amygdala play a pivotal role in the mediation of fearful emotion. This is
supported by numerous studies on the production of fear by electrical stimulation
of the amygdala.2, 3, 11
Stimulation of the hippocampus and the parahippocampal gyrus produced fear
less often.2, 12 However, this
research indicates that these structures are involved in the mediation of
fear, at least under certain circumstances.
We hypothesized that the presence of IF could be related to a satisfying
seizure outcome after surgical treatment, when resections include the amygdala,
the hippocampus, and the parahippocampal gyrus. Our study confirmed this hypothesis
in demonstrating a close relation between favorable postoperative seizure
control and the presence of IF. This was not seen for any other aura. Previous
studies33, 34 have addressed the
prognostic significance of the type of aura concerning postoperative seizure
control and could not find any aura to be of predictive value. This discrepancy
might be explained by differences in patient selection criteria,34
classification of aura types,33 or assessment
of IF. The term ictal fear should be used exclusively
for a sudden, often short, fearful affect at the beginning of or during an
epileptic seizure, without context or any relation to a precedent causal perception
or cognition. The intensity may vary from a slight trace of anxiety to a feeling
of intense terror.27 The predominance of other
auras or anterograde amnesia may reduce subjective awareness of fear in some
individuals. Thus, only a direct and standardized questioning, as performed
in our study, enables the most reliable assessment of IF.
Another interesting relation to the presence of IF could be detected
when we analyzed 1H-MRS data of the ipsilateral hippocampus (related
to the side that underwent operation). The IF patients had significantly higher
pathologic values in the anterior 2 voxels (voxels 1 and 2). These results
indicate different distribution patterns concerning the degree of neuronal
loss (or dysfunction) and reactive astrogliosis along the hippocampal axis
in IF and non-IF patients. On the basis of postmortem35
or postoperative36, 37 histopathological
examination, topographical differences of neuronal loss within the hippocampus
have been described repeatedly. When qualitative and volumetric MRI techniques
were applied for differentiation between focal and diffuse HS, contradicting
results were reported. Several studies38, 39, 40
described a focal accentuated atrophy in the anterior portion of the hippocampus
in most of their patients. However, 2 studies41, 42
reported diffuse atrophy to be the most frequent HS variant. Actually, it
is controversial whether a different distribution of sclerotic changes bears
any significance for seizure outcome. Kim et al41
suggested that distinction of focal and diffuse abnormality did not appear
to be essential for predicting postoperative seizure control. In contrast,
Babb et al36, 37 classified the
following 2 patterns of HS with implications concerning surgical outcome:
a diffuse pattern (ie, equally distributed neuronal loss in the hippocampal
head and body) with less favorable surgical outcome, and a focal pattern (neuronal
loss predominantly in the head of the hippocampus).
The present study confirms the latter observation and stresses the value
of the assessment of different distribution patterns. That IF is related to
focal anterior abnormality is important, as the resected brain volume should
be restricted to epileptogenic tissue. Moreover, the extent of resection influences
the degree of postoperative neuropsychological dysfunction.43, 44
Previous studies assessing the value of MRS in TLE have paid little
attention to the detection of different regional distribution patterns along
the hippocampal axis. Vermathen et al45 reported
a strong anterior-posterior difference within the hippocampus in patients
with epilepsy and in healthy individuals using multivoxel 1H-MRSI.
Similar observations were made by Hsu et al.32
When analyzing our control data, we could also observe an anterior-posterior
gradient with a higher NAA/Cho ratio in the posteriorly located voxels. We
took this into account when we calculated the pathologic voxel values.
Because the total volume of all 3 selected voxels is somewhat larger
(>6.48 cm3) than the estimated volume of the hippocampus (approximately
4 cm3), a certain influence of adjacent tissue could not be prevented.
This may be particularly true in cases with atrophied hippocampus. To assess
whether this volume loss influences MRS data, further correlation studies
between MRSI and volumetric measurements along the hippocampal axis are needed.
In our patient population, atrophy (assessed by means of visual inspection)
was not related to a higher prevalence of pathologic MRSI spectra.
When looking for differences along the hippocampal axis in IF patients,
we assumed the anterior voxel (voxel 1) would show the highest pathologic
values because of its close vicinity to the amygdala. Indeed, our results
demonstrate a significant relation of anterior abnormality in the IF patients,
which allows speculations about a concomitant sclerosis of the amygdala. The
fact that voxels 1 and 2 are similarly associated with IF argues for higher
involvement of the anterior hippocampal portion in the mechanisms of fear
than previously presumed. Interestingly, Miller et al46
found IF in a higher percentage when amygdala and hippocampus were both sclerotic
compared with sole sclerosis of amygdala. Actually, several authors estimated
sclerosis of the amygdala to be combined with HS in up to 60% of patients.28, 47, 48, 49, 50
To confirm our findings, future studies concerning the correlation between
amygdala volume and spectroscopic findings of the hippocampus and studies
on higher numbers of patients (to rule out possible sample bias due to small
patient number) are currently planned.
CONCLUSIONS
Our study supports the concept that IF is related to a measurable abnormality
within the anterior mesial temporal regions. It underlines the role of the
hippocampus in the presence of this affective ictal state and emphasizes the
importance of MRS for detecting different topographical patterns of HS. Our
observation that IF patients represent a population with favorable seizure
relief after anteromesial lobectomy may be clinically significant when planning
surgical therapy and when counseling patients with TLE.
AUTHOR INFORMATION
Accepted for publication October 4, 2000.
From the Department of Neurology, University Erlangen–Nuremberg,
Erlangen, Germany.
Corresponding author and reprints: Hermann Stefan, MD, Department
of Neurology, University Erlangen–Nuremberg, Schwabachanlage 6, D-91054
Erlangen, Germany (e-mail: hermann.stefan{at}neuro.med.uni-erlangen.de).
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