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Decreased hippocampal muscarinic cholinergic receptor binding measured by 123I-iododexetimide and single-photon emission computed tomography in epilepsy.

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Decreased Hippocampal
Muscarinic Cholinergic
Recemor Binding
MeaLred bv
Single-Photon Emission
Computed Tomography
in Epilepsy
antagonist atropine decreases the rate of such chemical
kindling [11. Concordantly, decreases in muscarinic
acetylcholine receptor (mAChR) have been demonstrated in or around the epileptogenic foci in animal
seizure models [2]. Ex vivo studies of temporal lobe
surgical specimens have also revealed a decrease in
mAChR number within the epileptogenic focus [3].
The present study addresses regional mAChR characteristics in vivo in patients with unilateral temporal lobe seizures using '231-iododexetimide ( L231-IDe~)
and single-photon emission computed tomography
(SPECT) [ S ] .
Hans W. Miiller-Gartner, MD," Helen S. Mayberg, MD,"
Robert S. Fisher, MD, PhD,t Ronald P. Lesser, MD,?
Alan A. Wilson, PhD," Hayden T. Ravert, PhD,"
Robert F. Dannals, PhD,' Henry N. Wagner, Jr, MD,"
Sumio Uematsu, MD,S and J. James Frost, MD, PhD,"§
Regional binding of '231-iododexetimide,a muscarinic
acetylcholine receptor antagonist, was measured in vivo
in the temporal lobes of 4 patients with complex partial
seizures using single-photon emission computed tomography. In the anterior hippocampus ipsilateral to the
electrical focus, 1231-iododexetimidebinding was decreased by 40 f 9% (mean f SD, p < 0.01) compared
with the contralateral hippocampus; '231-iododexetimide binding in other temporal lobe regions was symmetrical. The data indicate a regionally specific change
of muscarinic acetylcholine receptor in anterior hippocampus in complex partial seizures of temporal lobe origin.
Muller-Gktner HW, Mayberg HS, Fisher RS,
Lesser RP, Wilson AA, Ravert HT, Dannals RF,
Wagner HN Jr, Uematsu S, Frost JJ. Decreased
hippocampal muscarinic cholinergic receptor
binding measured by '231-iododexetimideand
single-photon emission computed tomography in
epilepsy. Ann Neurol 1993;34:235-238
The role of acetylcholine in the origination and propagation of electrical discharges in epilepsy is suggested
by several converging lines of evidence. Drugs that
enhance synaptic cholinergic transmission such as the
agonist carbachol or the cholinesterase inhibitor physostigmine induce epilepsy in animals; the cholinergic
From the Departments of *Radiology,Division of Nuclear Medicine,
?Neurology, *Neurosurgery, and $Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD.
Received Oct 29, 1992, and in revised form Mar 22, 1993. Accepted
for publication Mar 24, 1993.
Address correspondence to Dr Frost, Department of Radiology,
Room B1-130, The Johns Hopkins University School of Medicine,
600 North Wolfe Street, Baltimore, MD 21205.
mAChR and cerebral perfusion were measured on consecutive days using 1231-IDexand 33mTchexamethyl propyline
amine oxime (HMPAO), respectively, in 4 consecutive patients with unilateral partial complex epilepsy admitted for
presurgical evaluation of seizures. Five consecutive healthy
volunteers served as controls for each type of SPECT study
(mean age of lZ31-IDexcontrol group, 30.6
10.6 yr; perfusion control groups, 38.6 k 2.4 yr). All subjects provided
informed consent in compliance with the Joint Committee
on Clinical Investigation of the Johns Hopkins Medical Institutions.
Laterality of the seizure focus in patients was determined
by 24-hour-a-day video-scalp electroencephalography (EEG)
(n = 3) or, when EEG was nondiagnostic, by depth electrodes (n = 1). Mean patient age was 35
11 years (mean
t SD). Average illness duration in this group was 26 & 16
years with a mean frequency of 5 ? 2.6 seizures per month.
Patients were on antiepileptic medication during imaging
studies. None of the patients had a seizure within 2 days
before the first SPECT or during the 2-day scanning period.
A standardized protocol using published methods was used
to acquire and analyze magnetic resonance imaging (MRI),
perfusion, and mAChR images [4-8). To assess mAChR, a
four-detector rotating SPECT camera (Summit NuclcarHitachi, NeuroSPECT, Japan) was used for data acquisition.
Collimation was performed with a high-resolution collimator.
The in-plane resolution is 13.5 mm, the axial resolution 14
mm. Subjects were administered 5.5 to 6.8 mCi of '"I-IDex
as an intravenous bolus injection over 20 to 30 seconds. The
tomography was performed between 6 and 8 hours after
injection (matrix 64 x 64,64 frames, frame time 55 seconds,
360-degree rotation). The volume of the anterior hippocampus was measured using contiguous MRI slices. MRI scans
were acquired on a 1.5-T scanner (Signa, General Electric,
Milwaukee, WI). A spoiled grass (SPGR)pulse sequence (65,
5,45, 2; TR, TE, flip angle, NEX) was used in volume mode.
The field of view was 24 x 24 cm and the reconstruction
matrix 256 x 256 pixels, resulting in a final in-plane pixel
size of 0.94 x 0.94 mm. The number of slices was 32 or
64, the slice thickness 1.5 or 3 mm. The slices were parallel
to the long axis of the temporal lobe. The gray matteriwhite
mattericerebrospinal fluid segmentation procedure has been
previously described [9]. Results are expressed as ratios of
focus to nonfocus in patients and left-to-right ratios in controls.
Copyright 0 1993 by the American Neurological Association 235
Fig I . Morphology, muscarinic acetylcholine receptor binding,
and petfusion in temporal lobe in patient with left-sided temporal lobe epilepsy. (A) magnetic resonance imaging (AfRI) scan
showing normul temporal lobe morphology. A region of interest
template, each region measuring 7 x 7 mm, was drawn on the
MRI and transferred onto the coregistered single-photon emission
computed tomographic (SPECT) images for quantification. Regions were placed in the anterior hippocampus, amygdaka, and
temporal neocortex (three each anterior, middle. and posterior
temporal context). (B) Specz$c '"I-iododexetimide (1231-IDe~i
binding was measured 6 t o 7 hours after tracer injection 13).
Spec& binding was computed as (T - N ) / N , where T is the
mean pixel value in a given temporal region and N the mean
pixel values in cerebellum indicating nonspecz$c binding {3}. A
pronounced reduction in spec& l2jI-IDex binding in the anterior hippocampus ipsikateral to the electricalfocus is observed. A
slight circumscribed reduction in the middle temporal neocortex,
but no differencein other parts of the temporal lobe, was also
seen (NeuroSPECT, Summit Nuclear-Hitachi; in-plane resolution, 13.3 mm; z-axis resolution, 18 mm). (C) A slight reduction in cerebral perfusion in the anterior temporal neocortex and
left anterior hippocampus ipsilateral to the electrical focw compdred with the contralateral side was seen (NeuroSPECTi.
A representative example of the MRI, mAChR, and
perfusion findings is shown in Figure 1. MRI of the
temporal lobe is normal (Fig 1A). '231-IDexbinding in
the anterior hippocampus ipsilateral to the electrical
focus is markedly decreased (Fig lB), whereas hippocampal perfusion is only slightly reduced (Fig 1C).
Figure 2 summarizes the results of all subjects investigated. 12'I-IDex binding in anterior hippocampus ipsilateral to the electrical focus is reduced on average by
40% compared with the contralateral hippocampus
(Fig 2A). '231-IDexbinding in other temporal regions
is symmetrical. Perfusion in patients is significantly re-
236 Annals of Neurology Vol 34
No 2 August 1993
duced in hippocampus, amygdala, and anterior temporal lobe ipsilateral to the seizure focus (Fig 2B). The
magnitude of the reduction in hippocampal '231-IDex
binding is significantly greater than the corresponding
reduction in perfusion ( p < 0.01, analysis of variance).
Hippocampal volume ipsilateral to the electrical focus is not different from the contralateral hippocampal
volume (focus to nonfocus ratio = 1.01 k 0.03, n =
4). Hippocampal '*'I-IDex binding contralateral to the
electrical focus is normal: The ratio between 1231-IDex
binding in hippocampus and neocortical temporal lobe
is 0.91 k 0.1 in patients and does not differ from
corresponding ratios in controls (0.91 2 0.12 on the
left and 0.90 + 0.10 on the right side).
Individual clinical characteristics and hippocampal
12?I-IDexbinding are summarized in the Table. In the
current data set there is no indication for a correlation
between clinical characteristics such as age, seizure duration, seizure frequency, and hippocampal '231-IDex
binding. MRI data showed no abnormalities in any of
the 4 patients.
Reduction in regional perfusion ipsilateral to the electrical focus is a recognized feature of temporal lobe
epilepsy [lo), but reduced binding to mAChR in hippocampus is a new finding. Because the hippocampus
is often involved in the generation and propagation of
electrical discharges in temporal lobe epilepsy [111,
and because mAChR are thought to act as convulsive
ion channel modulators in neuronal membranes [123,
the finding may contribute to characterize biochemical
changes of neuronal synapses in partial. complex seizures.
1231-IDex binding
1 .o
1 .o
normal controls (n=5)
patients (n=4)
Fig 2. Regional ana(l1sis of 1231-iododexetimide(12-ibIDex)
binding and cerebrul perjkion in temporal lobe in patient with
partial complex temporal lobe epilepsy. Data are presented us
It$-to-right ratios for controls and as focus-to-nonfocus ratios in
patients. Data are given as the mean +. SD. Dafferences 1231IDex binding and regional pe$usion between patients and normals were tested using two-way analysis of oariance with one repeated measure and Duncan? mult@le rcrnge test for post hoc
comparisons. (a) I2-'I-IDexbinding in temporal lobe. Signzjkant
reduction (40%))in the anterior hippocampus ipsilateral t o the
seizuve farus. *'p < 0.01. Cb) Slight decrease in perjhion in all
regions of the temporal lobe ipsilutercrl t o the electricalfocus
when compared with n o m l controls. *p < 0.03.
The decrease in hippocampal '*'I-IDex binding is
thought to truly reflect reduced tracer binding to
mAChR per unit volume of hippocampus. It is not
an apparent decrease due to partial volume averaging
because the hippocampal volumes were identical on
both sides and because perfusion as measured directly
by """Tc-HMPAO was only minimally asymmetrical.
Asymmetry in entire hippocampal volumes has been
described in temporal lobe epilepsy 1131, yet was not
observed in the anterior part of the hippocampus in the
present 4 patients by using a similar MRI technique.
Similarly, the decrease in 1231-IDexbinding is unlikely to be an artifact of reduced tracer delivery to
mAChR because perfusion in hippocampus was only
minimally reduced, because there was no correlation
between perfusion and '231-IDexbinding in other regions of the temporal neocortex, and because we have
previously validated that '*'I-IDex binding reflects the
number or affinity of mAChR and is tracer transport
independent 15}.
There are four possible interpretations of reduced
li31-IDex binding demonstrated in these 4 patients.
Reduced 1231-IDexbinding to mAChR may be due to
an increase of endogenous acetylcholine competing
with '''I-IDex in binding to mAChR that are normal
in number and affinity. Because mAChR stimulation
in central mammalian neurons invokes the closure of
potassium channels 1127, which maintain the negative
resting potential of a cell and repolarize the membrane
after an action potential, an acetylcholine-induced closure of potassium channels could initiate a depolarization or retard the termination of a depolarization and
might thus contribute to the initiation or propagation
of seizures. Alternatively, reduced '231-IDex binding
may reflect mAChR downregulation in response to an
increase in endogenous acetylcholine, similar to that
shown in rats after chronic inhibition of acetylcholinesterase by diisopropylfluorophosphate 1141. Reduced
mAChR binding may also reflect loss of neurons expressing mAChR. These three alternatives cannot be
distinguished by using currently available in vivo imaging methods and need direct measurements of endogenous acetylcholine concentration, number, and affinity of mAChR in surgically resected hippocampal
tissue specimens. Alternatively, changes in mAChR
may be transient after seizure activity 121 and longitudinal in vivo studies in patients after known seizures
would be adequate to test this possibility.
We thank A. W KLmLall, PhD, for statistical consulcation, B. Cysyk,
RN, BSN, for pauent preparation, and J Khine, CNMT, for assistance in SPECT scan acquisition
This study was supported in part by U.S Public Health Service grant
CA-32845 and the Deucsche Forschungsgemeinschaft (Mu 735/2-2,
Brief Communication: Miiller-Gktner et al: Hippocampal Cholinergic Receptors in Epilepsy 237
Clinical Characteristicsand Decreuse in '2'I-lododexetimide (12'1-IDex)Binding in Anterior Hippocumpus lpsiluterul t o the Seizure
Focus in Percentage of the Contralateral Hippocampus 1231-IDexBinding in Patients with Complex Pavtiul Seizures
Age (yr)
Duration (yr)
per Month
Results of EEG
CPS: Lt Ant Temp
(7 Sz) Intcrictal: Lt
T e m p , Max T3,
Decrease in
Hippocampus '"I-IDex
Binding in %
Subdural: Lt Antmidbasal T e m p
CPS: Lt Ant T e m p
(12113 Sz; o n e
Interictal: Lt
Temp, max SP1
CPS: Rt T e m p ,
max SP2 (3 Sz)
Interictal: R t Ant
Temp max SP2;
less frequently,
Lt A n t T e m p
SPS: Lt Ant Temp
(12/20 SZ)
Interictal: 2 sharp
waves, SP2
EEG = electroencephalography, CPS = complex partial seizures, Lt = left, Ant = anterior, Temp = temporal, Sz = seizure, max =
maximum, SP1 and SP2 = left and right sphenoidal leads, Rt = right, SPS = simple partial seizures, f l 7 and € T 9 are in the left adterobasal
temporal regon using the terminology of the 10% system (American Electroen~ephalographicSociety Guidelines for Standard Electrode
Position Nomenclature J Chn Neurophysiol 1991,8 200-202)
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tomography, measures, epilepsy, decrease, hippocampus, single, emissions, photo, 123i, iododexetimide, muscarinic, receptov, binding, computer, cholinergic
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