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99Tc-HmPAO SPECT in 13 patients with classic lissencephaly
99
Tc-HmPAO SPECT in 13 Patients With Classic Lissencephaly
¨ zmen, MD*, Is¸ık Adalet, MD†, Mine C Yu¨ksel Yılmaz, MD*, Meral O ¸ alıs¸kan, MD*, † ¨ ¨ Seher Unal, MD , Nur Aydınlı˙, MD*, and Ozenc¸ Minareci, MD‡ In this study, technetium-99 (99Tc)-hexamethylpropyleneamine-oxine single-photon emission computed tomography (SPECT) was performed on 13 children with classic lissencephaly (nine with epileptic seizures, four without seizures). Focal or multifocal hypoperfusions were observed in 12 patients. The hypoperfused areas observed on SPECT scanning did not correlate with the localization of agyric-pachygyric regions in all patients. The distribution of perfusion abnormalities by SPECT and the localization of agyria-pachygyria as detected by magnetic resonance imaging did not correlate strongly. All nine patients with seizures and three of the four patients without seizures had focal or multifocal cerebral blood flow abnormalities on the SPECT scans. The presence of brain perfusion abnormalities detected by SPECT and the occurrence of epileptic seizures did not have a significant relationship. These results suggest that the role of SPECT studies in classic lissencephaly is not clearly defined. More sophisticated methods are needed to clarify the correlation between structural and functional abnormalities of patients diagnosed with lissencephaly. © 2000 by Elsevier Science Inc. All rights reserved. ¨ zmen M, Adalet I, C ¨ nal S, Yılmaz Y, O ¸ alıs¸kan M, U 99 ¨ Aydınlı N, Minareci O. Tc-HmPAO SPECT in 13 patients with classic lissencephaly. Pediatr Neurol 2000;22: 292-297.
Introduction Lissencephaly, a common type of neuronal migration disorder (NMD), is a disturbance of cortical architecture resulting from the arrest of neuronal migration toward the neocortex. It results in a total or partial absence of sulci, which demonstrate a typical flattened and thickened cerebral cortex [1-3]. On the basis of morphologic, genetic,
From the Departments of *Pediatrics, Division of Pediatric Neurology; † Nuclear Medicine; and ‡Radiology, Division of Neuroradiology; Istanbul University; Istanbul Medical Faculty; Istanbul, Turkey.
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and clinical criteria, several types of lissencephaly have been identified [2-7]. Type I (classic lissencephaly) and type II (cobblestone lissencephaly) are the most commonly encountered and well-established forms. Type I lissencephaly occurs most often as an isolated defect, referred to as an isolated lissencephaly sequence. It also occurs as part of a multiple congenital anomaly syndrome known as Miller-Dieker syndrome [3,4,8]. In patients with the isolated lissencephaly sequence the brain malformation may be severe as in Miller-Dieker syndrome or less severe [4]. Single-photon emission computed tomography (SPECT) is a functional imaging technique increasingly used in the investigation of patients with epilepsy, usually before epilepsy surgery [9-11]. Little is known about the cerebral blood flow of the disturbed architecture in the cortical plate in lissencephaly [12-14]. In this report the perfusion abnormalities detected by technetium-99 (99Tc)-hexamethylpropyleneamine-oxine (HmPAO) SPECT studies in 13 children with type I lissencephaly with and without epilepsy are presented. Subjects and Methods Subjects. Thirteen patients (six females and seven males) diagnosed with type I lissencephaly with a mean age of 28.4 months (range ⫽ 7 months to 5 years) were included in this study. The diagnosis of type I lissencephaly was made by magnetic resonance imaging (MRI) findings according to the criteria established by Dobyns and Truwit [5] and Barkovich [2]. The classification of lissencephaly was made according to the grading system recommended by Dobyns et al. [4] and Dobyns and Truwit [5]: grade 1, diffuse agyria; grade 2, widespread agyria with restricted areas of pachygyria; grade 3, a mixture of agyria and pachygyria; grade 4, diffuse pachygyria without agyria; grade 5, mixed pachygyria and subcortical band heterotopia; and grade 6, subcortical band heterotopia. Two patients were classified as having lissencephaly grade 2, five as having grade 3, and six as having grade 4. None of the patients had the characteristic facial appearance that occurs with Miller-Dieker syndrome. Chromosome analysis was performed in two patients with grade 2 lissencephaly to investigate a
Communications should be addressed to: Dr. Yılmaz; Acıbadem Tekin Sk. Turan Ap. No. 18/14; Kadıko¨y, Istanbul, Turkey. Received June 21, 1999; accepted January 6, 2000.
© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(00)00121-1 ● 0887-8994/00/$20.00
deletion of chromosome 17 (17p13.3), an indication of Miller-Dieker syndrome; no abnormality was detected. Nine patients (two with grade 2, three with grade 3, and four with grade 4 lissencephaly) had epileptic seizures. Interictal SPECT. Interictal 99Tc-HmPAO SPECT was performed in all patients (the epileptic patients had been seizure free for at least 24 hours before examination). The purpose and methods of the SPECT study were explained to the parents of each child, and informed consent was obtained. Hydroxyzine hydrochloride, 10 or 20 mg, in a single oral dose was given to all children for sedation after injection of the tracer. Freeze-dried HmPAO (Ceretec, Amersham, Buckinghamshire, UK) was reconstituted with 20-25 mCi (740-900 MBq) 99mTcO4 (pertechnetate) and injected into a peripheral vein within 15 minutes of preparation in a 0.2-0.3 mCi/kg dose. SPECT scans were performed within 2 hours of the tracer injection using a rotating gamma camera (Siemens Orbiter ZLC 7500, Erlangen, Germany). A low-energy all-purpose collimator was used. Sixty-four images were acquired over 360 degrees, with an acquisition time of 25 seconds per frame. Data was collected on a 64 ⫻ 64 matrix and then transaxial, coronal, and sagittal 6-mm slices were processed by back-filtered projection with a Butterwort prefilter after a uniformity and attenuation correction. Interictal electroencephalography (EEG), with scalp electrodes using the International 10-20 system, was recorded within 2 hours after the completion of the interictal SPECT. Visual evaluation of the MRI and 99Tc-HmPAO SPECT scans was performed independently. MRI scans were interpreted by a neuroradiologist unaware of the clinical manifestations and SPECT findings of the patients. SPECT investigations were interpreted by two nuclear medicine specialists who were unaware of either the MRI results or the clinical status. MRI, EEG, and SPECT findings were compared, and relationships between the localization of agyric-pachygyric areas and SPECT findings were examined. Statistical analyses were performed with Fisher’s Exact Test.
Results Interictal 99Tc-HmPAO SPECT, MRI, and interictal EEG findings for the patients are presented in Table 1. SPECT studies indicated that 13 children had cerebral blood flow abnormalities: three patients (Patients 2, 6, and 13) demonstrated focal hypoperfusion, nine patients (Patients 1, 3, 4, 5, 7, 8, 10, 11, and 12) had multifocal abnormalities, and normal results were observed in one patient (Patient 9). The areas of hypoperfusion detected by SPECT examinations were not consistent with the distribution of agyric-pachygyric regions in the study group. Only some areas of the agyric-pachygyric cortex revealed hypoperfusion by SPECT (Figs 1 and 2). On the other hand, in one patient with grade 4 lissencephaly (Patient 7), SPECT revealed hypoperfusion in an area that had a normal appearance on MRI. SPECT examinations revealed brain perfusion abnormalities in all patients with epilepsy and in three of the four patients without epilepsy. There was no significant relationship between the presence of brain perfusion abnormalities detected by SPECT and the occurrence of epileptic seizures (P ⫽ 0.3). The areas of hypoperfusion on interictal SPECT images were not entirely consistent with the interictal EEG pattern of the patients with epilepsy. In three patients, EEG revealed a diffuse, slow spike-and-wave discharge with high amplitude. Patient 2 had focal hypoperfusion on the right parietal region as
indicated by SPECT, and Patients 1 and 3 had multifocal hypoperfusion. The interictal EEG for Patient 6 revealed bilateral frontoparietal spikes, and the SPECT scan revealed hypoperfusion only on the left frontal region. Discussion Lissencephaly, a common and severe type of NMD, is a cortical malformation characterized by a smooth cerebral surface and the reduction or absence of cortical gyri [1-6,15-19]. Several different types of lissencephaly have been described. Classic lissencephaly (type I) results in a smooth cerebral surface, a notably thickened cortex, with four abnormal layers, widespread neuronal heterotopia, narrow white matter, and the absence of white-gray matter interdigitations [5,20]. Patients with lissencephaly present with various clinical findings, including microcephaly, developmental delay, seizures, and motor deficits. Seizures have been reported in 75-90% of the patients (infantile spasms in 35-50%) with lissencephaly [4,17,18,21,22]. It is not yet clear which factors are responsible for the occurrence of seizures in patients with lissencephaly and similar neuroradiologic abnormalities. SPECT, a functional neuroimaging method, has been used for imaging regional blood flow in patients with various neurologic disorders, such as epilepsy, encephalitis, brain tumors, movement disorders, neurodegenerative diseases, and cerebrovascular disorders [23-32]. Hypoperfused areas on SPECT scans may result from low cerebral blood flow caused by cerebral vasculature abnormalities or structural neuronal defects, including dysgenesia, gliotic lesions, tumor, and infarct [9,11,28]. Also, it may indicate that the functional activity of the cell groups in these hypoperfused areas is low. This study sought to investigate the relationship between the structural abnormalities visualized on MRI and the functional anomalies demonstrated by SPECT. Focal or multifocal hypoperfusion defects were detected in 12 patients in whom no strong correlation between dysplastic cortical areas observed on MRI scans and the distribution of brain perfusion abnormalities detected by 99TcHmPAO SPECT was evident. In some patients (Patients 1, 2, 4, 6, and 13), only limited areas of agyric-pachygyric cortex had hypoperfusion on SPECT, and the other dysplasic areas did not demonstrate any perfusion abnormality. In Patient 1, who had bilateral temporo-parietooccipital agyria, SPECT scans exhibited hypoperfusion only on the right mesial and left lateral temporal regions. In Patients 2 and 13, only focal hypoperfusion was detected on SPECT, although the MRI scans demonstrated diffuse pachygyria. The SPECT image was normal in one patient (Patient 9) with diffuse pachygyria, and in another patient (Patient 7), hypoperfusion was detected in the right temporal area, which appeared to be normal on the MRI scans. Why the areas of hypoperfusion were not consistent
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3
4
4
4
4
2
3
4
6
7
8
9
10
11
12
13
Diffuse
R, L frontal R, L parietal R, L temporal
—
R, L frontal R, L parietal R, L occipital Diffuse
R, L occipital R, L temporal R frontoparietal R, L frontal L temporal R, L parietal Diffuse
R, L frontal R, L temporal Anterior regions of bilateral parietal cortex R, L frontal L parietal R, L temporal R, L occipital Diffuse
Diffuse
—
R SGPE SPECT SSW
R, R, R, R,
⫽ ⫽ ⫽ ⫽
L L L L
⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫹
⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹
⫺
⫺
⫹
⫺
⫹
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
SPECT Findings Focal Hypoperfusion N
⫹
Multifocal Hypoperfusion
Right Secondary generalized partial epilepsy Single-photon emission computed tomography Slow spike-and-wave
—
parietal temporal occipital occipital
—
—
—
—
L frontoparietal
—
R parietal
R, L occipital Posterior regions of bilateral parietal cortex
R, L parietal R, L temporal R, L occipital —
Agyric Areas
MRI Findings
Pachygyric Areas
Abbreviations: EEG ⫽ Electroencephalography L ⫽ Left LGS ⫽ Lennox-Gastaut syndrome MRI ⫽ Magnetic resonance imaging N ⫽ Normal
4
3
3
5
4
2
3
2
1
4
Lissencephaly Grade
MRI, interictal SPECT, and interictal EEG findings of 13 patients with lissencephaly type I
Pt. No.
Table 1.
L temporoparietal R, L temporal R parietal R, L frontal R parieto-occipital
R, L frontal R, L parietal R occipital L parietal R temporoparietal
R, L frontal L temporal R, L parietal —
R, L temporal R, L parietal
R, L occipital R temporal R, L parietal L frontal
Bilateral parasagittal
R, L frontal R, L parietal R temporal
R parietal
R mesial temporal L lateral temporal
Hypoperfused Areas
LGS
WS
WS
LGS
—
SGPE
—
LGS
—
—
WS
LGS
LGS
Epilepsy
SSW and sharp waves in the right hemisphere, spikes on the left temporoparietal area
Irregular diffuse SSW discharges with high amplitude, multifocal spikes on the bilateral frontoparietal regions Generalized irregular SSW discharges
Irregular generalized spike-and-wave paroxysms
—
Bilateral temporal occasional sharp waves
—
Bilateral frontoparietal spikes
—
—
Diffuse 1.5- to 2-Hz SSW discharges, diffuse irregular spike waves Diffuse slow waves with high amplitude, generalized multifocal spikes
Diffuse 2- to 2.5-Hz SSW discharges with high amplitude
EEG Findings
Figure 1. Imaging studies of Patient 11 (grade 2 lissencephaly). (A) MRI T1-weighted, coronal scan; TR ⫽ 495 ms, TE ⫽ 25 ms). (B) SPECT scan (coronal view) revealing hypoperfusion in the left parietal area. (C) MRI (T1-weighted, sagittal scan; TR ⫽ 495 ms, TE ⫽ 25 ms). (D) SPECT (sagittal scan) exhibiting hypoperfusion in the left parietal area.
with the localization of agyric-pachygyric regions in all patients with lissencephaly is not clear. One explanation might be that the histologic abnormalities of the cortex, which cannot be detected by MRI, may result in perfusion abnormalities. Histologic analyses of agyric-pachygyric cortex reveal a chaotic pattern without discernible layering and extensive leptomeningeal gliomesenchymal proliferations and glioneuronal heterotopias [20]. Within all cortical layers, pyramidal cells are often abnormally oriented, with their apical dendrite pointing in an oblique direction or downward [1]. Houdou et al. [33], studying the immunohistochemical staining of the agyric cortex, suggested that the neurons with forming myelin sheaths in the superficial cellular layer regularly penetrate the surface of the molecular layer, forming arrested columns in the deep cellular layer. Although abnormal vascular drainage of pachygyric cortex has been described, evidence is limited about the microvasculature of the agyric-pachygyric cortex [34]. The underlying ultrastructural abnormality that cannot be visualized by MRI together with abnormal
microvasculature may result in an alteration of the cerebral blood flow status. Perfusion abnormalities and metabolic disturbances in the dysplastic cortical regions detected through MRI of patients with NMDs have been demonstrated by SPECT and positron emission tomography [35-43]. Relatively few SPECT studies of patients with lissencephaly have been conducted. In the SPECT study by Al-Suhaili et al. [13], diffuse cortical hypoperfusion was observed in three epileptic patients with lissencephaly. In the study of Ianetti et al. [14], interictal SPECT examinations were performed in seven patients with NMDs, two of whom had agyriapachygyria and seizures. In both of these patients the SPECT images manifested hypoperfused cortical areas; however, the focal perfusion abnormalities of the SPECT images were not totally consistent with the agyricpachygyric areas evident on MRI. Otsubo et al. [12] reported three epileptic patients with pachygyria, with one patient having normal interictal SPECT findings. The data obtained from these studies and current studies are not
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Figure 2. Imaging studies of Patient 13 (grade 4 lissencephaly). (A) MRI proton-density sagittal scan; TR ⫽ 2,500 ms, TE ⫽ 30 ms). (B) SPECT (sagittal scan) demonstrating hypoperfusion in the right parieto-occipital area. (C) MRI (proton-density coronal scan; TR ⫽ 2,500 ms, TE ⫽ 30 ms). (D) SPECT (coronal scan) with hypoperfusion in the right parietal area.
enough to clarify the underlying ultrastructural abnormalities and functional status of the lissencephalic cerebral cortex. Histopathologic evaluation of the hypoperfused areas may be able to demonstrate the microvasculature and histologic nature. What role SPECT scans should have in the evaluation of epileptic and nonepileptic patients with type I lissencephaly and whether the seizures in some patients with lissencephaly are caused by functional abnormalities has not been determined. In the present study, three of the four patients without seizures or epileptogenic discharges on EEG had perfusion abnormalities on SPECT, and all nine patients with seizures had focal or multifocal hypoperfusion on interictal SPECT images. No significant correlation was evident between the presence of cerebral blood flow abnormalities and the occurrence of seizures. Conversely, the hypoperfused regions on interictal SPECT were not consistent with interictal EEG abnormalities in the patients with seizures. Patients with diffuse, slow spike-and-wave discharges on EEG had focal or multifo-
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cal hypoperfusion on SPECT (Patients 1, 2, and 11). The EEG of Patient 8 revealed focal discharges only in the temporal regions; however, the SPECT images revealed hypoperfusion on the bilateral frontoparietal and left temporal cortex. Previous reports have proved that SPECT scanning may be helpful in localizing the epileptogenic focus in epileptic patients [23-25]. SPECT studies are routinely used to evaluate patients before epilepsy surgery [44]. The results of the SPECT studies in epileptic patients with cortical dysplasia have suggested that SPECT may help detect a functional abnormality in an epileptogenic dysplastic region. In some studies, ictal SPECT has identified lesions not detected by MRI [14,35-37]. The present results suggest that hypoperfused areas detected by interictal SPECT may not always be consistent with an epileptogenic focus in patients with type I lissencephaly. In conclusion the functional activity of agyric-pachygyric areas may vary in patients with lissencephaly. In addition, SPECT may not be a reliable method for detect-
ing the epileptogenic focus in these patients. More sophisticated methods are needed to clarify the questions concerning the lissencephalic cerebral cortex. This work was supported by the Research Fund of the University of Istanbul. Project number: 738/260495.
References [1] Aicardi J. The agyria-pachygyria complex: A spectrum of cortical malformations. Brain Dev 1991;13:1-8. [2] Barkovich AJ. Anomalies of neuronal migration and organization. In: Barkovich AJ, ed. Pediatric neuroimaging, 2nd ed. New York: Raven Press, 1995:203-30. [3] Dobyns WB, Reiner O, Carrozzo R, Ledbetter DH. Lissencephaly: A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. JAMA 1993;270:2838-42. [4] Dobyns WB, Elias ER, Newin AC, Pagon RA, Ledbetter DH. Causal heterogeneity in isolated lissencephaly. Neurology 1992;42: 1375-88. [5] Dobyns WB, Truwit CL. Lissencephaly and other malformations of cortical development: 1995 update. Neuropediatrics 1995;26: 132-47. [6] Barkovich AJ, Kuzniecky RI, Dobyns WB, Jackson GD, Becker LE, Evrard P. A classification scheme for malformations of cortical development. Neuropediatrics 1996;27:59-63. [7] Allanson JE, Ledbetter DH, Dobyns WB. Classical lissencephaly syndromes: Does the face reflect the brain? J Med Genet 1998;35:920-3. [8] Dobyns WB, Curry CJR, Hoyme HE, Turlington L, Ledbetter DH. Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Med Genet 1991;48:584-94. [9] O’Tuama LA, Bjorson B, Chugani H, Treves SYT. Brain. In: Treves ST, ed. Pediatric nuclear medicine, 2nd ed. New York: Springer Verlag, 1995:88-108. [10] Sperling MR. Neuroimaging in epilepsy: Recent developments in MR imaging, positron emission tomography, and single-photon emission tomography. Neurol Clin 1993;11:883-903. [11] Shields WD. Anatomic and functional imaging in epilepsy. Int Pediatr 1995;10 (Suppl 1):72-7. [12] Otsubo H, Hwang PA, Jay V, et al. Focal cortical dysplasia in children with localization-related epilepsy: EEG, MRI, and SPECT findings. Pediatr Neurol 1993;9:101-7. [13] Al-Suhaili AR, Sztriha L, Prais V, Nork M. Agyria-pachygyria: Cerebral perfusion studies by 99mTc-HMPAO. Brain Dev 1997;19: 138-43. [14] Iannetti P, Spalice A, Atzei G, Boemi S, Trasimeni G. Neuronal migration disorders in children with epilepsy: MRI, interictal SPECT and EEG comparisons. Brain Dev 1996;18:269-79. [15] Palmini A, Andermann F, de Grissac H, et al. Stages and patterns of centrifugal arrest of diffuse neuronal migration disorders. Dev Med Child Neurol 1993;35:331-9. [16] Osborn RE, Byrd SE, Naidich TP, Bohan TP, Friedman H. MR imaging of neuronal migrational disorders. Am J Neuroradiol 1988;9: 1101-6. [17] Barkovich JA, Koch TK, Carrol CL. The spectrum of lissencephaly: Report of ten patients analyzed by magnetic resonance imaging. Ann Neurol 1991;30:139-46. [18] Gastaut H, Pinsard N, Raybaund C, Aicardi J, Zifkin B. Lissencephaly (agyria-pachygyria): Clinical findings and serial EEG studies. Dev Med Child Neurol 1987;29:167-80. [19] de Rijk-van Andel JF, Arts WF, Barth PG, Loonen MC. Diagnostic features and clinical signs of 21 patients with lissencephaly type 1. Dev Med Child Neurol 1990;32:707-17. [20] Kuchelmeister K, Bergmann M, Gullotta F. Neuropathology of lissencephalies. Childs Nerv Syst 1993;9:394-9.
[21] Mori K, Hashimoto T, Tayama M, et al. Serial EEG and sleep polygraphic studies on lissencephaly (agyria-pachygyria). Brain Dev 1994;16:365-73. [22] Pavone L, Rizzo R, Dobyns WB. Clinical manifestation and evaluation of isolated lissencephaly. Childs Nerv Syst 1993;9:387-90. [23] Zubal IG, Spencer SS, Imam K, et al. Difference images calculated from ictal and interictal technetium-99m-HMPAO SPECT scans of epilepsy. J Nucl Med 1995;36:684-9. [24] Spencer SS. The relative contributions of MRI, SPECT, and PET imaging in epilepsy. Epilepsia 1994;35 (Suppl 6):72-89. [25] Rowe CC, Berkovic SF, Sia ST, et al. Localisation of epileptic foci with postictal single photon emission computed tomography. Ann Neurol 1989;26:660-8. [26] Nara T, Nozaki H, Nishimoto H. Brain perfusion in acute encephalitis: Relationship to prognosis studied using SPECT. Pediatr Neurol 1990;6:422-4. [27] Moretti JL, Caglar M, Weinmann P. Cerebral perfusion imaging tracers for SPECT: Which one to choose? J Nucl Med 1995;36: 359-63. [28] Messa C, Fazio F, Costa DC, Ell PJ. Clinical brain radionuclide imaging studies. Semin Nucl Med 1995;25:111-43. [29] Kao CH, Wang SJ, Mak SC, Shian WJ, Chi CS. Viral encephalitis in children: Detection with technetium-99m HMPAO brain single-photon emission CT and its value in prediction of outcome. Am J Neuroradiol 1994;15:1369-73. [30] Iivanainen M, Launes J, Pihko H, Nikkinen P, Lindroth L. Single-photon emission computed tomography of brain perfusion: Analysis of 60 paediatric cases. Dev Med Child Neurol 1990;32:63-8. [31] Harvey AS. Functional neuroimaging with SPECT and PET in childhood developmental disabilities. Int Pediatr 1995;10:177-87. [32] Hayashida K, Hirose Y, Kaminaga Y, et al. Detection of postural cerebral hypoperfusion with technetium-99m-HMPAO brain SPECT in patients with cerebrovascular disease. J Nucl Med 1993;34: 1931-5. [33] Houdou S, Kuruta H, Konomi H, Takashima S. Structure in lissencephaly determined by immunohistochemical staining. Pediatr Neurol 1990;6:402-6. [34] Barkovich AJ. Abnormal vascular drainage in anomalies of neuronal migration. Am J Neuroradiol 1988:9:939-42. [35] Matsuda H, Onuma T, Yagishita A. Brain SPECT imaging for laminar heterotopia. J Nucl Med 1995;36:238-40. [36] Kao CH, Han NT, Liao SQ, Wang SJ, Liu RS, Yeh SH. Infantile spasm induced by hemispheric pachygyria ultrasound, MRI and Tc-99m HMPAO SPECT. Pediatr Radiol 1991;21:373-4. [37] Kuzniecky R, Mountz JM, Wheatley G, Morawetz R. Ictal single-photon emission computed tomography demonstrates localized epileptogenesis in cortical dysplasia. Ann Neurol 1993;34:627-31. [38] Lee N, Radtke RA, Gray L, et al. Neuronal migration disorders: Positron emission tomography correlations. Ann Neurol 1994;35:290-7. [39] Konkol RJ, Maister BH, Wells RG, Sty JR. Hemimegalenencephaly: Clinical, EEG, neuroimaging, and IMP-SPECT correlation. Pediatr Neurol 1990;6:414-8. [40] Miura K, Watanabe K, Maeda N, et al. Magnetic resonance imaging and positron emission tomography of band heterotopia. Brain Dev 1993;15:288-90. [41] Sugama S, Nakanishi Y, Okazaki M, Ito F, Eto Y, Maekawa K. SPECT (single photon emission computed tomography) findings in 4 cases of neuronal migration disorders (in Japanese) (abstract). No To Shinkei 1993;45:39-42. [42] Tagawa T, Otani K, Futagi Y, Wakayama A, Morimoto K, Morita Y. Case report. Serial IMP-SPECT and EEG studies in an infant with hemimegalenencephaly. Brain Dev 1994;16:475-9. [43] Rintahaka PJ, Chugani HT, Messa C, Phels ME. Hemimegalenencephaly: Evaluation with positron emission tomography. Pediatr Neurol 1993;9:21-8. [44] Neville B. Evaluation of children for epilepsy surgery. Int Pediatr 1995;10 (Suppl 1):78-80.
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Tc-HmPAO SPECT in 13 Patients With Classic Lissencephaly
¨ zmen, MD*, Is¸ık Adalet, MD†, Mine C Yu¨ksel Yılmaz, MD*, Meral O ¸ alıs¸kan, MD*, † ¨ ¨ Seher Unal, MD , Nur Aydınlı˙, MD*, and Ozenc¸ Minareci, MD‡ In this study, technetium-99 (99Tc)-hexamethylpropyleneamine-oxine single-photon emission computed tomography (SPECT) was performed on 13 children with classic lissencephaly (nine with epileptic seizures, four without seizures). Focal or multifocal hypoperfusions were observed in 12 patients. The hypoperfused areas observed on SPECT scanning did not correlate with the localization of agyric-pachygyric regions in all patients. The distribution of perfusion abnormalities by SPECT and the localization of agyria-pachygyria as detected by magnetic resonance imaging did not correlate strongly. All nine patients with seizures and three of the four patients without seizures had focal or multifocal cerebral blood flow abnormalities on the SPECT scans. The presence of brain perfusion abnormalities detected by SPECT and the occurrence of epileptic seizures did not have a significant relationship. These results suggest that the role of SPECT studies in classic lissencephaly is not clearly defined. More sophisticated methods are needed to clarify the correlation between structural and functional abnormalities of patients diagnosed with lissencephaly. © 2000 by Elsevier Science Inc. All rights reserved. ¨ zmen M, Adalet I, C ¨ nal S, Yılmaz Y, O ¸ alıs¸kan M, U 99 ¨ Aydınlı N, Minareci O. Tc-HmPAO SPECT in 13 patients with classic lissencephaly. Pediatr Neurol 2000;22: 292-297.
Introduction Lissencephaly, a common type of neuronal migration disorder (NMD), is a disturbance of cortical architecture resulting from the arrest of neuronal migration toward the neocortex. It results in a total or partial absence of sulci, which demonstrate a typical flattened and thickened cerebral cortex [1-3]. On the basis of morphologic, genetic,
From the Departments of *Pediatrics, Division of Pediatric Neurology; † Nuclear Medicine; and ‡Radiology, Division of Neuroradiology; Istanbul University; Istanbul Medical Faculty; Istanbul, Turkey.
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and clinical criteria, several types of lissencephaly have been identified [2-7]. Type I (classic lissencephaly) and type II (cobblestone lissencephaly) are the most commonly encountered and well-established forms. Type I lissencephaly occurs most often as an isolated defect, referred to as an isolated lissencephaly sequence. It also occurs as part of a multiple congenital anomaly syndrome known as Miller-Dieker syndrome [3,4,8]. In patients with the isolated lissencephaly sequence the brain malformation may be severe as in Miller-Dieker syndrome or less severe [4]. Single-photon emission computed tomography (SPECT) is a functional imaging technique increasingly used in the investigation of patients with epilepsy, usually before epilepsy surgery [9-11]. Little is known about the cerebral blood flow of the disturbed architecture in the cortical plate in lissencephaly [12-14]. In this report the perfusion abnormalities detected by technetium-99 (99Tc)-hexamethylpropyleneamine-oxine (HmPAO) SPECT studies in 13 children with type I lissencephaly with and without epilepsy are presented. Subjects and Methods Subjects. Thirteen patients (six females and seven males) diagnosed with type I lissencephaly with a mean age of 28.4 months (range ⫽ 7 months to 5 years) were included in this study. The diagnosis of type I lissencephaly was made by magnetic resonance imaging (MRI) findings according to the criteria established by Dobyns and Truwit [5] and Barkovich [2]. The classification of lissencephaly was made according to the grading system recommended by Dobyns et al. [4] and Dobyns and Truwit [5]: grade 1, diffuse agyria; grade 2, widespread agyria with restricted areas of pachygyria; grade 3, a mixture of agyria and pachygyria; grade 4, diffuse pachygyria without agyria; grade 5, mixed pachygyria and subcortical band heterotopia; and grade 6, subcortical band heterotopia. Two patients were classified as having lissencephaly grade 2, five as having grade 3, and six as having grade 4. None of the patients had the characteristic facial appearance that occurs with Miller-Dieker syndrome. Chromosome analysis was performed in two patients with grade 2 lissencephaly to investigate a
Communications should be addressed to: Dr. Yılmaz; Acıbadem Tekin Sk. Turan Ap. No. 18/14; Kadıko¨y, Istanbul, Turkey. Received June 21, 1999; accepted January 6, 2000.
© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(00)00121-1 ● 0887-8994/00/$20.00
deletion of chromosome 17 (17p13.3), an indication of Miller-Dieker syndrome; no abnormality was detected. Nine patients (two with grade 2, three with grade 3, and four with grade 4 lissencephaly) had epileptic seizures. Interictal SPECT. Interictal 99Tc-HmPAO SPECT was performed in all patients (the epileptic patients had been seizure free for at least 24 hours before examination). The purpose and methods of the SPECT study were explained to the parents of each child, and informed consent was obtained. Hydroxyzine hydrochloride, 10 or 20 mg, in a single oral dose was given to all children for sedation after injection of the tracer. Freeze-dried HmPAO (Ceretec, Amersham, Buckinghamshire, UK) was reconstituted with 20-25 mCi (740-900 MBq) 99mTcO4 (pertechnetate) and injected into a peripheral vein within 15 minutes of preparation in a 0.2-0.3 mCi/kg dose. SPECT scans were performed within 2 hours of the tracer injection using a rotating gamma camera (Siemens Orbiter ZLC 7500, Erlangen, Germany). A low-energy all-purpose collimator was used. Sixty-four images were acquired over 360 degrees, with an acquisition time of 25 seconds per frame. Data was collected on a 64 ⫻ 64 matrix and then transaxial, coronal, and sagittal 6-mm slices were processed by back-filtered projection with a Butterwort prefilter after a uniformity and attenuation correction. Interictal electroencephalography (EEG), with scalp electrodes using the International 10-20 system, was recorded within 2 hours after the completion of the interictal SPECT. Visual evaluation of the MRI and 99Tc-HmPAO SPECT scans was performed independently. MRI scans were interpreted by a neuroradiologist unaware of the clinical manifestations and SPECT findings of the patients. SPECT investigations were interpreted by two nuclear medicine specialists who were unaware of either the MRI results or the clinical status. MRI, EEG, and SPECT findings were compared, and relationships between the localization of agyric-pachygyric areas and SPECT findings were examined. Statistical analyses were performed with Fisher’s Exact Test.
Results Interictal 99Tc-HmPAO SPECT, MRI, and interictal EEG findings for the patients are presented in Table 1. SPECT studies indicated that 13 children had cerebral blood flow abnormalities: three patients (Patients 2, 6, and 13) demonstrated focal hypoperfusion, nine patients (Patients 1, 3, 4, 5, 7, 8, 10, 11, and 12) had multifocal abnormalities, and normal results were observed in one patient (Patient 9). The areas of hypoperfusion detected by SPECT examinations were not consistent with the distribution of agyric-pachygyric regions in the study group. Only some areas of the agyric-pachygyric cortex revealed hypoperfusion by SPECT (Figs 1 and 2). On the other hand, in one patient with grade 4 lissencephaly (Patient 7), SPECT revealed hypoperfusion in an area that had a normal appearance on MRI. SPECT examinations revealed brain perfusion abnormalities in all patients with epilepsy and in three of the four patients without epilepsy. There was no significant relationship between the presence of brain perfusion abnormalities detected by SPECT and the occurrence of epileptic seizures (P ⫽ 0.3). The areas of hypoperfusion on interictal SPECT images were not entirely consistent with the interictal EEG pattern of the patients with epilepsy. In three patients, EEG revealed a diffuse, slow spike-and-wave discharge with high amplitude. Patient 2 had focal hypoperfusion on the right parietal region as
indicated by SPECT, and Patients 1 and 3 had multifocal hypoperfusion. The interictal EEG for Patient 6 revealed bilateral frontoparietal spikes, and the SPECT scan revealed hypoperfusion only on the left frontal region. Discussion Lissencephaly, a common and severe type of NMD, is a cortical malformation characterized by a smooth cerebral surface and the reduction or absence of cortical gyri [1-6,15-19]. Several different types of lissencephaly have been described. Classic lissencephaly (type I) results in a smooth cerebral surface, a notably thickened cortex, with four abnormal layers, widespread neuronal heterotopia, narrow white matter, and the absence of white-gray matter interdigitations [5,20]. Patients with lissencephaly present with various clinical findings, including microcephaly, developmental delay, seizures, and motor deficits. Seizures have been reported in 75-90% of the patients (infantile spasms in 35-50%) with lissencephaly [4,17,18,21,22]. It is not yet clear which factors are responsible for the occurrence of seizures in patients with lissencephaly and similar neuroradiologic abnormalities. SPECT, a functional neuroimaging method, has been used for imaging regional blood flow in patients with various neurologic disorders, such as epilepsy, encephalitis, brain tumors, movement disorders, neurodegenerative diseases, and cerebrovascular disorders [23-32]. Hypoperfused areas on SPECT scans may result from low cerebral blood flow caused by cerebral vasculature abnormalities or structural neuronal defects, including dysgenesia, gliotic lesions, tumor, and infarct [9,11,28]. Also, it may indicate that the functional activity of the cell groups in these hypoperfused areas is low. This study sought to investigate the relationship between the structural abnormalities visualized on MRI and the functional anomalies demonstrated by SPECT. Focal or multifocal hypoperfusion defects were detected in 12 patients in whom no strong correlation between dysplastic cortical areas observed on MRI scans and the distribution of brain perfusion abnormalities detected by 99TcHmPAO SPECT was evident. In some patients (Patients 1, 2, 4, 6, and 13), only limited areas of agyric-pachygyric cortex had hypoperfusion on SPECT, and the other dysplasic areas did not demonstrate any perfusion abnormality. In Patient 1, who had bilateral temporo-parietooccipital agyria, SPECT scans exhibited hypoperfusion only on the right mesial and left lateral temporal regions. In Patients 2 and 13, only focal hypoperfusion was detected on SPECT, although the MRI scans demonstrated diffuse pachygyria. The SPECT image was normal in one patient (Patient 9) with diffuse pachygyria, and in another patient (Patient 7), hypoperfusion was detected in the right temporal area, which appeared to be normal on the MRI scans. Why the areas of hypoperfusion were not consistent
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3
4
4
4
4
2
3
4
6
7
8
9
10
11
12
13
Diffuse
R, L frontal R, L parietal R, L temporal
—
R, L frontal R, L parietal R, L occipital Diffuse
R, L occipital R, L temporal R frontoparietal R, L frontal L temporal R, L parietal Diffuse
R, L frontal R, L temporal Anterior regions of bilateral parietal cortex R, L frontal L parietal R, L temporal R, L occipital Diffuse
Diffuse
—
R SGPE SPECT SSW
R, R, R, R,
⫽ ⫽ ⫽ ⫽
L L L L
⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫹
⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹
⫺
⫺
⫹
⫺
⫹
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
SPECT Findings Focal Hypoperfusion N
⫹
Multifocal Hypoperfusion
Right Secondary generalized partial epilepsy Single-photon emission computed tomography Slow spike-and-wave
—
parietal temporal occipital occipital
—
—
—
—
L frontoparietal
—
R parietal
R, L occipital Posterior regions of bilateral parietal cortex
R, L parietal R, L temporal R, L occipital —
Agyric Areas
MRI Findings
Pachygyric Areas
Abbreviations: EEG ⫽ Electroencephalography L ⫽ Left LGS ⫽ Lennox-Gastaut syndrome MRI ⫽ Magnetic resonance imaging N ⫽ Normal
4
3
3
5
4
2
3
2
1
4
Lissencephaly Grade
MRI, interictal SPECT, and interictal EEG findings of 13 patients with lissencephaly type I
Pt. No.
Table 1.
L temporoparietal R, L temporal R parietal R, L frontal R parieto-occipital
R, L frontal R, L parietal R occipital L parietal R temporoparietal
R, L frontal L temporal R, L parietal —
R, L temporal R, L parietal
R, L occipital R temporal R, L parietal L frontal
Bilateral parasagittal
R, L frontal R, L parietal R temporal
R parietal
R mesial temporal L lateral temporal
Hypoperfused Areas
LGS
WS
WS
LGS
—
SGPE
—
LGS
—
—
WS
LGS
LGS
Epilepsy
SSW and sharp waves in the right hemisphere, spikes on the left temporoparietal area
Irregular diffuse SSW discharges with high amplitude, multifocal spikes on the bilateral frontoparietal regions Generalized irregular SSW discharges
Irregular generalized spike-and-wave paroxysms
—
Bilateral temporal occasional sharp waves
—
Bilateral frontoparietal spikes
—
—
Diffuse 1.5- to 2-Hz SSW discharges, diffuse irregular spike waves Diffuse slow waves with high amplitude, generalized multifocal spikes
Diffuse 2- to 2.5-Hz SSW discharges with high amplitude
EEG Findings
Figure 1. Imaging studies of Patient 11 (grade 2 lissencephaly). (A) MRI T1-weighted, coronal scan; TR ⫽ 495 ms, TE ⫽ 25 ms). (B) SPECT scan (coronal view) revealing hypoperfusion in the left parietal area. (C) MRI (T1-weighted, sagittal scan; TR ⫽ 495 ms, TE ⫽ 25 ms). (D) SPECT (sagittal scan) exhibiting hypoperfusion in the left parietal area.
with the localization of agyric-pachygyric regions in all patients with lissencephaly is not clear. One explanation might be that the histologic abnormalities of the cortex, which cannot be detected by MRI, may result in perfusion abnormalities. Histologic analyses of agyric-pachygyric cortex reveal a chaotic pattern without discernible layering and extensive leptomeningeal gliomesenchymal proliferations and glioneuronal heterotopias [20]. Within all cortical layers, pyramidal cells are often abnormally oriented, with their apical dendrite pointing in an oblique direction or downward [1]. Houdou et al. [33], studying the immunohistochemical staining of the agyric cortex, suggested that the neurons with forming myelin sheaths in the superficial cellular layer regularly penetrate the surface of the molecular layer, forming arrested columns in the deep cellular layer. Although abnormal vascular drainage of pachygyric cortex has been described, evidence is limited about the microvasculature of the agyric-pachygyric cortex [34]. The underlying ultrastructural abnormality that cannot be visualized by MRI together with abnormal
microvasculature may result in an alteration of the cerebral blood flow status. Perfusion abnormalities and metabolic disturbances in the dysplastic cortical regions detected through MRI of patients with NMDs have been demonstrated by SPECT and positron emission tomography [35-43]. Relatively few SPECT studies of patients with lissencephaly have been conducted. In the SPECT study by Al-Suhaili et al. [13], diffuse cortical hypoperfusion was observed in three epileptic patients with lissencephaly. In the study of Ianetti et al. [14], interictal SPECT examinations were performed in seven patients with NMDs, two of whom had agyriapachygyria and seizures. In both of these patients the SPECT images manifested hypoperfused cortical areas; however, the focal perfusion abnormalities of the SPECT images were not totally consistent with the agyricpachygyric areas evident on MRI. Otsubo et al. [12] reported three epileptic patients with pachygyria, with one patient having normal interictal SPECT findings. The data obtained from these studies and current studies are not
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Figure 2. Imaging studies of Patient 13 (grade 4 lissencephaly). (A) MRI proton-density sagittal scan; TR ⫽ 2,500 ms, TE ⫽ 30 ms). (B) SPECT (sagittal scan) demonstrating hypoperfusion in the right parieto-occipital area. (C) MRI (proton-density coronal scan; TR ⫽ 2,500 ms, TE ⫽ 30 ms). (D) SPECT (coronal scan) with hypoperfusion in the right parietal area.
enough to clarify the underlying ultrastructural abnormalities and functional status of the lissencephalic cerebral cortex. Histopathologic evaluation of the hypoperfused areas may be able to demonstrate the microvasculature and histologic nature. What role SPECT scans should have in the evaluation of epileptic and nonepileptic patients with type I lissencephaly and whether the seizures in some patients with lissencephaly are caused by functional abnormalities has not been determined. In the present study, three of the four patients without seizures or epileptogenic discharges on EEG had perfusion abnormalities on SPECT, and all nine patients with seizures had focal or multifocal hypoperfusion on interictal SPECT images. No significant correlation was evident between the presence of cerebral blood flow abnormalities and the occurrence of seizures. Conversely, the hypoperfused regions on interictal SPECT were not consistent with interictal EEG abnormalities in the patients with seizures. Patients with diffuse, slow spike-and-wave discharges on EEG had focal or multifo-
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cal hypoperfusion on SPECT (Patients 1, 2, and 11). The EEG of Patient 8 revealed focal discharges only in the temporal regions; however, the SPECT images revealed hypoperfusion on the bilateral frontoparietal and left temporal cortex. Previous reports have proved that SPECT scanning may be helpful in localizing the epileptogenic focus in epileptic patients [23-25]. SPECT studies are routinely used to evaluate patients before epilepsy surgery [44]. The results of the SPECT studies in epileptic patients with cortical dysplasia have suggested that SPECT may help detect a functional abnormality in an epileptogenic dysplastic region. In some studies, ictal SPECT has identified lesions not detected by MRI [14,35-37]. The present results suggest that hypoperfused areas detected by interictal SPECT may not always be consistent with an epileptogenic focus in patients with type I lissencephaly. In conclusion the functional activity of agyric-pachygyric areas may vary in patients with lissencephaly. In addition, SPECT may not be a reliable method for detect-
ing the epileptogenic focus in these patients. More sophisticated methods are needed to clarify the questions concerning the lissencephalic cerebral cortex. This work was supported by the Research Fund of the University of Istanbul. Project number: 738/260495.
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