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Mechanism of tonic spasms in West syndrome viewed from ictal SPECT findings
Brain & Development 23 (2001) 496–501 www.elsevier.com/locate/braindev
Review article
Mechanism of tonic spasms in West syndrome viewed from ictal SPECT findings Kazuhiro Haginoya a,*, Mitsutoshi Munakata a, Hiroyuki Yokoyama a, Rie Kato a, Soichiro Tanaka a, Mieko Hirose a, Mamiko Ishitobi a, Kimiya Kon a, Yasushi Yoshihara a, Masaru Takayanagi a, Tetsuro Yamazaki b, Kazuie Iinuma a a
Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan Department of Radiology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
b
Received 19 July 2001; received in revised form 30 July 2001; accepted 2 August 2001
Abstract To clarify the pathophysiology of tonic spasms, 21 patients with West syndrome were analyzed using ictal and interictal single photon emission computed tomography (SPECT). We focused on whether ictal perfusion changes were observed in the focal cortical region. Eight of the patients studied showed definite focal cortical ictal hyperperfusion, indicating that there is a unique subset of West syndrome that can be classified as infantile localization-related epilepsy. Of those eight patients, only two showed asymmetric spasms, suggesting that seizure symptomatology in infants gives only limited information on the localization-related nature of epilepsy. Furthermore, the activation of subcortical structures by focal cortical regions might be attributable to the symmetric seizure phenomena. Thirteen patients showed a diffuse pattern in their ictal SPECTs; this probably included patients with diffuse hyperperfusion and those with no changes. The following have yet to be determined: (1) whether West syndrome is divided into subgroups based on the origin of spasms, in that some patients have the origin in the cortical hemisphere and some have the origin in structures other than the cortical hemisphere, such as the brain stem; (2) whether differences in ictal SPECT patterns reflect a unique nature of tonic spasms in West syndrome, where tonic spasms appear in clusters and the interval of each spasm is different among each patient. q 2001 Elsevier Science B.V. All rights reserved. Keywords: West syndrome; Single photon emission computed tomography; Tonic spasms; Infantile spasms; Hypsarrhythmia; Ictal single photon emission computed tomography; Asymmetric spasms
1. Introduction West syndrome is an age-dependent epileptic encephalopathy that has multiple etiologies and diverse psychomotor outcomes. Although West syndrome is classified as a generalized epileptic syndrome because of the generalized EEG abnormalities and its bilateral clinical manifestations [1], recent neuroimaging studies [2–5] indicate that pathologic conditions in the cortex play an important role in the pathogenesis of the tonic spasms in patients with West syndrome. However, the pathophysiology of West syndrome is still poorly understood, in spite of extensive work by many investigators [6–9]. Since regional cerebral blood flow (rCBF) increases at the epileptogenic focus during ictus and decreases in the same area during the interictal period, ictal single photon emis-
sion computed tomography (SPECT) has recently come to be considered as a reliable tool for the presurgical detection of epileptogenic foci in patients with intractable localization-related epilepsy [10,11]. Since cortical resection has also been considered as a treatment for West syndrome [3], ictal SPECT should be examined to determine whether patients have such a region when they have intractable seizures to anticonvulsants. However, most neuroimaging studies reported for West syndrome are based on interictal neuroimaging [3,4,12,13], and ictal SPECT studies of West syndrome in the literature are limited, except for our report [14,15]. We found heterogeneity in the ictal SPECT findings among patients, that is, ictal cortical hyperperfusion and subcortical hyperperfusion [14]. In order to clarify the heterogeneity of the ictal SPECT findings in West syndrome, we performed further studies using a larger patient population.
* Corresponding author. Fax: 181-22-717-7290. E-mail address: [email protected] (K. Haginoya). 0387-7604/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S03 87- 7604(01)0029 8-4
K. Haginoya et al. / Brain & Development 23 (2001) 496–501
2. Patients and methods All 21 patients, including patients who participated in the previous study [14], were diagnosed with West syndrome, which is defined by clusters of tonic spasms and hypsarrhythmia. We defined spasms as brief contractions of the extremities followed by a short tonic phase which lasted longer than myoclonic jerks but were shorter than a tonic seizure. A clinical summary of the patients is listed in Table 1. We received informed consent from the families of all of the patients during their first admission. For ictal SPECT, as soon as the attending pediatrician noticed the occurrence of tonic spasms, [ 99mTc]ethyl cysteinate dimer (ECD) was injected intravenously and flushed thoroughly with saline. The dose of [ 99mTc]ECD was 185 MBq. SPECT images were acquired 30 min after the injection using a MULTISPECT 3 (Siemens, Gerfahldt, Germany). In a period of 20 min, 120 projection datum points in a 128 £ 128 matrix were obtained. Using an Icon (Siemens) computer system, tomograms two pixels thick (5.8 mm) were reconstructed after a high-frequency cutoff with a Butterworth filter. Axial and coronal slices were constructed parallel and perpendicular to the orbitomeatal plane, while sagittal slices were constructed parallel to the longitudinal fissure. Infants were anesthetized with trichloryl hydrochloride or diazepam during the scanning. Interictal SPECT was done while the infants were awake, and none showed clinical evidence of seizures during the interictal SPECT study. The mean interval between ictal and interictal SPECT was 17 days. Spasms were classified as symmetric or asymmetric by the attending pediatrician. Asymmetric spasms were defined as spasms that were asymmetric on the two sides of the body, as defined by Fusco and Vigegano [16]. SPECT images were independently visually analyzed by a pediatric neurologist and a radiologist, and localized cerebral perfusion abnormalities were judged to be present only when both evaluations coincided. Since subcortical perfusion is difficult to assess without quantitative data, in this analysis we focused on whether cortical perfusion changes were focal and asymmetric or nonfocal. Ictal cortical perfusion changes were classified as Group A (focal asymmetric cortical hyperperfusion) or Group B (diffuse perfusion patterns that included those with diffuse cortical perfusion changes or no recognizable changes). The results were statistically evaluated using Fisher’s exact probability method. Significance was established at P , 0:05.
3. Results (Table 1) Eight of the 21 patients were classified into Group A (focal asymmetric cortical hyperperfusion). The rest of the patients were considered to be in Group B (diffuse perfusion patterns that included those with diffuse cortical perfusion changes or no recognizable changes). Three of seven (43%) patients with cryptogenic West syndrome were classified
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into Group A, whereas five of 14 (36%) patients with symptomatic West syndrome were classified into Group A (P . 0:99). One of eight (13%) patients with normal interictal SPECT findings showed focal cortical ictal hyperperfusion, whereas seven of 13 (54%) patients with abnormal interictal SPECT findings had focal cortical ictal hyperperfusion (P ¼ 0:09). Asymmetric spasms were observed in only four patients with symptomatic West syndrome (30%); however, there was no correlation between asymmetric spasms and symptomatic West syndrome (P ¼ 0:26), unlike the results reported by Fusco and Vigegano [16]. When focal signs like eye deviation were included in the asymmetric spasms, seven patients (50%) with symptomatic West syndrome were categorized into this group, whereas one patient (14%) with cryptogenic West syndrome was categorized into this group (P ¼ 0:17). Two of eight (25%) patients in Group A showed asymmetric spasms, whereas two of 13 (15%) patients in Group B showed asymmetric spasms (P ¼ 0:62). When focal signs, such as eye deviation, were included in the asymmetric spasms, three (38%) patients in Group A showed asymmetric spasms, whereas five (38%) patients in Group B showed asymmetric spasms (P . 0:99). Of the eight patients who were categorized into Group A, hyperperfused regions were observed in the right frontal area (four patients), right temporal area (one patient), left temporal area (one patient), and left temporal to occipital areas (one patient) (Fig. 1a–e). One patient (patient 2) that showed changes in the left parietal area from focal hypoperfusion to isoperfusion during spasms was also included in this category. Of four patients with tuberous sclerosis, three showed focal hyperperfusion in the right frontal area on ictal SPECT (Fig. 1b), but the other patient showed a diffuse pattern. In this study, cortical dysplasia was only recognized in one patient (patient 8) with tuberous sclerosis. This patient had periventricular nodules and a large area of ectopic gray matter in the right frontal base (Fig. 1a). In patient 3, who had ictal hyperperfusion of the left temporal area, focal spike-waves were frequently observed in this area, and diffuse and irregular spike-waves were also observed on the interictal EEG (Fig. 1e). The ictal EEG showed spikes and slow waves in all areas during each spasm; however, some of the discharges began in the left hemisphere. Patient 5 showed hemi-hypsarrhythmia on the right side, and her seizure showed hemi-spasms of the left extremities and leftward eye deviations. However, she had symmetric spasms on the day of the ictal SPECT study, and showed hyperperfusion of the right frontal area. Thirteen patients were classified into Group B (Fig. 2a– c). Patient 14 had congenital hydrocephalus, and a ventriculoperitoneal shunt operation was performed early in the postnatal period. Interictal EEG showed hemispheric hypsarrhythmia over the left hemisphere, the side on which the hydrocephalus was prominent. He had asymmetric spasms. Patient 17 had an intrauterine hemorrhage of the left thalamus (Fig. 2b). On the interictal SPECT, this
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Table 1 Clinical summary of patients and results of ictal SPECT study a Patient no.
Sex
Onset (months)
Class
Age at ictal SPECT (months)/interval (days)*
Etiology
CT/MRI
EEG interictal/ictal
SPECT
Interictal F F M M F M
1.5 4.5 5.5 3.5 7 6
C C C S S S
3/31 6/6 6/22 4/7 12/90 7.5/14
7 8
F F
3 2
S S
5/20 2/8
Unknown Tuberous sclerosis
9 10 11 12 13 14
F M F M F M
7 6 4 7 6.5 8
C C C C S S
9/5 6.6/7 6/20 8/4 11/49 8/17
15
F
S
15/13
Unknown Unknown Unknown Unknown Tuberous sclerosis Congenital hydrocephalus Porencephaly
16 17
F F
6.5 6
S S
7/7 7/13
18
F
4.5
S
4.5/5
19
M
7.5
S
10/5
Unknown
20 21
M F
S S
6/5 12/7
Unknown Hypoxic-ischemic encephalopathy
11
5 12
Unknown Unknown Unknown Tuberous sclerosis Tuberous sclerosis Neurofibromatosis 1
Fetal distress Intrauterine Lthalamic hemorrhage Unknown
Normal Normal Normal Multiple tubers Multiple tubers Normal
Hyps/n.d. Hyps/n.d. Hyps/diffuse spike-waves Hyps/diffuse HVS R-hemi-hyps/n.d. Hyps/diffuse HVS
Multifocal hypo L-P hypo Normal Multifocal hypo Multifocal hypo Bilateral basal ganglia hyper Brain atrophy Hyps/diffuse irregular spikes L-O hypo Multiple tubers/ectopic gray Asymmetric hyps/R-hemi-sharp R-F hypo matter waves or HVS Normal Hyps/diffuse HVS Normal Normal Hyps/n.d. Normal Normal Hyps/n.d. Normal Normal Hyps/n.d. Normal Multiple tubers Hyps/n.d. Multifocal hypo L-hydrocephalus (postL-hemi-hyps/L-HVS L-TPO hypo shunt op.) Defect of L-hemisphere L-F-focal hyps/L-F-HVS R-residual F hyper hydrocephalus (post-shunt op.) Normal Hyps/diffuse spike-waves Normal L-enlarged lateral ventricle, L-hemi-hyps/n.d. L-TO, L-thalamus L-thalamus atrophy hypo Enlarged both lateral Hyps/n.d. Normal ventricle L-chronic subdural Hyps/diffuse fast waves Bilateral P-O hypo hemorrhage, atrophy of bilateral O Normal Hyps/diffuse fast waves Normal Brain atrophy Hyps/diffuse fast waves Diffuse hypo
Ictal A (R-F) A (L-P hypo-iso) A (L-T) A (R-F) A (R-F) A (R-T)
a a a* a a a
A (L-O-T) A (R-F)
b b
B B B B B B
a a a a a b
B
a
B B
a a*
B
b
B
a
B B
a* a*
a S, symptomatic; C, cryptogenic; A, focal asymmetric cortical hyperperfusion; B, diffuse pattern; a, symmetric spasms; a*, symmetric spasms with eye deviation; b, asymmetric spasms; L, left; R, right; F, frontal area; T, temporal area; P, parietal area; O, occipital area; hyps, hypsarrhythmia; HVS, high voltage slow waves; hypo, hypoperfusion; hyper, hyperperfusion; n.d., not done; interval (days)*, interval period (in days) between ictal and interictal SPECT.
K. Haginoya et al. / Brain & Development 23 (2001) 496–501
1 2 3 4 5 6
Clinical feature of spasms
K. Haginoya et al. / Brain & Development 23 (2001) 496–501
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brain stem. Since her spasms were symmetrical, it seems as if the sensorimotor cortex is not required for the appearance of spasms. However, the brain stem, which contains the descending pathways controlling spinal reflexes and other infra-tentorial structures, seems to be essential for the occurrence of the spasms.
4. Discussion The focal asymmetric cortical hyperperfusion demonstrated in eight cases clearly indicates that there is a subset of West syndrome that can be classified into localizationrelated infantile epilepsy. Although abnormal interictal SPECT findings did not correlate significantly with focal cortical ictal hyperperfusion, patients with abnormal interictal SPECT findings may have focal cortical epileptogenic foci. There have been reports of patients with West syndrome who have asymmetric hypsarrhythmia or asymmetric tonic spasms [16–18]. Most of those reports emphasize that asymmetric tonic spasms are closely associated with symptomatic West syndrome or asymmetric hypsarrhythmia, indicating the existence of a cerebral lesion. We did not find a significant correlation between symptomatic West syndrome and asymmetric spasms, probably because of the small number of patients in this study. The important result in our study is that asymmetric spasms did not correlate with focal cortical ictal hyperperfusion. Even in patients
Fig. 1. Ictal SPECT showing focal asymmetric cortical hyperperfusion classified as Group A. (a) Patient 8; (b) patient 4; (c) patient 6; (d) patient 1; (e) patient 3. The arrowheads show hyperperfused regions.
patient showed focal hypoperfusion of the left occipital to temporal areas, as well as of the left thalamus. The interictal EEG showed a localized appearance of hypsarrhythmia over the left hemisphere. Since the hypoperfused areas in both of these patients remained unchanged on the ictal SPECT as compared to the surrounding areas, those areas did not seem to contribute directly to the occurrence of spasms in these patients, although the hypsarrhythmia might have been related to those areas. Patient 18 had asymmetric spasms every 5 s; however, the ictal SPECT showed no focal changes in cerebral perfusion patterns (Fig. 2a). Patient 15 had congenital extensive porencephaly and hydrocephalus [15]. Her spasms were quite symmetrical in spite of a massive defect in the left hemisphere. The interictal EEG showed very high voltage slow waves mixed with spikes and poly-spikes in the right frontal area. The ictal SPECT showed relatively high perfusion of the cerebellum and the
Fig. 2. Ictal SPECT showing diffuse perfusion patterns classified as Group B. (a) Patient 18; (b) patient 17; (c) patient 21.
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K. Haginoya et al. / Brain & Development 23 (2001) 496–501
with focal cortical epileptogenic foci proven by ictal SPECT, spasms can appear symmetrically. Alternatively, asymmetric spasms are not necessarily indicative of focal cortical ictal hyperperfusion. These results indicate that, as in the cases reported by Acharya et al. [19], seizure symptomatology in infants may give only limited clues to the localization-related nature of the epilepsy. Focal cortical epileptogenic lesions might have secondarily activated subcortical structures, resulting in bilateral contraction of the extremities [2]. To answer the question of why the rest of the patients showed diffuse patterns and no focal cortical changes, one must consider the unique nature of tonic spasms in West syndrome. The spasms appear in clusters and the interspasm interval is varied individually. [ 99mTc]ECD is a chemically stable, neutral, lipophilic compound. It can easily cross the blood-brain barrier, and the first pass extraction is proportional to the rCBF. Maximal activity is reached 1 min after administration. Subsequently, it is metabolized to a hydrophilic compound and trapped intracellularly, demonstrating prolonged intracerebral retention [20]. This allows us to freeze the cerebral blood flow at the time of ictus and to evaluate ictal changes in blood flow with [ 99mTc]ECD. Since we do not have any information about how brain perfusion temporarily changes during a series of spasms, we do not know if any differences in brain perfusion depend on the interval between spasms. From a clinical point of view, however, in patients whose spasms appear in rapid succession, e.g. every 5 s, an ‘ictal SPECT’ might reflect what is happening during ictus, whereas in patients whose spasms appear every 30 s, we might not see any changes on the ‘ictal SPECT’ images, even if there are focal cortical changes with each spasm. Another explanation is that West syndrome might be divided into subgroups based on the origin of the spasms. Some patients have spasms that originate in the cortical hemispheres [17–19], and some have spasms that originate in structures other than the cortical hemispheres, such as the brain stem. Even in a patient whose spasms appeared in a short interval, the ictal SPECT showed no focal changes in cerebral perfusion patterns as listed in Fig. 2. As described in the results section, the ictal SPECT findings of the three patients who had extensive MRI abnormalities in the hemisphere associated with hemi-hypsarrhythmia or focal hypsarrhythmia were informative. From these findings, it seems that subcortical structures are primarily important in generating tonic spasms in some patients with West syndrome. To further understand the pathophysiology of tonic spasms, the application of subtraction ictal SPECT co-registered with MRI (SISCOM) analysis might be helpful, as demonstrated in patients with localization-related epilepsy [21,22]. This method would overcome many of the limitations associated with the traditional side-by-side inspection of the images. Near infrared spectrophotometry (NIRS) is also a promising technique for understanding seizure
phenomena in infants, because it allows noninvasive and continuous monitoring of cerebral blood flow during seizures [23].
References [1] Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–399. [2] Chugani HT, Shewmon DA, Sankar R, Chen AC, Phelps ME. Infantile spasms: II. Lenticular nuclei and brain stem activation on positron emission tomography. Ann Neurol 1992;31:212–219. [3] Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990;27:406–411. [4] Chiron C, Dulac O, Bulteau C, Nuttin C, Depas G, Raynaud C, et al. Study of regional cerebral blood flow in West syndrome. Epilepsia 1993;34:707–715. [5] Haginoya K, Kon K, Yokoyama H, Tanaka S, Kato R, Munakata M, et al. The perfusion defect seen with SPECT in West syndrome is not correlated with seizure prognosis or developmental outcome. Brain Dev 2000;22:16–23. [6] Baram TZ, Mitchell WG, Snead III OC, Horton EJ, Saito M. Brainadrenal axis hormones are altered in the CSF of infants with massive infantile spasms. Neurology 1992;42:1171–1175. [7] Satoh J, Mizutani T, Morimatsu Y. Neuropathology of the brainstem in age-dependent epileptic encephalopathy. Especially of cases with infantile spasms. Brain Dev 1986;8:443–449. [8] Wenzel D. Evoked potentials in infantile spasms. Brain Dev 1987;9:365–368. [9] Carrazana EJ, Lombroso CT, Mikati M, Helmers S, Holmes GL. Facilitation of infantile spasms by partial seizures. Epilepsia 1993;34:97–109. [10] Stefan H, Bauer J, Feistel H, Schulemann H, Neubauer U, Wenzel B, et al. Regional cerebral blood flow during focal seizure of temporal and frontocentral onset. Ann Neurol 1990;27:162–166. [11] Harvey AS, Bowe JM, Hopkins IJ, Shield LK, Cook DJ, Berkovic SF. Ictal 99mTc-HMPAO single photon emission computed tomography in children with temporal lobe epilepsy. Epilepsia 1993;34:869–877. [12] Hwang PA, Otsubo H, Koo BKK, Gilday DL, Chuang SH, Jay V, et al. Infantile spasms: cerebral blood flow abnormalities correlate with EEG, neuroimaging, and pathologic findings. Pediatr Neurol 1996;14:220–225. [13] Miyazaki M, Hashimoto T, Fujii E, Tayama M, Kuroda Y. Infantile spasms: localized cerebral lesions on SPECT. Epilepsia 1994;35:988– 992. [14] Haginoya K, Kon K, Takayanagi M, Yoshihara Y, Kato R, Tanaka S, et al. Heterogeneity of ictal SPECT findings in nine cases of West syndrome. Epilepsia 1998;39(Suppl 5):26–29. [15] Haginoya K, Kon K, Tanaka S, Munakata M, Kato R, Nagai M, et al. The origin of hypsarrhythmia and tonic spasms in West syndrome: evidence from a case of porencephaly and hydrocephalus with focal hypsarrhythmia. Brain Dev 1999;21:129–131. [16] Fusco L, Vigegano F. Ictal clinical electroencephalographic findings of spasms in West syndrome. Epilepsia 1993;34:671–678. [17] Drury I, Beydoum A, Garofalo EA, Henry TR. Asymmetric hypsarrhythmia: clinical electroencephalographic and radiological findings. Epilepsia 1995;36:41–47. [18] Gaily EK, Shewmon DA, Chugani HT, Curran JG. Asymmetrical and asynchronous infantile spasms. Epilepsia 1995;36:873–882. [19] Acharya JN, Wyllie E, Luders HO, Kotagal P, Lancman M, Coelho M. Seizure symptomatology in infants with localization-related epilepsy. Neurology 1997;48:189–196. [20] Vallabhajosula S, Zimmerman RE, Picard M, Stritzke P, Mena I,
K. Haginoya et al. / Brain & Development 23 (2001) 496–501 Hellman R, et al. Technetium-99m ECD: a new brain imaging agent: in vitro kinetics and biodistribution studies in normal human subjects. J Nucl Med 1989;30:599–604. [21] Chiron C, Vera P, Kaminska A, Hollo A, Cieuta C, Ville D, et al. Single-photon emission computed tomography: ictal perfusion in childhood epilepsies. Brain Dev 1999;21:444–446. [22] O’Brien TJ, So EL, Mullan BP, Hauser MF, Brinkmann BH, Bohnen
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NI, et al. Subtraction ictal SPECT co-registered to MRI improves clinical usefulness of SPECT in localizing the surgical seizure focus. Neurology 1998;50:445–454. [23] Watanabe E, Maki A, Kawaguchi F, Yamashita Y, Koizumi H, Mayanagi Y. Noninvasive cerebral blood volume measurement during seizures using multichannel near infrared spectroscopic topography. J Epilepsy 1998;11:335–340.
Review article
Mechanism of tonic spasms in West syndrome viewed from ictal SPECT findings Kazuhiro Haginoya a,*, Mitsutoshi Munakata a, Hiroyuki Yokoyama a, Rie Kato a, Soichiro Tanaka a, Mieko Hirose a, Mamiko Ishitobi a, Kimiya Kon a, Yasushi Yoshihara a, Masaru Takayanagi a, Tetsuro Yamazaki b, Kazuie Iinuma a a
Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan Department of Radiology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
b
Received 19 July 2001; received in revised form 30 July 2001; accepted 2 August 2001
Abstract To clarify the pathophysiology of tonic spasms, 21 patients with West syndrome were analyzed using ictal and interictal single photon emission computed tomography (SPECT). We focused on whether ictal perfusion changes were observed in the focal cortical region. Eight of the patients studied showed definite focal cortical ictal hyperperfusion, indicating that there is a unique subset of West syndrome that can be classified as infantile localization-related epilepsy. Of those eight patients, only two showed asymmetric spasms, suggesting that seizure symptomatology in infants gives only limited information on the localization-related nature of epilepsy. Furthermore, the activation of subcortical structures by focal cortical regions might be attributable to the symmetric seizure phenomena. Thirteen patients showed a diffuse pattern in their ictal SPECTs; this probably included patients with diffuse hyperperfusion and those with no changes. The following have yet to be determined: (1) whether West syndrome is divided into subgroups based on the origin of spasms, in that some patients have the origin in the cortical hemisphere and some have the origin in structures other than the cortical hemisphere, such as the brain stem; (2) whether differences in ictal SPECT patterns reflect a unique nature of tonic spasms in West syndrome, where tonic spasms appear in clusters and the interval of each spasm is different among each patient. q 2001 Elsevier Science B.V. All rights reserved. Keywords: West syndrome; Single photon emission computed tomography; Tonic spasms; Infantile spasms; Hypsarrhythmia; Ictal single photon emission computed tomography; Asymmetric spasms
1. Introduction West syndrome is an age-dependent epileptic encephalopathy that has multiple etiologies and diverse psychomotor outcomes. Although West syndrome is classified as a generalized epileptic syndrome because of the generalized EEG abnormalities and its bilateral clinical manifestations [1], recent neuroimaging studies [2–5] indicate that pathologic conditions in the cortex play an important role in the pathogenesis of the tonic spasms in patients with West syndrome. However, the pathophysiology of West syndrome is still poorly understood, in spite of extensive work by many investigators [6–9]. Since regional cerebral blood flow (rCBF) increases at the epileptogenic focus during ictus and decreases in the same area during the interictal period, ictal single photon emis-
sion computed tomography (SPECT) has recently come to be considered as a reliable tool for the presurgical detection of epileptogenic foci in patients with intractable localization-related epilepsy [10,11]. Since cortical resection has also been considered as a treatment for West syndrome [3], ictal SPECT should be examined to determine whether patients have such a region when they have intractable seizures to anticonvulsants. However, most neuroimaging studies reported for West syndrome are based on interictal neuroimaging [3,4,12,13], and ictal SPECT studies of West syndrome in the literature are limited, except for our report [14,15]. We found heterogeneity in the ictal SPECT findings among patients, that is, ictal cortical hyperperfusion and subcortical hyperperfusion [14]. In order to clarify the heterogeneity of the ictal SPECT findings in West syndrome, we performed further studies using a larger patient population.
* Corresponding author. Fax: 181-22-717-7290. E-mail address: [email protected] (K. Haginoya). 0387-7604/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S03 87- 7604(01)0029 8-4
K. Haginoya et al. / Brain & Development 23 (2001) 496–501
2. Patients and methods All 21 patients, including patients who participated in the previous study [14], were diagnosed with West syndrome, which is defined by clusters of tonic spasms and hypsarrhythmia. We defined spasms as brief contractions of the extremities followed by a short tonic phase which lasted longer than myoclonic jerks but were shorter than a tonic seizure. A clinical summary of the patients is listed in Table 1. We received informed consent from the families of all of the patients during their first admission. For ictal SPECT, as soon as the attending pediatrician noticed the occurrence of tonic spasms, [ 99mTc]ethyl cysteinate dimer (ECD) was injected intravenously and flushed thoroughly with saline. The dose of [ 99mTc]ECD was 185 MBq. SPECT images were acquired 30 min after the injection using a MULTISPECT 3 (Siemens, Gerfahldt, Germany). In a period of 20 min, 120 projection datum points in a 128 £ 128 matrix were obtained. Using an Icon (Siemens) computer system, tomograms two pixels thick (5.8 mm) were reconstructed after a high-frequency cutoff with a Butterworth filter. Axial and coronal slices were constructed parallel and perpendicular to the orbitomeatal plane, while sagittal slices were constructed parallel to the longitudinal fissure. Infants were anesthetized with trichloryl hydrochloride or diazepam during the scanning. Interictal SPECT was done while the infants were awake, and none showed clinical evidence of seizures during the interictal SPECT study. The mean interval between ictal and interictal SPECT was 17 days. Spasms were classified as symmetric or asymmetric by the attending pediatrician. Asymmetric spasms were defined as spasms that were asymmetric on the two sides of the body, as defined by Fusco and Vigegano [16]. SPECT images were independently visually analyzed by a pediatric neurologist and a radiologist, and localized cerebral perfusion abnormalities were judged to be present only when both evaluations coincided. Since subcortical perfusion is difficult to assess without quantitative data, in this analysis we focused on whether cortical perfusion changes were focal and asymmetric or nonfocal. Ictal cortical perfusion changes were classified as Group A (focal asymmetric cortical hyperperfusion) or Group B (diffuse perfusion patterns that included those with diffuse cortical perfusion changes or no recognizable changes). The results were statistically evaluated using Fisher’s exact probability method. Significance was established at P , 0:05.
3. Results (Table 1) Eight of the 21 patients were classified into Group A (focal asymmetric cortical hyperperfusion). The rest of the patients were considered to be in Group B (diffuse perfusion patterns that included those with diffuse cortical perfusion changes or no recognizable changes). Three of seven (43%) patients with cryptogenic West syndrome were classified
497
into Group A, whereas five of 14 (36%) patients with symptomatic West syndrome were classified into Group A (P . 0:99). One of eight (13%) patients with normal interictal SPECT findings showed focal cortical ictal hyperperfusion, whereas seven of 13 (54%) patients with abnormal interictal SPECT findings had focal cortical ictal hyperperfusion (P ¼ 0:09). Asymmetric spasms were observed in only four patients with symptomatic West syndrome (30%); however, there was no correlation between asymmetric spasms and symptomatic West syndrome (P ¼ 0:26), unlike the results reported by Fusco and Vigegano [16]. When focal signs like eye deviation were included in the asymmetric spasms, seven patients (50%) with symptomatic West syndrome were categorized into this group, whereas one patient (14%) with cryptogenic West syndrome was categorized into this group (P ¼ 0:17). Two of eight (25%) patients in Group A showed asymmetric spasms, whereas two of 13 (15%) patients in Group B showed asymmetric spasms (P ¼ 0:62). When focal signs, such as eye deviation, were included in the asymmetric spasms, three (38%) patients in Group A showed asymmetric spasms, whereas five (38%) patients in Group B showed asymmetric spasms (P . 0:99). Of the eight patients who were categorized into Group A, hyperperfused regions were observed in the right frontal area (four patients), right temporal area (one patient), left temporal area (one patient), and left temporal to occipital areas (one patient) (Fig. 1a–e). One patient (patient 2) that showed changes in the left parietal area from focal hypoperfusion to isoperfusion during spasms was also included in this category. Of four patients with tuberous sclerosis, three showed focal hyperperfusion in the right frontal area on ictal SPECT (Fig. 1b), but the other patient showed a diffuse pattern. In this study, cortical dysplasia was only recognized in one patient (patient 8) with tuberous sclerosis. This patient had periventricular nodules and a large area of ectopic gray matter in the right frontal base (Fig. 1a). In patient 3, who had ictal hyperperfusion of the left temporal area, focal spike-waves were frequently observed in this area, and diffuse and irregular spike-waves were also observed on the interictal EEG (Fig. 1e). The ictal EEG showed spikes and slow waves in all areas during each spasm; however, some of the discharges began in the left hemisphere. Patient 5 showed hemi-hypsarrhythmia on the right side, and her seizure showed hemi-spasms of the left extremities and leftward eye deviations. However, she had symmetric spasms on the day of the ictal SPECT study, and showed hyperperfusion of the right frontal area. Thirteen patients were classified into Group B (Fig. 2a– c). Patient 14 had congenital hydrocephalus, and a ventriculoperitoneal shunt operation was performed early in the postnatal period. Interictal EEG showed hemispheric hypsarrhythmia over the left hemisphere, the side on which the hydrocephalus was prominent. He had asymmetric spasms. Patient 17 had an intrauterine hemorrhage of the left thalamus (Fig. 2b). On the interictal SPECT, this
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Table 1 Clinical summary of patients and results of ictal SPECT study a Patient no.
Sex
Onset (months)
Class
Age at ictal SPECT (months)/interval (days)*
Etiology
CT/MRI
EEG interictal/ictal
SPECT
Interictal F F M M F M
1.5 4.5 5.5 3.5 7 6
C C C S S S
3/31 6/6 6/22 4/7 12/90 7.5/14
7 8
F F
3 2
S S
5/20 2/8
Unknown Tuberous sclerosis
9 10 11 12 13 14
F M F M F M
7 6 4 7 6.5 8
C C C C S S
9/5 6.6/7 6/20 8/4 11/49 8/17
15
F
S
15/13
Unknown Unknown Unknown Unknown Tuberous sclerosis Congenital hydrocephalus Porencephaly
16 17
F F
6.5 6
S S
7/7 7/13
18
F
4.5
S
4.5/5
19
M
7.5
S
10/5
Unknown
20 21
M F
S S
6/5 12/7
Unknown Hypoxic-ischemic encephalopathy
11
5 12
Unknown Unknown Unknown Tuberous sclerosis Tuberous sclerosis Neurofibromatosis 1
Fetal distress Intrauterine Lthalamic hemorrhage Unknown
Normal Normal Normal Multiple tubers Multiple tubers Normal
Hyps/n.d. Hyps/n.d. Hyps/diffuse spike-waves Hyps/diffuse HVS R-hemi-hyps/n.d. Hyps/diffuse HVS
Multifocal hypo L-P hypo Normal Multifocal hypo Multifocal hypo Bilateral basal ganglia hyper Brain atrophy Hyps/diffuse irregular spikes L-O hypo Multiple tubers/ectopic gray Asymmetric hyps/R-hemi-sharp R-F hypo matter waves or HVS Normal Hyps/diffuse HVS Normal Normal Hyps/n.d. Normal Normal Hyps/n.d. Normal Normal Hyps/n.d. Normal Multiple tubers Hyps/n.d. Multifocal hypo L-hydrocephalus (postL-hemi-hyps/L-HVS L-TPO hypo shunt op.) Defect of L-hemisphere L-F-focal hyps/L-F-HVS R-residual F hyper hydrocephalus (post-shunt op.) Normal Hyps/diffuse spike-waves Normal L-enlarged lateral ventricle, L-hemi-hyps/n.d. L-TO, L-thalamus L-thalamus atrophy hypo Enlarged both lateral Hyps/n.d. Normal ventricle L-chronic subdural Hyps/diffuse fast waves Bilateral P-O hypo hemorrhage, atrophy of bilateral O Normal Hyps/diffuse fast waves Normal Brain atrophy Hyps/diffuse fast waves Diffuse hypo
Ictal A (R-F) A (L-P hypo-iso) A (L-T) A (R-F) A (R-F) A (R-T)
a a a* a a a
A (L-O-T) A (R-F)
b b
B B B B B B
a a a a a b
B
a
B B
a a*
B
b
B
a
B B
a* a*
a S, symptomatic; C, cryptogenic; A, focal asymmetric cortical hyperperfusion; B, diffuse pattern; a, symmetric spasms; a*, symmetric spasms with eye deviation; b, asymmetric spasms; L, left; R, right; F, frontal area; T, temporal area; P, parietal area; O, occipital area; hyps, hypsarrhythmia; HVS, high voltage slow waves; hypo, hypoperfusion; hyper, hyperperfusion; n.d., not done; interval (days)*, interval period (in days) between ictal and interictal SPECT.
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1 2 3 4 5 6
Clinical feature of spasms
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brain stem. Since her spasms were symmetrical, it seems as if the sensorimotor cortex is not required for the appearance of spasms. However, the brain stem, which contains the descending pathways controlling spinal reflexes and other infra-tentorial structures, seems to be essential for the occurrence of the spasms.
4. Discussion The focal asymmetric cortical hyperperfusion demonstrated in eight cases clearly indicates that there is a subset of West syndrome that can be classified into localizationrelated infantile epilepsy. Although abnormal interictal SPECT findings did not correlate significantly with focal cortical ictal hyperperfusion, patients with abnormal interictal SPECT findings may have focal cortical epileptogenic foci. There have been reports of patients with West syndrome who have asymmetric hypsarrhythmia or asymmetric tonic spasms [16–18]. Most of those reports emphasize that asymmetric tonic spasms are closely associated with symptomatic West syndrome or asymmetric hypsarrhythmia, indicating the existence of a cerebral lesion. We did not find a significant correlation between symptomatic West syndrome and asymmetric spasms, probably because of the small number of patients in this study. The important result in our study is that asymmetric spasms did not correlate with focal cortical ictal hyperperfusion. Even in patients
Fig. 1. Ictal SPECT showing focal asymmetric cortical hyperperfusion classified as Group A. (a) Patient 8; (b) patient 4; (c) patient 6; (d) patient 1; (e) patient 3. The arrowheads show hyperperfused regions.
patient showed focal hypoperfusion of the left occipital to temporal areas, as well as of the left thalamus. The interictal EEG showed a localized appearance of hypsarrhythmia over the left hemisphere. Since the hypoperfused areas in both of these patients remained unchanged on the ictal SPECT as compared to the surrounding areas, those areas did not seem to contribute directly to the occurrence of spasms in these patients, although the hypsarrhythmia might have been related to those areas. Patient 18 had asymmetric spasms every 5 s; however, the ictal SPECT showed no focal changes in cerebral perfusion patterns (Fig. 2a). Patient 15 had congenital extensive porencephaly and hydrocephalus [15]. Her spasms were quite symmetrical in spite of a massive defect in the left hemisphere. The interictal EEG showed very high voltage slow waves mixed with spikes and poly-spikes in the right frontal area. The ictal SPECT showed relatively high perfusion of the cerebellum and the
Fig. 2. Ictal SPECT showing diffuse perfusion patterns classified as Group B. (a) Patient 18; (b) patient 17; (c) patient 21.
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with focal cortical epileptogenic foci proven by ictal SPECT, spasms can appear symmetrically. Alternatively, asymmetric spasms are not necessarily indicative of focal cortical ictal hyperperfusion. These results indicate that, as in the cases reported by Acharya et al. [19], seizure symptomatology in infants may give only limited clues to the localization-related nature of the epilepsy. Focal cortical epileptogenic lesions might have secondarily activated subcortical structures, resulting in bilateral contraction of the extremities [2]. To answer the question of why the rest of the patients showed diffuse patterns and no focal cortical changes, one must consider the unique nature of tonic spasms in West syndrome. The spasms appear in clusters and the interspasm interval is varied individually. [ 99mTc]ECD is a chemically stable, neutral, lipophilic compound. It can easily cross the blood-brain barrier, and the first pass extraction is proportional to the rCBF. Maximal activity is reached 1 min after administration. Subsequently, it is metabolized to a hydrophilic compound and trapped intracellularly, demonstrating prolonged intracerebral retention [20]. This allows us to freeze the cerebral blood flow at the time of ictus and to evaluate ictal changes in blood flow with [ 99mTc]ECD. Since we do not have any information about how brain perfusion temporarily changes during a series of spasms, we do not know if any differences in brain perfusion depend on the interval between spasms. From a clinical point of view, however, in patients whose spasms appear in rapid succession, e.g. every 5 s, an ‘ictal SPECT’ might reflect what is happening during ictus, whereas in patients whose spasms appear every 30 s, we might not see any changes on the ‘ictal SPECT’ images, even if there are focal cortical changes with each spasm. Another explanation is that West syndrome might be divided into subgroups based on the origin of the spasms. Some patients have spasms that originate in the cortical hemispheres [17–19], and some have spasms that originate in structures other than the cortical hemispheres, such as the brain stem. Even in a patient whose spasms appeared in a short interval, the ictal SPECT showed no focal changes in cerebral perfusion patterns as listed in Fig. 2. As described in the results section, the ictal SPECT findings of the three patients who had extensive MRI abnormalities in the hemisphere associated with hemi-hypsarrhythmia or focal hypsarrhythmia were informative. From these findings, it seems that subcortical structures are primarily important in generating tonic spasms in some patients with West syndrome. To further understand the pathophysiology of tonic spasms, the application of subtraction ictal SPECT co-registered with MRI (SISCOM) analysis might be helpful, as demonstrated in patients with localization-related epilepsy [21,22]. This method would overcome many of the limitations associated with the traditional side-by-side inspection of the images. Near infrared spectrophotometry (NIRS) is also a promising technique for understanding seizure
phenomena in infants, because it allows noninvasive and continuous monitoring of cerebral blood flow during seizures [23].
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