原発性眼瞼けいれん(EB)は顔面の上半部の筋の不随意な収縮によって特徴付けられる局所失調症の1つの形として分類されます。 原発性眼瞼けいれんを引き起こす基本的な神経学的過程はまだ知られていません。 この研究の目的は、痙攣がボツリヌス菌-A毒素の注射で抑圧されている時の原発性眼瞼けいれん患者の脳のグルコース代謝を調査することです。それは、以前の研究では失調症状による異常な筋からの知覚のフィードバック活動の影響を受けていたからです。
陽電子放射断層撮影(PET)で脳のグルコース代謝を原発性眼瞼けいれんの25人の患者(8人の男性と17人の女性;年齢52.6±10.1年)で18F-fluorodeoxyglucose(FDG)で調べられました。 患者は、覚醒状態で、痙攣はボツリヌス菌-A毒素の注射で抑制されました。 38人の正常なボランティア(14人の男性と24人の女性; 年齢58.2±7.3歳)がコントロールとして調べられました。 統計的なパラメトリックマッピング(SPM99)によって2つのグループの違いが調べられました。 彼らの不随意な眼瞼運動が抑圧されている状態で、グルコース代謝の有意な増加は原発性眼瞼けいれん患者の視床と橋に検出されました。 視床の活動過剰は原発性眼瞼けいれんと他のタイプの焦点の失調症に共通で主要な病態生理学的な変化であるかもしれません。
Glucose Hypermetabolism in the Thalamus
of Patients with Essential Blepharospasm
Yukihisa Suzuki1,２, Shoichi Mizoguchi1,２, Motohiro Kiyosawa1, Manabu Mochizuki1, Kiichi Ishiwata2 , Masato Wakakura3 , and Kenji Ishii2
1Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan.
2Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
3Inouye Eye Hospital, Tokyo, Japan.
Correspondence and reprint requests: Kenji Ishii, MD
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi, Tokyo, Japan.
Phone: 81-3-3964-3241 (X3503)
Essential blepharospasm (EB) is classified as a form of focal dystonia characterized by involuntary spasms of the musculature of the upper face. The basic neurological process causing EB is not known. The purpose of this study was to investigate cerebral glucose metabolism in patients with EB while the symptoms were suppressed by an injection of botulinum-A toxin because earlier studies were confounded by sensory feedback activities derived from dystonic symptom itself. Cerebral glucose metabolism was examined by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in 25 patients (8 men and 17 women; age 52.6±10.1 years) with EB. The patients were awake but with the spasms suppressed by an injection of botulinum-A toxin. Thirty-eight normal volunteers (14 men and 24 women; age 58.2±7.3 years) were examined as controls. The difference between the two groups was examined by statistical parametric mapping (SPM99). A significant increase in the glucose metabolism was detected in the thalamus and pons in the EB patients with their involuntary eyelid movements suppressed. Hyperactivities in the thalamus may be a key pathophysiological change common to EB and other types of focal dystonia.
Key Words: essential blepharospasm, focal dystonia, glucose metabolism, positron emission tomography, thalamus
Essential blepharospasm (EB) is a form of focal dystonia characterized by involuntary spasms of the musculature of the upper face. Earlier studies have reported a glucose hypermetabolism in the thalamus and basal ganglia in patients with dystonia, and it has been widely held that dysfunction of cortical-striato-thalamo-cortical motor circuits may have a major role in the pathophysiology of dystonia.1 It has also been reported that dystonia is caused by thalamic infarctions 2, and patients with EB have been reported to be associated with increased glucose metabolism in the thalamus 3 and cerebellum 4 by 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET) studies.
There have been several studies on other forms of focal dystonia using PET. In patients with spasmodic torticollis, Galardi et al reported hypermetabolism in the thalamus, basal ganglia, anterior cingulate gyrus, and cerebellum, 5 and Eidelberg et al found a relative increase of metabolic activity in the lentiform nucleus and premotor cortices of patients with idiopathic torsion dystonia. 6 In EB and other dystonias, the majority of the studies have demonstrated a hypermetabolism of the thalamus and basal ganglia. A common limitation of earlier neuroimaging studies of dystonia lies in that they observed integral brain activities reflecting both the cause and the consequence of abnormal involuntary movements.
In order to separate the effects of cause and consequence on EB, Hutchinson et al measured the glucose metabolism of EB patients during wakefulness and during induced sleep because the involuntary movements disappear during sleep. They found a hypermetabolism in the cerebellum and pons only during wakefulness. 4
We hypothesized that the hyperactivity in the thalamus and basal ganglia is not a secondary phenomenon accompanies the abnormal movement, but is a primary pathophysiological condition that cause the symptoms. To test this hypothesis and to determine the responsible cerebral regions, PET measurements were made to evaluate regional cerebral glucose metabolism while the patients were awake, but the involuntary eyelid movements were suppressed by a botulinum-A injection.
Materials and Methods
Twenty-five patients (8 men and 17 women; age 52.6±10.1 years), who visited the Ophthalmology Outpatient Clinic of Tokyo Medical and Dental University Hospital and were diagnosed with bilateral EB, were studied. The mean duration of their illness was 5.2±4.7 years. None had an organic brain disorder or other neuro-psychiatric disease as evaluated by neurologists from conventional diagnostic magnetic resonance images (MRIs). No one had a family history of dystonic disorders. Patients who had not taken any neuropsychiatric drugs such as neuroleptic drugs, anti-depressant drugs, anti-Parkisonian drugs, and anti-epileptic drugs were selected by careful history taking because drug related cases might confound 7.
Informed consents were obtained from all the subjects and the patients before participation in the PET study. This study protocol was approved by the Institutional Ethics Committee. All of the procedures conformed to the tenets of the Declaration of Helsinki.
Thirty-eight normal volunteers (14 men and 24 women; age 58.2±7.3 years) were recruited as the normal control group. Their MRI scans and PET scans were obtained with same protocol as that for the EB patients.
All of the patients received an injection of botulinum-A toxin (18 to 36 units bilaterally) into the orbicularis oculi (OO) muscle, and the PET scans were obtained when the spasms of the OO were effectively restrained. We expected that this procedure eliminated the secondary effects of involuntary movements because the action of botulinum-A toxin is peripheral on the neuro-muscular junction level and the injection does not alter the central activity directly. Several previous studies have reported no significant alterations in the level of cerebral blood flow after botulinum toxin treatment8, 9.
MRI scans were obtained from all of the patients to screen for organic brain disorders with a 1.5 Tesla scanner Signa Horizon (General Electric, Milwaukee). Transaxial images with T1-weighted contrast (3DSPGR, TR = 9.2 ms, TE = 2.0 ms, matrix size = 256 x 256 x 124, voxel size = 0.94 x 0.94 x 1.3 mm), and T2-weighted contrast (First Spin Echo, TR = 3000 ms, TE = 100 ms, matrix size = 256 x 256 x 20, voxel size = 0.7 x 0.7 x 6.5 mm) were obtained. None of the patients showed any abnormalities in brain morphology and intensities.
PET Data Acquisition
PET scans were obtained with the Headtome-V scanner SET 2400W (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. For the PET scan, a bolus of 120 MBq [18F] FDG was injected intravenously. Each patient was then requested to lie down comfortably with their eyes closed. A 6-minute emission scan in 3D acquisition mode was started 45 minutes after the injection, and 50 transaxial images with an interslice interval of 3.125 mm were obtained. The spatial resolution of the reconstructed images was 6 x 6 x 7.5 mm FWHM.
Data Processing and Statistical Analysis
PET images were registered three-dimensionally to the individual 3DSPGR MR images with the Automated Medical Images Registration (AMIR) program.10 The data were then processed and analyzed with the statistical parametric mapping (SPM99) software11 implemented in Matlab (Mathworks Inc., Sherborn, MA, USA). Statistical parametric maps combine the general linear model and the theoretical Gaussian fields to make statistical inferences about regional effects. The MR images were spatially normalized to a standard template produced by Montreal Neurological Institute. All PET images were normalized using the transformation matrix of the co-registered MRI and smoothed with Gaussian filter for 16 mm FWHM to increase the signal to noise ratio before statistical processing.
After the appropriate design matrix was specified, the subject and group effects were estimated according to the general linear model at each voxel. The design matrix included the global activity as a confounding covariate, and this analysis can therefore be regarded as an ANCOVA.12 Statistical inference on the SPM (Z) was corrected using the theory of Gaussian Fields. To test hypotheses about regionally specific group effects, the estimates were compared using linear contrast. The threshold for SPM (Z) was set at P < 0.05 with a correction.
A regional glucose hypermetabolism was found in the thalamus and pons bilaterally in patients with EB while their eyelid spasms were blocked by botulinum-A toxin (Table 1, Figure 1). The regional glucose metabolism was increased in the EB group 6.5% in the thalamus and 5.3% in the pons. There was no regional glucose hypometabolism above the statistical significant level.
The term dystonia is used to describe a syndrome characterized by prolonged muscle contractions causing sustained twisting movements and abnormal posture of the affected body parts. “Writer’s cramp” is a form of focal dystonia, and involuntary spasms occur during writing tasks. Patients with “writer’s cramp” were reported to have impaired cortical inhibition which most likely arises from striatal dysfunction.13 In EB patients, hypermetabolism in the thalamus was also found using PET.3 Thus hyperactivity in the thalamus and basal ganglia has been commonly found in patients with dystonia14. Based on these neuroimaging and other physiological findings, it is commonly accepted that blepharospasms are a subtype of the focal dystonias sharing common pathophysiological mechanism with writer’s cramp and spasmodic torticollis.1
Effect of Involuntary Movements
A majority of the studies on EB and other dystonias have demonstrated hypermetabolism of the thalamus and basal ganglia, however, there is a problem in interpreting these results because these studies were performed while the patients had active symptoms of dystonia, e,g., involuntary eyelid movements in EB patients. Thus, the observed abnormal cerebral activities could be due not only to the primary cause of the dystonia, but also to the sensory input secondary from the involuntary movements. To overcome this criticism in EB patients, it is necessary to suppress the spasms of the eyelids. Hutchinson et al hypothesized that there is metabolic increase in the thalamus and basal ganglia in EB patients because of an overactivity of a cortico-striato-thalamo-cortical motor circuit, and measured the glucose metabolism of 6 EB patients by PET while they were awake and while they were awake with active symptoms and while they were asleep without symptoms.4 Although they found hypermetabolism in the cerebellum and pons during wakefulness, they did not find a hypermetabolism in the thalamus and basal ganglia during either condition. We suggest two possible reasons why they miss the hyperactivity in the thalamus and basal ganglia. First, the number of the patients and normal subjects in their study might not be enough. As the difference of mean between two groups was relatively small compared to the standard deviation (6 and 5 in thalamus, for example), we have to increase the number of subject more than 20 to get a consistent statistical significance. Second, sleep might have depressed not only the involuntary movements but also the primary functional alteration in the brain of EB.
Ceballos-Baumann et al examined patients with writer’s cramp by PET during writing words before and after botulinum toxin.15 They found higher activity before and after botulinum-toxin in the thalamus, left insula, bilateral premotor cortex, and bilateral primary sensory cortex than in normal subjects. In patients, activation in the cerebeller vermis was found before botulinum-toxin, but the activation disappeared after the treatment. We suggest that they succeeded in reducing the effect of involuntary movement, although the voluntary movements may still be a confounding factor.
Because the botulinum-toxin inhibits neuro-muscular conduction by a presynaptic blockade, we expected that the botulinum-toxin has minimum influence on the central causative mechanism of EB. Therefore, we performed a PET study in the patients while awake and their spasms were effectively suppressed by the injection of botulinum toxin into the OO muscle bilaterally. Under these conditions, we found a significant glucose hypermetabolism in the thalamus bilaterally in EB patients (P < 0.05, corrected).
Regional Glucose Metabolism in Patients with EB
A trend of glucose hypermetabolism was also found in the putamen bilaterally in EB patients, but the increase was not significant (P < 0.01, uncorrected). These results agree with previous reports that examined glucose metabolism in EB and other focal dystonias in the striatum and thalamus compared to other regions of the brain using PET.3, 5 Macia et al reported that injection of bicuculline, an anTAGSonist to GABAA, into the monkey thalamus induced dystonic symptoms contralaterally and found an overactivity of thalamic neurons ipsilateral to the treatment.16 On the other hand, Kaji reported that one of the important functions of basal ganglia is the gating of sensory input for motor control.17 From these observations, hyperactivation of the thalamus may be one of the primary causes of dystonia and EB. The hyperactivity of the striatum might be secondary to the involuntary movements because it was less significant in our study. Hypermetabolism in the thalamus, basal ganglia, anterior cingulate gyrus and cerebellum of patients with spasmodic torticollis using PET were reported.5 The results of functional imaging studies are often interpreted using the present anatomical model of information flow in cortico-striato-thalamo-cortical motor circuit (Figure 2).14 Based on this model, there are three possible points which might alter thalamic activity. All of them are the alterations in inhibitory synaptic functions mediated by GABA. Recent reports suggest that altered GABAergic inhibition may play a role in the symptomatology of dystonia. Previous studies found a reduction of GABA levels in the sensorimotor cortex and striatum of patients with focal dystonia.18 We suspect that a reduction of GABA levels in the striatum or thalamus might cause the hyperactivity in these areas. Hutchinson et al reported that EB patients exhibit hypermetabolism of the cerebellum and pons during wakefulness, but not during sleeping using PET.4 They suggested that although these regions may be active in EB, their functional interrelationship differs from that observed in more generalized forms of dystonia. Aramideh et al reported a secondary blepharospasm patient with a small dorsomedial pontine lesion,19 and LeDoux et al reported a secondary cervical dystonia patients due to infarctions or hemorrhage in the pons.20 They hypothesized that abnormalities of olivocerebellar circuit and cortico-striato-thalamo-cortical motor circuit might produce similar movement disorders, and they suggested that lesions in the pons obstructed the cerebellar afferent pathways, and produced cervical dystonia. The facial nerve is the final output pathway of focal facial dystonia from the nervous system. As the effect of botulinum-A toxin is peripheral, the facial nuclei and related structure in pons may remain hyperactive even after the treatment as we observe in our results.
A glucose hypermetabolism was detected in the thalamus and pons bilaterally in EB patients. Hyperactivity in the thalamus may be related to the primary cause of EB sharing the common pathophysiological mechanism to other types of focal dystonia.
This work was supported by the Benign Essential Blepharospasm Ressearch Foundation. The authors thank K. Kawamura, K. Oda, and M. Ando for technical support.
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Area x y z Z score
Thalamus (R) 12 -20 -2 5.00
Thalamus (L) -8 -22 -2 5.54
Pons (R) 6 -40 -34 4.47
Pons (L) -12 -40 -34 4.83
Figure Legends (not listed here yet. MK)
Figure 1. Areas of glucose hypermetabolism in patients with essential blepharospasm are showed.
Left; Sagittal and transverse views of a statistical parametric map (SPM) rendered into standard stereotactic space and projected onto a glass brain.
Right; Six axial slices of brain are shown. The left side of the figure corresponds to the left hemisphere.
Figure 2. Principal pathways of the normal corticobasal ganglia-cortical loops and hypothetical alterations. In the normal loops (left), striatum receives input from the primary somatosensory area (PSA) and from other areas of the motor and sensory cortex. Striatum projects by direct and an indirect pathways to the major output structures of the basal ganglia, the globus pallidus interna (GPi) and substantia nigra reticulate (SNr). An indirect pathway includes a striatal-globus pallidus externa (GPe) projection. Some GPe fibers project to the subthalamic nucleus (STN) and GPi/SNr, and other fibers project directly to the GPi/SNr. GPi/SNr, which in turn, projects to the thalamus with a subsequent feedback to motor cortex, primarily the SMA. The effect of each structure on subsequent structures is to increase (+) or decrease (-) neuronal activity as indicated, Adapted from Tempel et al 15 and Garfen.21 For glucose hypermetabolism in the thalamus and striatum of EB patients (right), the possible points of impairments are; 1) to impaired inhibition from GPi / SNr, 2) decreased GPi / SNr activity may result in increased activity of the direct pathway from Striatum to GPi / SNr, and 3) impaired the indirect pathway at the level of Striatum-GPe connection.
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