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Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathy.

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Clinical and Imaging
Evidence of Zolpidem Effect
in Hypoxic Encephalopathy
Christine Brefel-Courbon, MD,1–3 Pierre Payoux, MD,3
Fabierine Ory, MD,2 Agnes Sommet, MD,1
Tarik Slaoui, MD,2 Gaelle Raboyeau, PhD,3
Beatrice Lemesle, MA,2 Michele Puel, MD,2,3
Jean-Louis Montastruc, MD,1
Jean-Francois Demonet, PhD,3
and Dominique Cardebat, PhD3‡
We conducted a randomized, double-blind, placebocontrolled, single-patient (N ⫽ 1) trial to evaluate the efficacy of zolpidem in a 48-year-old woman with an akinetic
mutism. Motor and cognitive examinations and functional
imaging were performed. Acute administration of zolpidem
markedly improved motor performance and neuropsychological status. Cerebral metabolism (18F-fluorodeoxyglucose
positron emission tomography) increased in postrolandic territories and in frontal cortex. Using the H215O positron
emission tomography, we found a drug-induced activation in
the anterior cingulate and orbitofrontal cortices. Zolpidem
induced a transient improvement in motor and cognitive
performances. This paradoxical effect could result from an
activation of limbic loops modulating motivational processes.
Ann Neurol 2007;62:102–105
We studied the case of a 48-year-old woman who developed an akinetic mutism related to a postanoxic encephalopathy a few days after a suicide attempt (hanging). Her clinical presentation was typical with severe
reduction of motor and verbal spontaneous behavior.
The patient was unable to communicate, although
comprehension was spared. She was totally dependent,
unable to walk, and fed with a gastrostomy. She had
minimal weakness of all four limbs with hyperreflexia,
ankle clonus, and bilateral extensor plantar response.
Sensory function appeared not to be impaired. Mag-
From the 1Department of Pharmacology and Centre Midi-Pyrenees
de Pharmacovigilance, de Pharmacoepidemiologie et d’Informations
sur le Medicament, Faculty of Medecine, University Toulouse; 2Department of Neurology, Toulouse University Hospital; and 3Institut
National de la Sante et de la Recherche Médicale U825, Toulouse
University Hospital, Toulouse, France.
‡Dr D. Cardebat is deceased.
Received Dec 5, 2006, and in revised form Jan 16, 2007. Accepted
for publication Feb 2, 2007.
Published online Mar 13, 2007, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21110
Address correspondence to Dr Brefel-Courbon, Department of
Pharmacology, Faculty of Medicine, 37 allées jules Guesde, 31000
Toulouse, France. E-mail: brefel@cict.fr
102
netic resonance imaging did not show abnormalities,
and electroencephalographic recordings did not demonstrate any epileptic discharges.
Two years after her suicide attempt, nocturnal insomnia was observed and the patient was administered
10mg zolpidem in addition to her usual treatment.
Twenty minutes later, her family noticed surprising
signs of enhanced arousal. She became able to communicate to her family, to eat without deglutition troubles, and to move alone in her bed. These effects
started 20 minutes after drug administration and lasted
for 2 to 3 hours. The different drugs (piribedil 50mg,
fluoxetine 20mg, baclofen 10mg, omeprazole 20mg,
dihydroergotoxine mesylate 4.5mg, fluindione 20mg,
and meprobamate 200mg by day) were progressively
stopped and reintroduced to identify which of them
was responsible for these unexpected effects. No
change occurred after withdrawing any of these drugs.
It was only after administration of zolpidem that positive effect on arousal was observed. This drug was
then used every time that a better attention was expected. This phenomenon was so reproducible that
caregivers used to give the patient up to three tablets
each day without sleepiness as “side effect.”
To investigate this surprising effect on objective
bases, we systematically assessed the influence of zolpidem on motor and cognitive functions and explored its
effect on cerebral activity using positron emission tomography (PET).
Methods
We conducted a single-patient (N ⫽ 1) crossover trial that
was randomized, placebo controlled, and double blind. The
caregiver (husband) of this patient gave written informed
consent.
The schedule consisted of six modules of either drug or
placebo separated by an interval of 24 hours. During each
module, the patient received an acute administration of zolpidem (20mg) or placebo through her gastrostomy catheter.
In the first two modules (clinical modules) (one placebo
and one zolpidem), at baseline and 30 minutes after drug
administration, the same blinded clinician applied the following: for motor tests: Finger Tapping (30 seconds), NineHole Peg test and Walking (10m); and for language tests:
spontaneous speech, repetition (words and sentences), word
reading, comprehension (picture-matching task with words
and sentences) and object naming. For the latter task, object
pictures were presented every 10 seconds; should the patient
fail to name items, the examiner named it aloud and the
patient was encouraged to repeat that word. In the other
modules (four imaging modules), the patient underwent two
brain imaging studies, a brain metabolism measurement using the 18-fluorodeoxyglucose PET (FDG-PET) method,
and a cognitive activation study using the H215O PET
method, performed on EXACT HR⫹ PET camera (CTI,
Siemens CTI, Knoxville, TN).
For brain metabolism measurement, the subject was
scanned 30 minutes after injection of 300MBq 18FDG in
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Table. Motor and Language Assessments
Repetition
Reading Comprehension Naming/
Drug
Finger Nine-Hole Walking: Spontaneous
Repetition
speech
Words
Therapy Tapping: Peg Test
10m
Object
/3
30
(sec)a
(sec)
Word Sentence
Word Sentence
Names/30
Seconds
/5
/3
/28
/3
(number)a
Baseline 16
Placebo
19
Zolpidem 94
49
45
30
Unable
Unable
42
None
0
None
0
The patient 5
spoke on
stimulation
0
0
3
0
0
3
25
25
25
1
1
3
0
0
10
a
For Finger Tapping test, the patient’s score was expressed as the sum of the dominant and nondominant hands. The Nine-Hole Peg
test concerned only the dominant hand.
“resting state,” performed with either placebo or zolpidem
treatment.
The same blind zolpidem versus placebo scheme was applied in two sessions of the H215O PET activation study. In
each session, the subject received four injections of 300MBq
H215O to measure regional cerebral blood flow (rCBF) during two conditions: (1) “activation state,” the language examiner (D.C.) applied the same object naming/repetition test
as described earlier; and (2) “resting state” involving neither
external stimulation nor specific response from the patient.
The two conditions were alternated from scan to scan, and
each scan lasted 2 minutes with an 8-minute gap.
Placebo and zolpidem FDG-PET metabolic measurements
were compared using Neurogam (Segami Corporation, Columbia, MD). H215O PET activation data analysis was performed using Statistical Parametric Mapping 2 (SPM2).1
Global differences in rCBF between resting and activation
states for both placebo and zolpidem were covaried out for
all voxels, and comparisons across conditions were made using t statistics and then converted to Z-scores. Only regions
that exceeded a threshold of p less than 0.001 uncorrected
were considered significant.
Results
Clinical Performances
Zolpidem (20mg) markedly improved motor performance (Table). The patient was able to stand up and
to walk.
At baseline and after placebo, a complete mutism coexisted with relative sparing of auditory and visual
comprehension for single words. After zolpidem administration, although spontaneous language remained
absent, this patient was able to repeat aloud single
words and sentences, to read words, and to name
and/or repeat object names.
Imaging Studies
After placebo intake, FDG-PET showed a decrease of
brain metabolism in large, bilateral rostral/subcortical
territories, especially in the medial and lateral frontal
cortex and the thalamic areas. With zolpidem therapy,
cerebral metabolism increased mainly in postrolandic
territories (by 30%), as well as in limited portions of
the lateral frontal cortex, and to a lesser extent, in anterior cingulate, medial, and orbitofrontal cortices and
thalami (by 25%) (Fig 1).
During the H215O PET session performed under
placebo, the naming task did not induce any significant
change in rCBF and the patient performance was poor.
With zolpidem therapy, there was a similar improvement in her naming/repetition performance as previously observed in clinical module. rCBF image analysis
showed a drug-induced activation mainly localized in
the anterior cingulate and orbitofrontal cortices (Fig 2).
Discussion
This case report demonstrated that zolpidem transiently improved motor and language status in a patient with akinetic mutism. She recovered some spontaneous movement and walking. After zolpidem
administration, Finger Tapping test score was within
the reference range,2 but Nine-Hole Peg test remained
below the lowest limit of healthy subjects.3 Although
she presented with a total mutism before, her language
behavior evolved after zolpidem therapy to a pattern
resembling transcortical motor aphasia, consistent responses to stimulation without spontaneous expression.
Previous studies have shown this potential effect of zolpidem on improvement of catatonia, aphasia, and
semicomatose state.4 – 8 To our knowledge, this is the
first study to assess the impact of zolpidem of postanoxic brain injury using the modern methodological
standards of clinical pharmacology. This single-patient
trial (N ⫽ 1) strategy may help to advance a few more
conclusions eliminating placebo effect.
The effect of zolpidem on cerebral perfusion was observed experimentally in baboons9 and in humans5,6,10
using single-photon emission computed tomography.
rCBF was generally increased in areas that were hypoactive before drug administration. In agreement with
Cohen and colleagues,6 we showed increased cerebral
activity in the frontal cortex with zolpidem therapy.
Brefel-Courbon et al: Zolpidem in Akinetic Mutism
103
Fig 1. Brain metabolism images in placebo and zolpidem sessions using 18F-fluorodeoxyglucose positron emission tomography.
This increase was observed both with FDG-PET (at
resting state) and H215O PET in an activating condition relative to resting state. Our activation H215O
PET experiment suggested that zolpidem modulation
of signal changes elicited by the language task concerned mainly the anterior cingulate and orbitofrontal
cortices. According to the classic neuroanatomic modeling of the connections between basal ganglia and
frontal cortex,11 it is well recognized that corticalsubcortical connections are organized in several loops
functioning in parallel with interconnections.12 Two of
the cortical-subcortical loops mainly originating from
anterior cingulate and orbitofrontal cortices are described as limbic loops.13 Damage to anterior cingulate
and orbitofrontal cortex is known to induce behavioral
and cognitive changes, especially lack of motivation.
Akinetic mutism has been reported with bilateral lesions of anterior cingulate.14
The mechanism of this paradoxical effect of zolpidem was unknown. Some authors have suggested that
the action of this drug would be due to the reversal of
a diaschisis phenomenom.6,10,15 We also propose that
zolpidem-stimulating GABA function could interact
with limbic loops, modulating subcortical pathways
(globus pallidus and substantia nigra), then leading to
disinhibition and thalamocortical overactivity.16 The
improvement of these limbic loops function could be
related, in part, to the reversal of a cortical-subcortical
diaschisis. Nevertheless, considering that our patient
had diffuse bilateral postanoxic lesions, we hypothesize
that the zolpidem effect not only concerned areas involved in diaschisis but all the GABAergic part of the
loop. Then, for this patient, the paradoxical effect of
zolpidem resulted from an activation of motivational
circuits allowing movement execution and verbal expression. Thus, the activation of medial ventral frontal
areas observed in our PET experiment would not reflect a specific effect on the language-related neural
structures, but might represent enhanced activity in the
Fig 2. Statistical Parametric Mapping 2 results during denomination task in placebo and zolpidem sessions. There was no
denomination-induced activation in placebo session. By contrast, zolpidem induced activation in anterior cingulate and orbitofrontal
cortices (Talairach coordinates: x ⫽ ⫺8mm; y ⫽ 64mm; z ⫽ ⫺2mm; Z-score ⫽ 4.48; p ⬍ 0.001).
104
Annals of Neurology
Vol 62
No 1
July 2007
neural circuits governing motivational processes.17 This
also accounts for improvements in the general motor
behavior. In our language-based PET experiment, it
was only at a much lower statistical threshold ( p ⬍
0.05) that we observed activation in the sylvian areas
bilaterally (result not shown). The drug-induced modulation in the medial ventral frontal cortex and its connections was therefore sufficient to allow the patient to
produce appropriate verbal responses to stimulation,
but it did not restore further functions of the language
system such as production of spontaneous speech. Anoxic lesions in these parts of subcortical territories
might have been too severe to allow any pharmacological improvement of spontaneous behavior.
Finally, this study underlies the fact that singlepatient (N ⫽ 1) trials would be a logical approach to
identifying new utilizations of drugs, especially in the
case of rare or orphan diseases.
This work is dedicated to the memory of D. Cardebat.
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Brefel-Courbon et al: Zolpidem in Akinetic Mutism
105
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