Positive Correlation between Severity of Blepharospasm and Thalamic Glucose Metabolism.

Abstract

A 43-year-old woman with drug-related blepharospasm was followed up for 22 months. She had undergone etizolam treatment for 19 years for indefinite complaints. We examined her cerebral glucose metabolism 5 times (between days 149 and 688 since presentation), using positron emission tomography, and identified regions of interest in the thalamus, caudate nucleus, putamen, and primary somatosensory area on both sides. The severity of the blepharospasm was evaluated by PET scanning using the Wakakura classification. Sixteen women (mean age 42.4 ± 11.7 years) were examined as normal controls. The thalamic glucose metabolism in our patient was significantly increased on days 149, 212, and 688. The severity of the blepharospasm was positively correlated with the thalamic glucose metabolism, suggesting that the severity of blepharospasms reflects thalamic activity.

Full text

Page 1

Case Rep Ophthalmol 2011;2:50–54
DOI: 10.1159/000324459
Published online:
February 5, 2011
© 2011 S. Karger AG, Basel
ISSN 1663–2699
www.karger.com/cop
This is an Open Access article licensed under the terms of the Creative Commons Attribution-
NonCommercial-NoDerivs 3.0 License (www.karger.com/OA-license), applicable to the online
version of the article only. Distribution for non-commercial purposes only.

Kenji Ishii

Positron Medical Center, Tokyo Metropolitan Institute of Gerontology
35-2 Sakaecho
Itabashi, Tokyo (Japan)
Tel. +81 3 3964 3241, ext. 3503, E-Mail ishii @ pet.tmig.or.jp

50


Positive Correlation between
Severity of Blepharospasm and
Thalamic Glucose Metabolism
Hideki Muraia, b Yukihisa Suzukia, b Motohiro Kiyosawaa
Masato Wakakurac Manabu Mochizukia Kiichi Ishiwatab
Kenji Ishiib
aDepartment of Ophthalmology and Visual Science, Tokyo Medical and Dental
University, Graduate School, bPositron Medical Center, Tokyo Metropolitan
Institute of Gerontology, and cInouye Eye Hospital, Tokyo, Japan

Key Words
Blepharospasm · Cerebral glucose metabolism · Dystonia · Positron-emission
tomography · Thalamus
Abstract
A 43-year-old woman with drug-related blepharospasm was followed up for 22 months.
She had undergone etizolam treatment for 19 years for indefinite complaints. We
examined her cerebral glucose metabolism 5 times (between days 149 and 688 since
presentation), using positron emission tomography, and identified regions of interest in
the thalamus, caudate nucleus, putamen, and primary somatosensory area on both sides.
The severity of the blepharospasm was evaluated by PET scanning using the Wakakura
classification. Sixteen women (mean age 42.4 ± 11.7 years) were examined as normal
controls. The thalamic glucose metabolism in our patient was significantly increased on
days 149, 212, and 688. The severity of the blepharospasm was positively correlated with
the thalamic glucose metabolism, suggesting that the severity of blepharospasms
reflects thalamic activity.
Introduction
Essential blepharospasm (EB) is a form of focal dystonia characterized by involuntary
movement of the musculature in the upper face. Several researchers have studied focal
dystonia using positron emission tomography (PET) and 18F-fluorodeoxyglucose (18F-
FDG). Galardi et al. [1] reported hypermetabolism in the thalamus, basal ganglia, anterior
cingulate gyrus, and cerebellum in patients with spasmodic torticollis, and Esmaeli-
Gutstein et al. [2] found a relative increase in metabolic activity in the thalamus of
patients with EB. Suzuki et al. [3] have reported glucose hypermetabolism in the thalamus

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Case Rep Ophthalmol 2011;2:50–54
DOI: 10.1159/000324459
Published online:
February 5, 2011
© 2011 S. Karger AG, Basel
ISSN 1663–2699
www.karger.com/cop


51
of patients with EB and suggested that dysfunction of the basal ganglia-thalamocortical
motor circuit may play a major role in the pathophysiology of dystonia.
We hypothesized that the severity of blepharospasm is correlated to the activity in the
thalamus or basal ganglia. In the present study, a patient with drug-induced
blepharospasm was followed up and her cerebral glucose metabolism was recorded 5
times using PET and 18F-FDG. We assume that the pathophysiologies of drug-related
blepharospasm and EB are similar. Glucose metabolism in the thalamus, the basal ganglia,
and the primary somatosensory area (PSA) were evaluated and the relationship between
the severity of blepharospasm and glucose metabolism in these areas was analyzed.
Materials and Methods
A 43-year-old woman presented with difficulty in opening her eyes (day 0). She had no organic brain
disorder or other neuropsychiatric disease as evaluated by neurologists using conventional diagnostic
magnetic resonance imaging (MRI) and no family history of dystonic diseases. She had taken 3 mg/day
of etizolam for 19 years for the treatment of indefinite complaints, and the blepharospasm had
developed recently [4]. She received an injection of botulinum-A toxin administered bilaterally to the
orbicularis oculi on day 72, with unsatisfactory results. However, upon discontinuation of etizolam, her
symptoms gradually improved in the course of a year. PET scanning was performed 5 times in the
course of 22 months (on days 149, 212, 310, 443, and 688), and the severity of the spasms at the time of
PET scanning was evaluated according to the Wakakura classification [5].
Sixteen women (mean age, 42.4 ± 11.7 years) were recruited as normal controls, and MRI and 18F-
FDG PET were performed. Informed consent was obtained from all study participants. The protocol of
this study was approved by the institutional ethics committee of the Tokyo Metropolitan Institute of
Gerontology. All the procedures conformed to the tenets of the Declaration of Helsinki.
MR images were obtained with a 1.5-Tesla Signa Horizon scanner (General Electric, Milwaukee,
Wisc., USA) in order to register PET and MR images. Transaxial images with T1-weighted contrast
[3D-SPGR, repetition time (TR) = 9.2 ms, echo time (TE) = 2.0 ms, matrix size = 256 × 256 × 124, voxel
size = 0.94 × 0.94 × 1.3 mm] and T2-weighted contrast (first spin echo, TR = 3,000 ms, TE = 100 ms,
matrix size = 256 × 256 × 20, voxel size = 0.7 × 0.7 × 6.5 mm) were obtained.
PET scans were obtained using the SET 2400W whole-body scanner (Shimadzu, Kyoto, Japan) at the
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology. Attenuation was corrected by a
transmission scan with a 68Ga/68Ge rotating source. A bolus of 150 MBq 18F-FDG was injected
intravenously. The subjects were then requested to lie down comfortably with their eyes closed. A 6-min
emission scan in the 3D acquisition mode was started 45 min after the injection, and 50 transaxial
images with an interslice interval of 3.125 mm were obtained. The tomographic images were
reconstructed using a filtered backprojection method with a Butterworth filter (cutoff frequency: 1.25
cycles/cm and order of 2).
PET images were three-dimensionally registered to their 3D-SPGR MR images using the Automated
Medical Images Registration (AMIR) program [6]. Further data analysis was performed on LINUX
workstations using the Dr. View program (AJS, Tokyo, Japan). Regions of interest (ROIs), i.e. 8.5-mm-
diameter circles, were defined interactively on the resliced PET images by visual inspection with
reference to the corresponding MR image. The ROIs were placed over the bilateral thalamus, caudate,
putamen, and PSA, and the cerebral glucose metabolism in each region was measured. The values of
cerebral glucose metabolism in the ROIs were normalized according to the global cerebral glucose
metabolism, which was calculated by averaging voxels >20% of the maximum value. The normalized
values of glucose metabolism in each area in the patient were compared to the corresponding average
values in the normal controls, and a difference of 2.5 SD from the controls was considered statistically
significant. The correlation coefficient between the severity of blepharospasm and the normalized
glucose metabolism in each area studied was also calculated.

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Case Rep Ophthalmol 2011;2:50–54
DOI: 10.1159/000324459
Published online:
February 5, 2011
© 2011 S. Karger AG, Basel
ISSN 1663–2699
www.karger.com/cop


52
Results
The glucose metabolism in the thalamus of the patient was increased significantly on
days 149 and 212 (table 1). However, a significant change was not observed in the other
areas (caudate, putamen, and PSA). The severity of the blepharospasm was 3 on day 149,
2 on day 212, 1 on day 310, 1 on day 443, and 2 on day 688. Regression analyses with the
data of the bilateral thalamus demonstrated a significant positive correlation between
cerebral glucose metabolism and the severity of the blepharospasm [correlation
coefficient (r): right: 0.853 (p < 0.05), left: 0.953 (p < 0.01)] (fig. 1).
Discussion
We observed cerebral glucose hypermetabolism in the thalamus of a patient with drug-
related blepharospasm. Reduced cerebral glucose metabolism in the thalamus was found
to be correlated with an improvement in the blepharospasm. Thus, the activity in the
thalamus may be related to the severity of blepharospasms.
Blepharospasm is a dystonic disorder, and there are several reports on cerebral glucose
hypermetabolism in the thalamus of patients with dystonia [1–3, 7], including our
previous report. Esmaeli-Gutstein et al. [2] classified blepharospasms on the basis of
severity (mild, moderate, and severe) in 10 patients and examined the relationship
between the severity and cerebral glucose metabolism in the thalamus using 18F-FDG
PET. They did not find a correlation between glucose metabolism and blepharospasm
severity in their study, possibly because the interval between the most recent botulinum
toxin injection and PET was not uniform in each patient.
Further, Odergren et al. [7] measured cerebral blood flow in four patients with writer’s
cramp and four controls, using PET. They reported that the perceived difficulty and signs
of dystonia progressed with the duration of writing, which in turn correlated with
increased activity in the thalamus of the patients. Many studies have reported thalamic
hyperactivity in patients with dystonic diseases, but the neurophysiological mechanisms
of this hyperactivity are not well defined. In our previous study, we observed glucose
hypermetabolism in the thalamus of EB patients whose spasms were suppressed by
botulinum toxin treatment [3]. This result may indicate that the hyperactivity in the
thalamus is caused by the blepharospasm itself.
On the other hand, the hyperactivity in the thalamus may be secondary to dystonic
muscle spasms. There are 2 possible explanations for the hyperactivity in the thalamus.
First, the somatosensory input from the skin induced by dystonic movement may activate
the basal ganglia-thalamocortical motor circuit. Gobbelé et al. [8] investigated the
interference of tactile and painful stimuli on thalamocortical processing of somatosensory
information in humans, using somatosensory evoked potentials. They observed that the
thalamic source was significantly increased during pain interference. Second, the
activation of the thalamus may be due to neuronal projection from the muscle spindle
that contracts with dystonic muscle spasms. Katter et al. [9] observed that the neurons
that project from the jaw-muscle spindle to the thalamus were activated with
microelectrodes in the rat. In the present study, we observed a patient who developed
blepharospasm after long-term etizolam treatment. Wakakura et al. [4] examined 254
patients with blepharospasm and reported that 13.8% of them had used etizolam before

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Case Rep Ophthalmol 2011;2:50–54
DOI: 10.1159/000324459
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February 5, 2011
© 2011 S. Karger AG, Basel
ISSN 1663–2699
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53
the onset of blepharospasm. They concluded that prolonged use of benzodiazepines or
thienodiazepines may induce blepharospasm. The clinical features of drug-related
blepharospasm are similar to those of EB, and the spasms may resolve on discontinuing
the use of related drugs [4]. In our case, the symptoms of blepharospasm improved to
some extent after etizolam was discontinued and, thus, the patient’s condition could be
diagnosed as drug-related blepharospasm.
Acknowledgements
The authors have no conflict of interest. However, this research was supported by Grants-in-Aid for
Scientific Research (B) 21791725 (Y. Suzuki) and (C) 20591038 (K. Ishii) from the Japan Society for the
Promotion of Science.



Table 1. Cerebral glucose metabolism in a patient with blepharospasm
Brain area
thalamus
Day Severity R/L
caudate putamen PSA
149

212

310

443

688

Normal average R

3

2

1

1

2

R
L
R
L
R
L
R
L
R
L
1.64*
1.66*
1.57*
1.63*
1.52
1.51
1.49
1.52
1.52
1.56
1.37±0.07 1.41±0.08 1.51±0.14 1.15±0.07
1.37±0.08 1.41±0.09 1.51±0.12 1.15±0.06
1.28
1.24
1.39
1.43
1.45
1.33
1.31
1.45
1.41
1.43
1.46
1.44
1.46
1.47
1.53
1.39
1.44
1.42
1.48
1.44
1.20
1.15
1.18
1.12
1.23
1.25
1.13
1.14
1.17
1.18
L
Values indicate glucose metabolism in the ROIs, as normalized
according to the global cerebral glucose metabolism.
* Significant increase (>normal average + 2.5 SD).

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DOI: 10.1159/000324459
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February 5, 2011
© 2011 S. Karger AG, Basel
ISSN 1663–2699
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Fig. 1. Images of PET with 18F-FDG in a patient with blepharospasm on days 149 (left) and 443 (right)
after presentation. The severity of the blepharospasm was 3 on day 149 and 1 on day 443. The glucose
metabolism in the thalamus was high on day 149 and low on day 443 (arrows).

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