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Positron emission tomography scanning in essential blepharospasm
Positron Emission Tomography Scanning in Essential Blepharospasm JOHN B. KERRISON, MD, JACK L. LANCASTER, PHD, FRANK E. ZAMARRIPA, BS, LONDE A. RICHARDSON, MD, JOHN C. MORRISON, MD, DAVID E. E. HOLCK, MD, KURT W. ANDREASON, MD, SEAN M. BLAYDON, MD, AND PETER T. FOX, MD
● PURPOSE: To localize in the brain using positron emission tomography neuroimaging with 18fluorodeoxyglucose [PET (18FDG)] differences in glucose metabolism between patients with essential blepharospasm (EB) and controls. ● DESIGN Prospective case-control study ● METHODS: Positron emission tomography neuroimaging with 18fluorodeoxyglucose was performed in 11 patients with EB and 11 controls matched for age and gender. Global analysis of images was used to localize differences in glucose metabolism between groups. ● RESULTS: Multiple cortical and subcortical abnormalities were observed in EB patients in comparison with controls. Cortical areas with the largest and most significant clusters of increased glucose uptake were the inferior frontal gyri, right posterior cingulate gyrus, left middle occipital gyrus, fusiform gyrus of the right temporal lobe, and left anterior cingulate gyrus. Cortical areas with the largest and most significant clusters of decreased glucose uptake were the inferior frontal gyri, ventral to the area of increased glucose metabolism. Subcortical abnormalities, consisting of increased glucose uptake, involved the right caudate and consisting of decreased glucose uptake, involved the left inferior cerebellar hemisphere and thalamus. ● CONCLUSIONS: Global analysis of positron emission tomography neuroimaging with 18fluorodeoxyglucose Accepted for publication Dec 24, 2002. From the Departments of Ophthalmology (J.B.K., D.E.E.H., K.W.A.) and Nuclear Medicine (L.A.R., J.C.M.), Wilford Hall Medical Center, Lackland AFB, San Antonio, Texas; Research Imaging Center, University of Texas Health Science Center, San Antonio, Texas (J.L.L., F.E.Z, P.T.F.); and Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, San Antonio, Texas (S.M.B.). Presented at the Annual Meeting of the North American NeuroOphthalmology Society, Copper Mountain, Colorado, Feb 10 –14, 2002. Supported by a grant (FWH20010122H) from the Office of the Surgeon General of the United States Air Force. The features expressed in the article are those of the authors and do not reflect the official policy of the Department of Defense or other departments of the United States government. Inquiries to John B. Kerrison, MD, Wilmer Eye Institute, Johns Hopkins Hospital, 600 North Wolfe St., Maumenee B109, Baltimore, MD 21287; fax: (410) 614-9240; e-mail: [email protected]
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neuroimaging in EB patients in comparison with controls demonstrates a pattern of abnormalities involving several cortical and subcortical areas that control blinking, including the inferior frontal lobe, caudate, thalamus, and cerebellum. (Am J Ophthalmol 2003;136:846 – 852. © 2003 by Elsevier Inc. All rights reserved.)
E
SSENTIAL BLEPHAROSPASM (EB) IS A DISORDER CHAR-
acterized by bilateral episodic contractions of the orbicularis oculi muscles. The onset typically occurs between the ages of 40 and 60, increasing in prevalence with age.1 It is more common in women, and the population-based prevalence in Europe is estimated to be 361 and 1332 per million. Although many physicians consider EB a chronic, unremitting disorder, a small percentage of patients will experience spontaneous remittance.3 The first-line therapy for EB is chemodenervation with botulinum neurotoxin injections,4 which has a duration of efficacy of about 8 to 10 weeks.5,6 Injections must be given repeatedly, may be associated with diplopia and ptosis, and may fail over the long term. Nevertheless, botulinum injections are well accepted by patients.7 Alternative treatments include chemomyectomy with doxyrubicin,8 surgical myectomy,9 and surgical frontalis suspension.10 Limited success has also been reported with oral administration of mexiletine.11 Early diagnosis of EB could potentially lead to alternative therapeutic interventions. Whereas blepharospasm has been reported secondary to a variety of focal central nervous system (CNS) lesions,12–18 the location and etiology of the underlying defect in EB is not known. Magnetic resonance imaging has failed to show any structural abnormalities in patients with essential blepharospasm. Studies to determine localization and etiology have consisted of animal modeling, genetic association study, postmortem studies, proton magnetic resonance spectroscopy, and positron emission tomography (see review by Hallet19). An animal model of blepharospasm and a genetic case control study in which blepharospasm was associated with a dopamine receptor DRD5 polymorphism both suggest that this focal dystonia
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is associated with abnormal dopamine neurotransmission.20,21 Postmortem study of a patient with EB demonstrated a small angioma in the dorsal pons of uncertain significance.22 Proton magnetic spectroscopy of the basal ganglia of 10 patients with EB demonstrated decreased N-acetyl aspartate, suggestive of a loss of striatal neurons.23 Positrom emission tomography with 18fluorodeoxyglucose in EB patients in comparison with controls has suggested abnormalities of the cerebellum and brainstem.24 Additional studies of EB patients without controls or comparing glucose metabolism during wakefulness and sleep have observed defects in the basal ganglia,25 lenticular nuclei,26 thalami,25,26 and sensory motor cortex.26 The use of PET(18FDG) to study glucose metabolism in the brain is well established. Promising results of previous studies in EB suggest that it may have diagnostic value.24,25 The purpose of this study is to further identify areas of the brain associated with abnormal glucose metabolism that may serve as potential regions of interest for future hypothesis or diagnostic testing.
DESIGN IN A PROSPECTIVE CASE CONTROL STUDY, PATIENTS WERE
recruited from two hospital-based ophthalmology clinics.
METHODS ELEVEN PATIENTS WITH A DIAGNOSIS OF EB AND 11 AGE-
and gender-matched controls were identified in the ophthalmology clinics at Wilford Hall Medical Center and Brooke Army Medical Center. Participants were excluded if they had any history of neurologic disease. Patients selfgraded their symptoms as “mild” if they had increased blinking that was not functionally incapacitating, “moderate” if they had noticeable spasms of the eyelids with some incapacitation, and “severe” if the eyelid spasms were incapacitating or involved other facial muscles.25 Study participants signed informed consent statements approved by the Institutional Review Board at Wilford Hall and Brooke Army Medical Centers. Diabetics who participated in the study were required to have their glucose in good control prior to participation. Subjects were maintained in a dark, quiet room for 45 minutes prior to injection of 3 to 5 mCi of 18FDG (Syncorp of UT Houston, Houston, Texas, USA) through an intravenous line. Following injection, they were maintained in a dark, quiet room for 20 minutes, and 40 minutes later they underwent whole brain tomographic scanning in a CPET scanner (ADAC Laboratories, Milpitas, California, USA) using 2-mm voxel dimensions. They were positioned in the scanner, with their heads immobilized by a head holder, and axial section images were acquired. Subjects received no sedation and were awake during the study. They were VOL. 136, NO. 5
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given instruction not to move and were not spoken to during the study. Initially, a region of interest analysis was performed on six patients with EB and five controls using the ADAC analysis software package to examine specifically regions reported to be abnormal in EB. For each individual, composite images consisting of 10 slices through the basal ganglia were constructed. Regions of interest (ROI) were defined for the caudate, putamen, striatum, thalamus, and cortex of each hemisphere. The mean count per pixel for each ROI of each hemisphere was averaged and divided by the mean uptake for the entire composite image, thus accounting for individual variations caused by differences in mean cerebral metabolic rate for glucose among individuals.25,27,28 Similarly, a composite image was constructed using five slices through the cerebellum and pons, and ROIs encompassing the pons, cerebellum, deep cerebellar nuclei, and pons ⫹ cerebellum were drawn. The mean count per pixel within each ROI was divided by the mean uptake for the entire composite image. Statistical comparison was performed using the Student t test (2 tailed, unequal variance). For global analysis to determine cross-group differences, PET brain volume was defined by an intensity-thresholding of 30% maximum voxel value of the individual data. Voxels with values lower than the threshold were considered as nonbrain region. Global normalization (valuenormalized to whole brain mean activity) was performed and then scaled to an arbitrary mean of 1,000 for each individual PET scan image.29,30 The 3D PET images were spatially normalized into registration with the Talairach Atlas Brain31 using the algorithm developed by Lancaster and associates and implemented in the software Convex Hull (RIC, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA).32,33 All images were transformed (that is, resliced) into 75 slices using trilinear interpolation, with matrix size 75⫻128⫻12⫻ 3D spatially normalized image volumes, with isomorphic voxels, 2⫻2⫻2 mm3, enabling grand-averaging. Significant differences in 18FDG uptake were detected using a region of interest-free image subtraction strategy. The PET images were divided into an EB group and a control group. A voxel-by-voxel group t test was performed to create a statistical parametric image (SPI). The SPI was then thresholded using both an intensity threshold and a cluster-size threshold to delimit the differential foci.33 An intensity threshold of z ⫽ 2.07 was used to produce a significant signal at the P ⫽ .05 level, uncorrected for multiple comparisons. The critical value threshold for regional effects (P ⬍ .05) is not raised to correct for multiple comparisons, because extrema data were also thresholded by cluster size, large clusters having a very low probability of occurrence in Gaussian random fields.33–35 Differential foci with a spatial extent less than 20 voxels (160 mm3) were eliminated from final images to further suppress random noise.33 The location of each focus was
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six patients and five controls failed to demonstrate differences in glucose metabolism in the caudate, putamen, striatum, thalamus, cerebral cortex, pons, cerebellum, deep cerebellar nuclei, and pons ⫹ cerebellum. Global cross-group analysis was used to survey the entire brain in 11 EB patients and 11 controls for areas of abnormal metabolism (Table 2; Figure 1). This technique normalizes the data for overall glucose metabolism and differences in brain size. A complex network of increased and decreased glucose metabolism involving cortical and subcortical regions was observed (Table 2). Among cortical regions with increased glucose metabolism, the largest and most significant clusters of increased uptake included the inferior frontal gyri, right posterior cingulate gyrus, left middle occipital gyrus, fusiform gyrus of the right temporal lobe, and left anterior cingulate gyrus. Among cortical regions with decreased glucose metabolism, the largest and most significant clusters of decreased uptake were the inferior frontal gyri. The subcortical regions with the most significant changes in glucose metabolism were the caudate, with increased glucose metabolism, and the left cerebellar hemisphere and thalamus, with decreased glucose metabolism. Lateralization of inferior frontal gyrus and superior temporal gyrus glucose hypermetabolism to the right cerebrum was contralateral to lateralization of cerebellar glucose hypometabolism to the left cerebellum (Table 2).
TABLE 1. Characteristics of Blepharospasm Cases and Controls
Males:Females Average age (range) Average years since diagnosis (range) Average number of months since last injection (range)* Average total number of injections (range)
Blepharospasm Cases
Controls
2:9 62.9 (44–80) 8 (2–18)
2:9 62.5 (46–80) —
2 (1–4)
—
23 (8–70)
—
*One case had undergone myectomy and required no botulinum toxin injections.
determined as the center-of-mass for that focus.36 The x-, y-, and z-coordinates of the center-of-mass were calculated in Talairach-atlas coordinates.31 To further remove edge effects and artifact arising from dural sinuses, regions of interest were drawn around significant areas to test for outliers with no 18FDG uptake that would be consistent with non-brain tissue.
RESULTS DISCUSSION
THE STUDY CONSISTED OF 11 BLEPHAROSPASM PATIENTS
and 11 controls who were similar in age and gender (Table 1). The blepharospasm patients had been diagnosed for an average of 8 years (range, 2–18 years), and all patients had been receiving botulinum toxin injections every 3 to 4 months, except one patient who had undergone surgical myectomy (Table 1). The interval between the last injection and PET scan averaged 2 months. Eight patients selfgraded their symptoms to be “mild,” and three self graded their symptoms as “moderate” based on the above described criteria. No patients had other cranial dystonias. No blepharospasm patients had any other known neurologic disease, and all patients had undergone neuroimaging, which was normal, at some point in their evaluation. Ten patients in each group were right-handed. One blepharospasm patient was ambidextrous. One control individual was left-handed. Based on previous studies suggesting focal areas of abnormal glucose metabolism in EB, the striatum, thalamus, pons, and cerebellum were evaluated for differences in glucose metabolism between EB patients and controls using a region of interest analysis. Whereas this type of analysis is easily performed on typical scanner software and allows for a crude normalization for overall CNS 18FDG metabolism, it does not allow for spatial normalization and standardization of brain space for comparison and accurate identification of regions of interest. Analysis of the initial 848
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THE GOALS OF FUNCTIONAL NEUROIMAGING STUDIES IN EB
are to comprehend the pathophysiology in a way that ultimately encompasses the prognosis, severity of disease, and response to treatment. The CNS pathophysiology of EB has not been defined. As EB is characterized by prolonged abnormal contraction of the orbicularis muscles, sometimes with co-contraction or abnormal reciprocal inhibition of the levator palpebrae superioris muscle, it is classified as a primary focal dystonia.37 Essential blepharospasm might be caused by a focal abnormality or multiple defects that decrease the threshold for spontaneous or reflex blinking, leading to orbicularis oculi spasm.38,39 In either case, we hypothesize that this would lead to an abnormal network response, involving the neural substrates of blinking and resulting in intermittent blepharospasm. One would expect to see CNS changes consisting of areas of both increased and decreased glucose metabolism. If EB is due to a single, hypofunctioning, focal CNS abnormality, it might be reflected in one of the hypo-functioning spots in the present study, with other areas of either increased or decreased activity representing downstream effects. The present study observed multiple regions of increased and decreased glucose metabolism, including cortical and subcortical regions, in EB patients in comparison with controls. Interpretation of OF
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TABLE 2. Results of Global Analysis Peak t Location X
Y
Z
Hemisphere
Lobe
Gyrus/Subgyrus/Nuclei
Cluster t Average t Avg* Brodmann Area & P Value Volume Within Volume Subnuclei Peak t (two tail, 20 DOF) (mm3) Volume (t*mm3)
Cortical Regions of Increased Glucose Uptake 3.76 4.10 4.26 4.48 3.49 3.31 3.62 3.76 3.25
⬍.0020 ⬍.0010 ⬍.0010 ⬍.0010 ⬍.0050 ⬍.0050 ⬍.0020 ⬍.0020 ⬍.0050
5344 4304 2920 2448 1696 1680 1288 624 512
2.60 2.54 2.75 2.63 2.49 2.35 2.66 2.57 2.45
13891 10952 8031 6449 4229 3947 3426 1602 1254
Frontal lobe Inferior frontal gyrus 47 ⫺4.50 Frontal lobe Inferior frontal gyrus 47 ⫺3.81 Occipital lobe Middle occipital gyrus 18 ⫺2.93 Occipital lobe Cuneus 19 ⫺2.97 Frontal lobe Precentral gyrus 6 ⫺3.41 Parietal lobe Precuneus 7 ⫺2.82 Frontal lobe Paracentral lobule 31 ⫺3.29 Frontal lobe Medial frontal gyrus — ⫺2.88 Frontal lobe Middle frontal gyrus 10 ⫺3.11 Subcortical Region of Increased Glucose Uptake
⬍.0010 ⬍.0020 ⬍.0100 ⬍.0100 ⬍.0050 ⬍.0150 ⬍.0050 ⬍.0150 ⬍.0075
9800 6968 3832 2368 2048 1928 1416 712 664
⫺2.88 ⫺2.52 ⫺2.39 ⫺2.38 ⫺2.50 ⫺2.32 2.45 ⫺2.35 ⫺2.49
28244 17580 9141 5631 5124 4467 3464 1672 1652
⬍.0050
440
2.44
1074
⬍.0010 ⬍.0150 ⬍.0050
6464 1664 1384
⫺2.77 ⫺2.33 ⫺2.37
17880 3879 3274
36 7 ⫺39 47 ⫺11 57 ⫺32 10 ⫺42
31 14 Right cerebrum Frontal lobe Inferior frontal gyrus 45/46 ⫺53 24 Right cerebrum Limbic lobe Posterior cingulate 31/23 ⫺71 1 Left cerebrum Occipital lobe Middle occipital gyrus 37 ⫺4 ⫺25 Right cerebrum Temporal lobe Fusiform gyrus 20 2 41 Left cerebrum Limbic lobe Cingulate gyrus 24 ⫺44 15 Right cerebrum Temporal lobe Superior temporal gyrus 22 34 2 Left cerebrum Frontal lobe Inferior frontal gyrus 45/46 ⫺69 ⫺5 Right cerebrum Occipital lobe Lingual gyrus 18 ⫺44 11 Left cerebrum Temporal lobe Superior temporal gyrus — Cortical Regions of Decreased Glucose Uptake
40 ⫺34 ⫺30 ⫺8 ⫺30 ⫺7 0 15 ⫺35
26 ⫺10 Right cerebrum 28 ⫺12 Left cerebrum ⫺92 0 Left cerebrum ⫺83 30 Left cerebrum ⫺15 63 Left cerebrum ⫺56 56 Left cerebrum ⫺16 44 Right cerebrum 42 ⫺15 Right cerebrum 42 18 Left cerebrum
9
21
0 Right cerebrum Sub-lobar
Caudate
Caudate head
3.16
Subcortical Regions of Decreased Glucose Uptake ⫺47 ⫺64 ⫺33 Left cerebellum Posterior lobe Cerebellar tonsil 6 ⫺30 7 Right cerebrum Sub-lobar Thalamus ⫺28 ⫺32 14 Left cerebrum Sub-lobar Insula
— Pulvinar —
⫺4.74 ⫺2.81 ⫺3.25
DOF ⫽ degree of freedom. *Listed are the areas of increased and decreased glucose metabolism of the cortical and subcortical regions following analysis of EB PET images in comparison with age and gender matched controls. Areas listed are those that are the largest and most significant {(t average ⫻ volume) greater than 1000}. Within each group, locations are listed in descending order. Peak t location refers to the position in Talairach brain coordination space. To rule out edge artifact, regions of interest were examined within significant areas to test for outliers.
these complex results was performed with attention to the most significant and largest clusters of activation and deactivation. It is helpful to first review the CNS pathways involved in blinking. While the early, oligosynaptic, ipsilateral component of the blink reflex conducted through the pons is generally agreed upon, the late, polysynaptic, bilateral component is not well understood.40,41 The cortical and subcortical control of voluntary and spontaneous blinking are poorly understood as well.26 Positron emission tomography (15O) neuroimaging during reflex eyeblinking shows activation of the inferior right frontal cortex and pons along with deactivation of the left cerebellum and right temporal cortex.42 Functional magnetic resonance imaging (fMRI) of voluntary eyeblinking shows activation of the orbitofrontal cortex and visual cortex.43 The basal ganglia VOL. 136, NO. 5
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play a role in modulating lid movements through both the pallidal-thalamic and nigral-collicular output pathways.44 The inhibitory projection of the globus pallidus to the thalamus can significantly modulate cortical activity associated with blinks.41,44 Nigral-collicular modulation of reflex blinks does not involve cortical projections.44 The caudate is involved in the regulation of blinking, as evidenced by a positive correlation between the blink rate and dopamine concentration in the caudate nucleus of MPTP-treated monkeys.45 The cerebellum is thought to be essential for adaptive changes to the blink reflex.46 Many of these neural substrates of blinking were activated or deactivated in EB patients in comparison with controls. The activation of the inferior frontal cortex in the present study as well as PET(15O) and fMRI studies of blinking suggest this to be an important cortical compo-
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FIGURE 1. Positron emission tomography scan and essential blepharospasm. The largest and most significant clusters of increased (red-yellow) and decreased (blue-green) glucose metabolism in 11 essential blepharospasm patients vs 11 age- and gender-matched controls are projected onto axial positron emission tomography images of the brain. The rostral-caudal z coordinates are displayed. (A-F) The inferior frontal gyri show increased glucose metabolism, lateralized to the right, and decreased glucose uptake ventral to this region. Also depicted are thalamic deactivation and caudate activation. (F) The left cerebellum shows deactivation.
nent of the pathophysiology of EB. The deactivation of the inferior frontal cortex ventral to this is of unclear significance. Interestingly, asymmetric blepharospasm, more pronounced in the ipsilateral eye, has been observed in a patient with a left frontal cortex venous infarct.18 Lateralization of activation of the frontal and temporal cortex to the right with contralateral deactivation of the left cerebellum suggests a connection mediated by the corticopontocerebellar pathway. Deactivation of the thalamus may be the primary defect in EB. This is underscored by the observation of bilateral blepharospasm in association with bilateral thalamic infarcts13 and unilateral blepharospasm caused by an ipsilateral thalamomesencephalic hemorrhage.14 This is consistent with the hypothesis that primary dystonia is a manifestation of abnormal modification of cortical motor control.36 Although this study is the largest reported series of EB patients and controls, there are differences in the topography of glucose metabolism in comparison with prior 850
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reports. Hutchinson and colleagues performed PET scans and statistical parametric mapping, similar to the analysis in the present study, in six EB patients and six controls and observed increased metabolic activity in the pons and cerebellum.24 Differences in the regions identified in the present study and the study by Hutchinson and colleagues, may reflect differences in the study population in terms of age, gender, stage of disease, and activity in response to treatment. Differences in the technique and analysis of scanning must also be taken into consideration. Hutchinson and colleagues do not appear to have performed a global value normalization to control for differences in whole brain 18FDG uptake between individuals.24 Finally, EB may be caused by a heterogeneous network of abnormalities. Other PET studies in EB differ in design from the present study. Hutchinson and colleagues also compared EB patients during wakefulness and following sleep induction with secobarbital and observed superior medial frontal OF
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hypometabolism.24 Hallett and Daroff discussed results of a similar awake–sleep study in which abnormalities of the thalami, lenticular nuclei, and sensory motor cortex were observed.26 Using a region of interest analysis on nonspatially normalized images, Esmaeli-Gutstein and colleagues reported increased glucose metabolism in the striatum and thalami in comparison with the frontal, temporal, and parietal regions in a series 10 EB patients and one patient with Meige syndrome.25 No control patients were included in the study, making the significance of their findings difficult to interpret. Of note, they demonstrated no significant changes in metabolism in three botulinum-treated patients examined at two different intervals. A limitation of the present study, similar to prior studies24,25, is that all EB patients had been treated with botulinum injections. Although it seems unlikely that botulinum injections affect cortical metabolism, this cannot be assumed. While a large study of untreated EB patients in comparison with controls would be worthwhile, there are practical limitations to such a study. Identified regional differences in glucose metabolism are areas that might be used clinically for diagnosis, follow-up, grading, and evaluation of response to treatment. In the present study, a region of interest analysis was performed on nonspatially normalized images using standard software available on a typical PET scanner. Regions identified in previous studies were examined using this technique but failed to show any differences. Failure to find metabolic differences that were apparent on global analysis is likely due to the inherent inaccuracy in drawing regions of interest around distinct brain structures, resulting in averaging the uptake of some unintended regions. We recommend that future studies test specific regions of interest or hypothetical networks of increased and decreased glucose metabolism. Based on the present analysis, the inferior frontal gyrus, left cerebellum, and thalamus appear to be most promising. Ideally, these studies should be performed on spatially normalized PET scans co-registered with MRIs and referenced to Talairach space. This would allow the most accurate anatomic comparison. If possible, patients would be standardized with respect to onset, severity, and treatment. In the present cohort of patients, PET imaging suggests that EB involves the pallidal-thalamic outputs that influence cortical modulation of blinking. Although PET offers promise as a diagnostic modality, its use in EB has not been demonstrated.
4. 5. 6. 7. 8.
9.
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16. 17. 18. 19. 20.
21.
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resonance spectroscopy in primary blepharospasm. Neurology 1998;51:892–895. Hutchinson M, Nakamura T, Moeller JR, et al. The metabolic topography of essential blepharospasm: a focal dystonia with general implications. Neurology 2000;55:673–677. Esmaeli-Gutstein B, Nahmias C, Thompson M, Kazdan M, Harvey J. Positron emission tomography in patients with benign essential blepharospasm. Ophthal Plast Reconstr Surg 1999;15:23–27. Hallett M, Daroff RB. Blepharospasm: report of a workshop. Neurology 1996;46:1213–1218. Metter EJ, Riege WH, Kuhl DE, Phelps ME. Cerebral metabolic relationships for selected brain regions in healthy adults. J Cereb Blood Flow Metab 1984;4:1–7. Tyler JL, Strother SC, Zatorre RJ, et al. Stability of regional cerebral glucose metabolism in the normal brain measured by positron emission tomography. J Nucl Med 1988;29:631– 642. Fox PT, Raichle ME, Mintun MA, Dence C. Nonoxidative glucose consumption during focal physiologic neural activity. Science 1988;241:462–464. Friston KJ, Frith CD, Liddle PF, Dolan RJ, Lammertsma AA, Frackowiak RS. . The relationship between global and local changes in PET scans. J Cereb Blood Flow Metab 1990;10: 458 –466. Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain. New York: Thieme Medical Publishers, 1988. Lancaster JL, Fox PT, Downs H, et al. Global spatial normalization of human brain using convex hulls. J Nucl Med 1999;40:942–955. Xiong J, Gao J-H, Lancaster JL, Fox PT. Clustered pixels analysis for functional MRI activation studies of the human brain. Human Brain Mapping 1995;3:287–301. Poline J-B, Mazoyer BM. Analysis of individual positron emission tomography activation maps by detection of high signal-to-noise-ratio pixel clusters. J Cereb Blood Flow Metab 1993;13:425–437. Roland PE, Levin B, Kawashima R, Akerman S. Threedimensional analysis of clustered voxels in 15O-butanol brain activation images. Human Brain Mapping 1993;1:3–9.
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● PURPOSE: To localize in the brain using positron emission tomography neuroimaging with 18fluorodeoxyglucose [PET (18FDG)] differences in glucose metabolism between patients with essential blepharospasm (EB) and controls. ● DESIGN Prospective case-control study ● METHODS: Positron emission tomography neuroimaging with 18fluorodeoxyglucose was performed in 11 patients with EB and 11 controls matched for age and gender. Global analysis of images was used to localize differences in glucose metabolism between groups. ● RESULTS: Multiple cortical and subcortical abnormalities were observed in EB patients in comparison with controls. Cortical areas with the largest and most significant clusters of increased glucose uptake were the inferior frontal gyri, right posterior cingulate gyrus, left middle occipital gyrus, fusiform gyrus of the right temporal lobe, and left anterior cingulate gyrus. Cortical areas with the largest and most significant clusters of decreased glucose uptake were the inferior frontal gyri, ventral to the area of increased glucose metabolism. Subcortical abnormalities, consisting of increased glucose uptake, involved the right caudate and consisting of decreased glucose uptake, involved the left inferior cerebellar hemisphere and thalamus. ● CONCLUSIONS: Global analysis of positron emission tomography neuroimaging with 18fluorodeoxyglucose Accepted for publication Dec 24, 2002. From the Departments of Ophthalmology (J.B.K., D.E.E.H., K.W.A.) and Nuclear Medicine (L.A.R., J.C.M.), Wilford Hall Medical Center, Lackland AFB, San Antonio, Texas; Research Imaging Center, University of Texas Health Science Center, San Antonio, Texas (J.L.L., F.E.Z, P.T.F.); and Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, San Antonio, Texas (S.M.B.). Presented at the Annual Meeting of the North American NeuroOphthalmology Society, Copper Mountain, Colorado, Feb 10 –14, 2002. Supported by a grant (FWH20010122H) from the Office of the Surgeon General of the United States Air Force. The features expressed in the article are those of the authors and do not reflect the official policy of the Department of Defense or other departments of the United States government. Inquiries to John B. Kerrison, MD, Wilmer Eye Institute, Johns Hopkins Hospital, 600 North Wolfe St., Maumenee B109, Baltimore, MD 21287; fax: (410) 614-9240; e-mail: [email protected]
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neuroimaging in EB patients in comparison with controls demonstrates a pattern of abnormalities involving several cortical and subcortical areas that control blinking, including the inferior frontal lobe, caudate, thalamus, and cerebellum. (Am J Ophthalmol 2003;136:846 – 852. © 2003 by Elsevier Inc. All rights reserved.)
E
SSENTIAL BLEPHAROSPASM (EB) IS A DISORDER CHAR-
acterized by bilateral episodic contractions of the orbicularis oculi muscles. The onset typically occurs between the ages of 40 and 60, increasing in prevalence with age.1 It is more common in women, and the population-based prevalence in Europe is estimated to be 361 and 1332 per million. Although many physicians consider EB a chronic, unremitting disorder, a small percentage of patients will experience spontaneous remittance.3 The first-line therapy for EB is chemodenervation with botulinum neurotoxin injections,4 which has a duration of efficacy of about 8 to 10 weeks.5,6 Injections must be given repeatedly, may be associated with diplopia and ptosis, and may fail over the long term. Nevertheless, botulinum injections are well accepted by patients.7 Alternative treatments include chemomyectomy with doxyrubicin,8 surgical myectomy,9 and surgical frontalis suspension.10 Limited success has also been reported with oral administration of mexiletine.11 Early diagnosis of EB could potentially lead to alternative therapeutic interventions. Whereas blepharospasm has been reported secondary to a variety of focal central nervous system (CNS) lesions,12–18 the location and etiology of the underlying defect in EB is not known. Magnetic resonance imaging has failed to show any structural abnormalities in patients with essential blepharospasm. Studies to determine localization and etiology have consisted of animal modeling, genetic association study, postmortem studies, proton magnetic resonance spectroscopy, and positron emission tomography (see review by Hallet19). An animal model of blepharospasm and a genetic case control study in which blepharospasm was associated with a dopamine receptor DRD5 polymorphism both suggest that this focal dystonia
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is associated with abnormal dopamine neurotransmission.20,21 Postmortem study of a patient with EB demonstrated a small angioma in the dorsal pons of uncertain significance.22 Proton magnetic spectroscopy of the basal ganglia of 10 patients with EB demonstrated decreased N-acetyl aspartate, suggestive of a loss of striatal neurons.23 Positrom emission tomography with 18fluorodeoxyglucose in EB patients in comparison with controls has suggested abnormalities of the cerebellum and brainstem.24 Additional studies of EB patients without controls or comparing glucose metabolism during wakefulness and sleep have observed defects in the basal ganglia,25 lenticular nuclei,26 thalami,25,26 and sensory motor cortex.26 The use of PET(18FDG) to study glucose metabolism in the brain is well established. Promising results of previous studies in EB suggest that it may have diagnostic value.24,25 The purpose of this study is to further identify areas of the brain associated with abnormal glucose metabolism that may serve as potential regions of interest for future hypothesis or diagnostic testing.
DESIGN IN A PROSPECTIVE CASE CONTROL STUDY, PATIENTS WERE
recruited from two hospital-based ophthalmology clinics.
METHODS ELEVEN PATIENTS WITH A DIAGNOSIS OF EB AND 11 AGE-
and gender-matched controls were identified in the ophthalmology clinics at Wilford Hall Medical Center and Brooke Army Medical Center. Participants were excluded if they had any history of neurologic disease. Patients selfgraded their symptoms as “mild” if they had increased blinking that was not functionally incapacitating, “moderate” if they had noticeable spasms of the eyelids with some incapacitation, and “severe” if the eyelid spasms were incapacitating or involved other facial muscles.25 Study participants signed informed consent statements approved by the Institutional Review Board at Wilford Hall and Brooke Army Medical Centers. Diabetics who participated in the study were required to have their glucose in good control prior to participation. Subjects were maintained in a dark, quiet room for 45 minutes prior to injection of 3 to 5 mCi of 18FDG (Syncorp of UT Houston, Houston, Texas, USA) through an intravenous line. Following injection, they were maintained in a dark, quiet room for 20 minutes, and 40 minutes later they underwent whole brain tomographic scanning in a CPET scanner (ADAC Laboratories, Milpitas, California, USA) using 2-mm voxel dimensions. They were positioned in the scanner, with their heads immobilized by a head holder, and axial section images were acquired. Subjects received no sedation and were awake during the study. They were VOL. 136, NO. 5
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given instruction not to move and were not spoken to during the study. Initially, a region of interest analysis was performed on six patients with EB and five controls using the ADAC analysis software package to examine specifically regions reported to be abnormal in EB. For each individual, composite images consisting of 10 slices through the basal ganglia were constructed. Regions of interest (ROI) were defined for the caudate, putamen, striatum, thalamus, and cortex of each hemisphere. The mean count per pixel for each ROI of each hemisphere was averaged and divided by the mean uptake for the entire composite image, thus accounting for individual variations caused by differences in mean cerebral metabolic rate for glucose among individuals.25,27,28 Similarly, a composite image was constructed using five slices through the cerebellum and pons, and ROIs encompassing the pons, cerebellum, deep cerebellar nuclei, and pons ⫹ cerebellum were drawn. The mean count per pixel within each ROI was divided by the mean uptake for the entire composite image. Statistical comparison was performed using the Student t test (2 tailed, unequal variance). For global analysis to determine cross-group differences, PET brain volume was defined by an intensity-thresholding of 30% maximum voxel value of the individual data. Voxels with values lower than the threshold were considered as nonbrain region. Global normalization (valuenormalized to whole brain mean activity) was performed and then scaled to an arbitrary mean of 1,000 for each individual PET scan image.29,30 The 3D PET images were spatially normalized into registration with the Talairach Atlas Brain31 using the algorithm developed by Lancaster and associates and implemented in the software Convex Hull (RIC, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA).32,33 All images were transformed (that is, resliced) into 75 slices using trilinear interpolation, with matrix size 75⫻128⫻12⫻ 3D spatially normalized image volumes, with isomorphic voxels, 2⫻2⫻2 mm3, enabling grand-averaging. Significant differences in 18FDG uptake were detected using a region of interest-free image subtraction strategy. The PET images were divided into an EB group and a control group. A voxel-by-voxel group t test was performed to create a statistical parametric image (SPI). The SPI was then thresholded using both an intensity threshold and a cluster-size threshold to delimit the differential foci.33 An intensity threshold of z ⫽ 2.07 was used to produce a significant signal at the P ⫽ .05 level, uncorrected for multiple comparisons. The critical value threshold for regional effects (P ⬍ .05) is not raised to correct for multiple comparisons, because extrema data were also thresholded by cluster size, large clusters having a very low probability of occurrence in Gaussian random fields.33–35 Differential foci with a spatial extent less than 20 voxels (160 mm3) were eliminated from final images to further suppress random noise.33 The location of each focus was
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six patients and five controls failed to demonstrate differences in glucose metabolism in the caudate, putamen, striatum, thalamus, cerebral cortex, pons, cerebellum, deep cerebellar nuclei, and pons ⫹ cerebellum. Global cross-group analysis was used to survey the entire brain in 11 EB patients and 11 controls for areas of abnormal metabolism (Table 2; Figure 1). This technique normalizes the data for overall glucose metabolism and differences in brain size. A complex network of increased and decreased glucose metabolism involving cortical and subcortical regions was observed (Table 2). Among cortical regions with increased glucose metabolism, the largest and most significant clusters of increased uptake included the inferior frontal gyri, right posterior cingulate gyrus, left middle occipital gyrus, fusiform gyrus of the right temporal lobe, and left anterior cingulate gyrus. Among cortical regions with decreased glucose metabolism, the largest and most significant clusters of decreased uptake were the inferior frontal gyri. The subcortical regions with the most significant changes in glucose metabolism were the caudate, with increased glucose metabolism, and the left cerebellar hemisphere and thalamus, with decreased glucose metabolism. Lateralization of inferior frontal gyrus and superior temporal gyrus glucose hypermetabolism to the right cerebrum was contralateral to lateralization of cerebellar glucose hypometabolism to the left cerebellum (Table 2).
TABLE 1. Characteristics of Blepharospasm Cases and Controls
Males:Females Average age (range) Average years since diagnosis (range) Average number of months since last injection (range)* Average total number of injections (range)
Blepharospasm Cases
Controls
2:9 62.9 (44–80) 8 (2–18)
2:9 62.5 (46–80) —
2 (1–4)
—
23 (8–70)
—
*One case had undergone myectomy and required no botulinum toxin injections.
determined as the center-of-mass for that focus.36 The x-, y-, and z-coordinates of the center-of-mass were calculated in Talairach-atlas coordinates.31 To further remove edge effects and artifact arising from dural sinuses, regions of interest were drawn around significant areas to test for outliers with no 18FDG uptake that would be consistent with non-brain tissue.
RESULTS DISCUSSION
THE STUDY CONSISTED OF 11 BLEPHAROSPASM PATIENTS
and 11 controls who were similar in age and gender (Table 1). The blepharospasm patients had been diagnosed for an average of 8 years (range, 2–18 years), and all patients had been receiving botulinum toxin injections every 3 to 4 months, except one patient who had undergone surgical myectomy (Table 1). The interval between the last injection and PET scan averaged 2 months. Eight patients selfgraded their symptoms to be “mild,” and three self graded their symptoms as “moderate” based on the above described criteria. No patients had other cranial dystonias. No blepharospasm patients had any other known neurologic disease, and all patients had undergone neuroimaging, which was normal, at some point in their evaluation. Ten patients in each group were right-handed. One blepharospasm patient was ambidextrous. One control individual was left-handed. Based on previous studies suggesting focal areas of abnormal glucose metabolism in EB, the striatum, thalamus, pons, and cerebellum were evaluated for differences in glucose metabolism between EB patients and controls using a region of interest analysis. Whereas this type of analysis is easily performed on typical scanner software and allows for a crude normalization for overall CNS 18FDG metabolism, it does not allow for spatial normalization and standardization of brain space for comparison and accurate identification of regions of interest. Analysis of the initial 848
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THE GOALS OF FUNCTIONAL NEUROIMAGING STUDIES IN EB
are to comprehend the pathophysiology in a way that ultimately encompasses the prognosis, severity of disease, and response to treatment. The CNS pathophysiology of EB has not been defined. As EB is characterized by prolonged abnormal contraction of the orbicularis muscles, sometimes with co-contraction or abnormal reciprocal inhibition of the levator palpebrae superioris muscle, it is classified as a primary focal dystonia.37 Essential blepharospasm might be caused by a focal abnormality or multiple defects that decrease the threshold for spontaneous or reflex blinking, leading to orbicularis oculi spasm.38,39 In either case, we hypothesize that this would lead to an abnormal network response, involving the neural substrates of blinking and resulting in intermittent blepharospasm. One would expect to see CNS changes consisting of areas of both increased and decreased glucose metabolism. If EB is due to a single, hypofunctioning, focal CNS abnormality, it might be reflected in one of the hypo-functioning spots in the present study, with other areas of either increased or decreased activity representing downstream effects. The present study observed multiple regions of increased and decreased glucose metabolism, including cortical and subcortical regions, in EB patients in comparison with controls. Interpretation of OF
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TABLE 2. Results of Global Analysis Peak t Location X
Y
Z
Hemisphere
Lobe
Gyrus/Subgyrus/Nuclei
Cluster t Average t Avg* Brodmann Area & P Value Volume Within Volume Subnuclei Peak t (two tail, 20 DOF) (mm3) Volume (t*mm3)
Cortical Regions of Increased Glucose Uptake 3.76 4.10 4.26 4.48 3.49 3.31 3.62 3.76 3.25
⬍.0020 ⬍.0010 ⬍.0010 ⬍.0010 ⬍.0050 ⬍.0050 ⬍.0020 ⬍.0020 ⬍.0050
5344 4304 2920 2448 1696 1680 1288 624 512
2.60 2.54 2.75 2.63 2.49 2.35 2.66 2.57 2.45
13891 10952 8031 6449 4229 3947 3426 1602 1254
Frontal lobe Inferior frontal gyrus 47 ⫺4.50 Frontal lobe Inferior frontal gyrus 47 ⫺3.81 Occipital lobe Middle occipital gyrus 18 ⫺2.93 Occipital lobe Cuneus 19 ⫺2.97 Frontal lobe Precentral gyrus 6 ⫺3.41 Parietal lobe Precuneus 7 ⫺2.82 Frontal lobe Paracentral lobule 31 ⫺3.29 Frontal lobe Medial frontal gyrus — ⫺2.88 Frontal lobe Middle frontal gyrus 10 ⫺3.11 Subcortical Region of Increased Glucose Uptake
⬍.0010 ⬍.0020 ⬍.0100 ⬍.0100 ⬍.0050 ⬍.0150 ⬍.0050 ⬍.0150 ⬍.0075
9800 6968 3832 2368 2048 1928 1416 712 664
⫺2.88 ⫺2.52 ⫺2.39 ⫺2.38 ⫺2.50 ⫺2.32 2.45 ⫺2.35 ⫺2.49
28244 17580 9141 5631 5124 4467 3464 1672 1652
⬍.0050
440
2.44
1074
⬍.0010 ⬍.0150 ⬍.0050
6464 1664 1384
⫺2.77 ⫺2.33 ⫺2.37
17880 3879 3274
36 7 ⫺39 47 ⫺11 57 ⫺32 10 ⫺42
31 14 Right cerebrum Frontal lobe Inferior frontal gyrus 45/46 ⫺53 24 Right cerebrum Limbic lobe Posterior cingulate 31/23 ⫺71 1 Left cerebrum Occipital lobe Middle occipital gyrus 37 ⫺4 ⫺25 Right cerebrum Temporal lobe Fusiform gyrus 20 2 41 Left cerebrum Limbic lobe Cingulate gyrus 24 ⫺44 15 Right cerebrum Temporal lobe Superior temporal gyrus 22 34 2 Left cerebrum Frontal lobe Inferior frontal gyrus 45/46 ⫺69 ⫺5 Right cerebrum Occipital lobe Lingual gyrus 18 ⫺44 11 Left cerebrum Temporal lobe Superior temporal gyrus — Cortical Regions of Decreased Glucose Uptake
40 ⫺34 ⫺30 ⫺8 ⫺30 ⫺7 0 15 ⫺35
26 ⫺10 Right cerebrum 28 ⫺12 Left cerebrum ⫺92 0 Left cerebrum ⫺83 30 Left cerebrum ⫺15 63 Left cerebrum ⫺56 56 Left cerebrum ⫺16 44 Right cerebrum 42 ⫺15 Right cerebrum 42 18 Left cerebrum
9
21
0 Right cerebrum Sub-lobar
Caudate
Caudate head
3.16
Subcortical Regions of Decreased Glucose Uptake ⫺47 ⫺64 ⫺33 Left cerebellum Posterior lobe Cerebellar tonsil 6 ⫺30 7 Right cerebrum Sub-lobar Thalamus ⫺28 ⫺32 14 Left cerebrum Sub-lobar Insula
— Pulvinar —
⫺4.74 ⫺2.81 ⫺3.25
DOF ⫽ degree of freedom. *Listed are the areas of increased and decreased glucose metabolism of the cortical and subcortical regions following analysis of EB PET images in comparison with age and gender matched controls. Areas listed are those that are the largest and most significant {(t average ⫻ volume) greater than 1000}. Within each group, locations are listed in descending order. Peak t location refers to the position in Talairach brain coordination space. To rule out edge artifact, regions of interest were examined within significant areas to test for outliers.
these complex results was performed with attention to the most significant and largest clusters of activation and deactivation. It is helpful to first review the CNS pathways involved in blinking. While the early, oligosynaptic, ipsilateral component of the blink reflex conducted through the pons is generally agreed upon, the late, polysynaptic, bilateral component is not well understood.40,41 The cortical and subcortical control of voluntary and spontaneous blinking are poorly understood as well.26 Positron emission tomography (15O) neuroimaging during reflex eyeblinking shows activation of the inferior right frontal cortex and pons along with deactivation of the left cerebellum and right temporal cortex.42 Functional magnetic resonance imaging (fMRI) of voluntary eyeblinking shows activation of the orbitofrontal cortex and visual cortex.43 The basal ganglia VOL. 136, NO. 5
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play a role in modulating lid movements through both the pallidal-thalamic and nigral-collicular output pathways.44 The inhibitory projection of the globus pallidus to the thalamus can significantly modulate cortical activity associated with blinks.41,44 Nigral-collicular modulation of reflex blinks does not involve cortical projections.44 The caudate is involved in the regulation of blinking, as evidenced by a positive correlation between the blink rate and dopamine concentration in the caudate nucleus of MPTP-treated monkeys.45 The cerebellum is thought to be essential for adaptive changes to the blink reflex.46 Many of these neural substrates of blinking were activated or deactivated in EB patients in comparison with controls. The activation of the inferior frontal cortex in the present study as well as PET(15O) and fMRI studies of blinking suggest this to be an important cortical compo-
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FIGURE 1. Positron emission tomography scan and essential blepharospasm. The largest and most significant clusters of increased (red-yellow) and decreased (blue-green) glucose metabolism in 11 essential blepharospasm patients vs 11 age- and gender-matched controls are projected onto axial positron emission tomography images of the brain. The rostral-caudal z coordinates are displayed. (A-F) The inferior frontal gyri show increased glucose metabolism, lateralized to the right, and decreased glucose uptake ventral to this region. Also depicted are thalamic deactivation and caudate activation. (F) The left cerebellum shows deactivation.
nent of the pathophysiology of EB. The deactivation of the inferior frontal cortex ventral to this is of unclear significance. Interestingly, asymmetric blepharospasm, more pronounced in the ipsilateral eye, has been observed in a patient with a left frontal cortex venous infarct.18 Lateralization of activation of the frontal and temporal cortex to the right with contralateral deactivation of the left cerebellum suggests a connection mediated by the corticopontocerebellar pathway. Deactivation of the thalamus may be the primary defect in EB. This is underscored by the observation of bilateral blepharospasm in association with bilateral thalamic infarcts13 and unilateral blepharospasm caused by an ipsilateral thalamomesencephalic hemorrhage.14 This is consistent with the hypothesis that primary dystonia is a manifestation of abnormal modification of cortical motor control.36 Although this study is the largest reported series of EB patients and controls, there are differences in the topography of glucose metabolism in comparison with prior 850
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reports. Hutchinson and colleagues performed PET scans and statistical parametric mapping, similar to the analysis in the present study, in six EB patients and six controls and observed increased metabolic activity in the pons and cerebellum.24 Differences in the regions identified in the present study and the study by Hutchinson and colleagues, may reflect differences in the study population in terms of age, gender, stage of disease, and activity in response to treatment. Differences in the technique and analysis of scanning must also be taken into consideration. Hutchinson and colleagues do not appear to have performed a global value normalization to control for differences in whole brain 18FDG uptake between individuals.24 Finally, EB may be caused by a heterogeneous network of abnormalities. Other PET studies in EB differ in design from the present study. Hutchinson and colleagues also compared EB patients during wakefulness and following sleep induction with secobarbital and observed superior medial frontal OF
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hypometabolism.24 Hallett and Daroff discussed results of a similar awake–sleep study in which abnormalities of the thalami, lenticular nuclei, and sensory motor cortex were observed.26 Using a region of interest analysis on nonspatially normalized images, Esmaeli-Gutstein and colleagues reported increased glucose metabolism in the striatum and thalami in comparison with the frontal, temporal, and parietal regions in a series 10 EB patients and one patient with Meige syndrome.25 No control patients were included in the study, making the significance of their findings difficult to interpret. Of note, they demonstrated no significant changes in metabolism in three botulinum-treated patients examined at two different intervals. A limitation of the present study, similar to prior studies24,25, is that all EB patients had been treated with botulinum injections. Although it seems unlikely that botulinum injections affect cortical metabolism, this cannot be assumed. While a large study of untreated EB patients in comparison with controls would be worthwhile, there are practical limitations to such a study. Identified regional differences in glucose metabolism are areas that might be used clinically for diagnosis, follow-up, grading, and evaluation of response to treatment. In the present study, a region of interest analysis was performed on nonspatially normalized images using standard software available on a typical PET scanner. Regions identified in previous studies were examined using this technique but failed to show any differences. Failure to find metabolic differences that were apparent on global analysis is likely due to the inherent inaccuracy in drawing regions of interest around distinct brain structures, resulting in averaging the uptake of some unintended regions. We recommend that future studies test specific regions of interest or hypothetical networks of increased and decreased glucose metabolism. Based on the present analysis, the inferior frontal gyrus, left cerebellum, and thalamus appear to be most promising. Ideally, these studies should be performed on spatially normalized PET scans co-registered with MRIs and referenced to Talairach space. This would allow the most accurate anatomic comparison. If possible, patients would be standardized with respect to onset, severity, and treatment. In the present cohort of patients, PET imaging suggests that EB involves the pallidal-thalamic outputs that influence cortical modulation of blinking. Although PET offers promise as a diagnostic modality, its use in EB has not been demonstrated.
4. 5. 6. 7. 8.
9.
10. 11. 12. 13. 14. 15.
16. 17. 18. 19. 20.
21.
REFERENCES 1. The Epidemiological Study of Dystonia in Europe (EDSE) Collaborative Group. A prevalence study of primary dystonia in eight European countries. J Neurol 2000;247:787–792. 2. Defazio G, Livrea P, De Salvia R, et al. Prevalence of primary
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