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Transient focal cortical hypometabolism in idiopathic West syndrome
Transient Focal Cortical Hypometabolism in Idiopathic West Syndrome Norihide M a e d a , M D * , Kazuyoshi Watanabe, M D * , Tamiko Negoro, M D * , K o s a b u r o Aso, M D * , Yoshiko Haga, M D * , M a s a o Kito, M D * , Takashi Ohki, M D * , Kengo Ito, MD*, and Takashi Kato, M D t
Positron emission tomography (PET) using 18F-labeled 2-deoxy-D-glucose was performed serially in 5 infants with idiopathic West syndrome. While tonic spasms persisted, 2 infants had hypometabolism in the bilateral temporo-parieto-occipital regions, which disappeared after cessation of spasms. In 2 other infants, PET revealed focal hypometabolism in the temporal region a few months after the disappearance of tonic spasms, but subsequent PET studies were normal. PET can detect transient metabolic abnormalities of the cerebral cortex which may be associated with the pathophysiology of West syndrome. Maeda N, Watanabe K, Negoro T, Aso K, Haga Y, Kito M, Ohki T, Ito K, Kato T. Transient focal cortical hypometabolism in idiopathic West syndrome. Pediatr Neurol 1993;9:430-4.
Introduction West syndrome is an epileptic encephalopathy of infancy characterized by clusters of tonic spasms and hypsarrhythmia on electroencephalography (EEG). This syndrome can be caused by a variety of brain lesions; however, some infants exhibit normal development before the onset of West syndrome and current diagnostic techniques cannot identify any etiology. A recent workshop on infantile spasms identified these infants as having idiopathic West syndrome [1]. The prognosis is better for patients with the idiopathic type of West syndrome [2-4], but the clinical course varies even among these patients. Some do not respond to treatment and demonstrate developmental retardation while others respond well to treatment and exhibit normal psychomotor development. The reason for these differences in outcome remains unknown at present. It is also unclear why epileptic encephalopathy accompanied by marked EEG abnormalities occurs in infants without any apparent abnormalities of the central nervous system.
From the Departments of *Pediatrics and *Radiology; Nagoya University School of Medicine; Nagoya, Japan.
430
PEDIATRIC NEUROLOGY
Vol. 9 No. 6
Studies of West syndrome by positron emission tomography (PET) demonstrated brain abnormalities that could not be detected by computed tomography (CT) or magnetic resonance imaging (MRI) [5,6]; however, there has been no study in which serial PET was used to evaluate infants with idiopathic West syndrome. In order to investigate the etiology and pathophysiology of this syndrome, we performed a prospective PET study of 5 newly diagnosed patients with idiopathic West syndrome.
Methods Between April, 1991 and March, 1993, serial 18F-labeled 2-deoxy-Dgluco~ 08F-FDG) PET was performed in 17 infants who developed clusters of tonic spasms. Among them, 5 patients were diagnosed as having idiopathic West syndrome. The criteria for making this diagnosis were as follows: (1) Onset of spasms before 1 year of age; (2) Normal birth and the absence of any probable or definite etiologic factors related to tonic spasms; (3) Normal development before onset and no neurologic abnormalities at the onset of seizures; (4) The occurrence of clusters of symmetric tonic spasms without any other types of seizures before the onset of tonic spasms; (5) Hypsarrhythmia in the interictal EEG without any focal abnormalities; and, (6) Normal CT and MRI findings at onset. On admission, the following laboratory investigations were performed: complete blood count, serum lactate, pyruvate, copper, ceruloplasmin, ammonia, and amino acid levels, viral antibody titers, urinalysis, cerebrospinal fluid analysis, and karyotyping. Neurologic evaluation included a physical examination, fundoscopy, EEG, auditory brainstem responds, cranial CT and MRI, and 18F-FDG PET. All patients were treated by the following protocol. Initially, sodium valproate or clonazepam was administered for 1 week. If no respon~ were obtained, pyridoxine would be administered at 30 mg/kg/day for 3 days and at 50 mg/kg/day for another 3 days. If pyridoxine could not control the spasms, thyrotropin-releasing hormone (TRH) was administered intramu~ularly at 1 mg/day for 2 weeks [7]. If TRH failed to control the seizures, adrenocorticotropic hormone was given intramuscularly at 0.015 mg/kg/day for 2 weeks. The effectiveness of each drug was evaluated on the basis of the frequency and intensity of spasms and the interictal EEG findings. During follow-up, neurologic examination was performed at 2-month intervals. Interictal EEGs were performed at l-month intervals until the age of I year and at 3-month intervals thereafter. In addition, develop-
Communications should be addressed to: Dr. Maeda; Department of Pediatrics; Nagoya University School of Medicine; 65 Turuma-cho, Showa-ku; Nagoya 466, Japan. Received June 29, 1993; accepted September 21, 1993.
Table 1. Clinical profiles of the patients Pt.
No.
Sex
1
M
2
M
Age (mos) at OTS 6
6
Age (mos) at CTS 8
7
Medkafion PET
Interictal EEG Findings at PET
Development at Follow-up
7 mos: Normal
CZP
Hypsarrhythmia
22 mos: Normal
10 mos: Normal
CZP
Normal
7 mos: Bilateral temporo-parieto-occipital hypometabolism
TRH
Hypsarrhythmia
PET Findings
Normal
10 mos: Normal 3
4
5
F
M
M
4
4
4
Abbreviations: CTS = Cessation of tonic spasms CZP = Clonazepam HVS = High-voltage slow waves
5
5
5
5 mos: Bilateral temporo-parieto-occipital hypometabolism
21 mos: Normal
Pyfidoxine
Hypsarrhythmia
10 mos: Normal
Normal
4 mos: Normal
Hypsarrhythmia
10 mos: Bilateral temporal hypometabolism (L > R)
CZP
Sporadic R posterior HVS
21 mos: Normal
CZP
Normal
10 mos: L temporal hypometabolism
VPA, CZP
Bilateral temporal HVS with spikes or polyspikes (L > R)
18 mos: Normal
VPA, CZP
Sporadic R frontal sharp waves
28 mos: Normal
30 mos: Mild delay
35 mos: Mild delay
OTS = Onset of tonic spasms TRH = Thyrotropin-releasing hormone VPA = Valproic acid
ment was evaluated by the Tsumori-Inage developmental quotient (DQ) at the age of 10 months and at 6-month intervals after age 1 year. PET and MRI were performed both at the onset of seizures and at age 10 months. Infants with MRI or PET abnormalities at 10 months were re-examined a few months later. MRI was performed using a 1.5 T superconducting MRI unit (Signa, General Electric Medical). Axial scans were obtained parallel to and from the level of the orbito-meatal line with a slice thickness of 5 mm and an interslice gap of 1.5 mm. In addition, coronal and sagittal scans were obtained. With axial and coronal scanning, Tl-weighted images (TR: 500, TE: 20), proton-density images (TR: 2,000, TE: 30), and T2-weighted images (TR: 2,000, TE :80) were obtained, while TIweighted images were obtained with sagittal scanning. Myelination was considered to be delayed when it was at least 2 months later than the standards given in the atlas by Barkovich et al. [8]. After informed consent was obtained, PET was performed using a Headtome IV scanner (Shimadzu) with an in-plane spatial resolution of 4.5 mm full width at half maximum. Before PET, an intravenous line was established to infuse normal saline and a chloral hydrate suppository (30-50 mg/kg) was administered to induce sleep. After transmission scanning, 31-61 MBq of 18F-FDG was injected intravenously through the intravenous line. After 50 min, 14 axial images (11 mm thick) were collected at 6.5 mm intervals in parallel to and starting from the orbitomeatal line. PET scans were compared to MRI in the same plane and were considered abnormal if decreased 18F-FDG accumulation was observed in 2 or more slices of 2 or more gyri.
Results The data of the 5 patients (4 males, 1 female) are summarized in Table 1. The age of onset ranged from 4-6 months (mean: 5 months). Patient 3 had the 47-XXX chromosomal abnormality. In the other 4 patients, no abnormalities were demonstrated by either laboratory tests or CT and MRI. Experienced pediatric neurologists confirmed the occurrence of symmetric tonic spasms in all patients. Simultaneous video-EEG recordings were obtained in 3 patients (Patients 2-4). With various treatments, the tonic spasms disappeared within 8 weeks of onset in all patients and did not recur. In Patients 1 and 5, administration of clonazepam or valproate was effective and was continued after the cessation of spasms. In the other 3 patients, the tonic spasms disappeared after administration of TRH (Patient 3) or adrenocorticotropic hormone (Patients 2,4), and no drugs were administered thereafter. Patient 4 developed complex partial seizures 20 days after the disappearance of tonic spasms, but these seizures were easily controlled with clonazepam.
Maeda et al: Idiopathic West Syndrome 431
Interictal EEGs at the onset of spasms revealed hypsarrhythmia in all patients; in Patients 1-3, EEG was normalized when the spasms disappeared. In Patients 4 and 5, however, focal epileptic discharges persisted up to 20 months of age after the disappearance of hypsarrhythmia, and one of them had partial seizures as mentioned above. In all patients, neurologic examination detected no significant abnormalities throughout the follow-up period. In 3 patients, the DQ remained above 100. In the other 2 patients, the DQ was 70-80 at age 10 months and mild developmental retardation was observed at the most recent evaluation. MRI at the onset of seizures and during follow-up revealed no morphologic abnormalities, such as atrophy, deformities, migration disorders, or foreign tissue lesions; however, myelination appeared to be delayed at age 10 months in Patients 4 and 5 with mild developmental retardation. No tonic spasms occurred during PET or in the 2 hours before the procedure; therefore, all PET images obtained in this study were regarded as interictal. PET images were abnormal in 4 of 5 patients during the follow-up period, but subsequently became normal in all of them. In 4 patients, the initial PET was performed while they still had tonic spasms and the interictal EEG disclosed hypsarrhythmia. In 2 of these 4 patients, PET demonstrated a decrease in 18F-FDG accumulation in the bilateral temporo-parieto-occipital regions, which were normal at age 10 months (Fig 1). After the disappearance of spasms, PET displayed a decrease in 18F-FDG accumulation limited to the temporal lobe in the other 2 patients (Patients 4,5), but later demonstrated normal findings (Figs 2,3). In these 2 patients, EEG revealed localized epileptic discharges after the disappearance of spasms, and development was slightly delayed. Discussion All 5 of our patients fulfilled the criteria for idiopathic West syndrome. Patient 3 had the 47-XXX chromosomal aberration, but 47-XXX superfemales often exhibit normal mental development and lead a normal life [9-11 ]. In this patient, development during the follow-up period was normal and the chromosomal aberration may have been an incidental finding. Chugani et al. performed 18F-FDG PET in 13 patients with infantile spasms in whom CT and MRI findings were normal, and found hypometabolic areas in the cerebral cortex in 5 patients [5]. Four of these 5 patients underwent resection of the hypometabolic cortical areas, and the surgical specimens revealed microscopic dysgenesis; however, the clinical courses of their 5 patients were different from those of our patients. When PET was performed, the patients reported by Chugani et al. had neurologic deficits and intractable partial seizures or infantile spasms [5]. Although Chugani et al. concluded that these patients had "cryptogenic" West syndrome [5], it is uncertain whether developmental retardation was present
432 PEDIATRICNEUROLOGY Vol.9 No. 6
before the onset of infantile spasms. In contrast, our patients did not exhibit any developmental delay before the onset of spasms, and there were no neurologic deficits detected throughout the follow-up period. In addition, tonic spasms and partial seizures were easily controlled by treatment, and the PET abnormalities were transient and disappeared before the last evaluation. In contrast to the changes reported by Chugani et al. 15], the focal cortical hypometabolic areas observed in our patients may have reflected functional changes rather than organic lesions. Involvement of the cortex in the development of tonic spasms has been suggested by several studies. Yamamoto et al. reported infants who had tonic spasms preceded by partial seizures [12]; there have been several reports of infantile spasms due to brain tumors or porencephalic cysts [13-15]. These studies, however, were mainly concerned with symptomatic patients. Conversely, all of our patients fulfilled the strict criteria for idiopathic West syndrome; therefore, the PET abnormalities detected in our patients are more likely to be related to the pathophysiology of infantile spasms than the changes observed in patients with symptomatic West syndrome; however, it is still unclear whether the transient cortical hypometabolism observed in our patients was directly related to the development of tonic spasms. While tonic spasms persisted, 2 patients demonstrated focal hypometabolism on PET, but no abnormalities occurred in another 2. After the cessation of spasms, PET revealed hypometabolic areas in the temporal lobes of 2 patients but not in the other 3. The following factors could have been responsible for these differences among the patients: (1) Some patients with idiopathic West syndrome may not have functional abnormalities of the cerebral cortex; (2) Functional cortical abnormalities may not have been demonstrated in some patients because of fluctuation; and, (3) The imaging technique used may have missed some patients with focal or generalized cortical hypometabolism. In order to elucidate the actual cause of these differences, further studies involving multiple evaluations or quantitative PET may be needed. The 3 patients with normal PET studies after the cessation of tonic spasms exhibited normal development, while the 2 patients who displayed focal cortical hypometabolism after the disappearance of spasms had developmental delay. The reason for this difference is unknown. One possible explanation may be that the persistence of focal hypometabolism reflected a more severe functional abnormality in 2 patients with delay. It is also uncertain whether the detection of focal cortical hypometabolism after the cessation of tonic spasms is an indicator of a worse prognosis for mental function in idiopathic West syndrome. Further studies are needed to demonstrate the value of PET for prognostic evaluation.
Figure 1. PET findings of Patient 2. lnterictal PET performed at ages 7 and 10 months. PET at 7 months displayed hypometabolism in the bilateral temporo-parieto-occipital regions (arrows), but PET at 10 months demonstrated improvement. The images are not shown to the same scale.
Figure 2. PET findings of Patient 4. lnterictal PET performed at 4, 10, and 21 months o f age. PET at 4 months disclosed no abnormalities, but PET at 10 months revealed hypometabolic regions in the bilateral temporal lobes (left > right, arrows). PET at 21 months demonstrated improvement of these changes. The images are not shown to the same scale.
Figure 3. PET findings of Patient 5. lnterictal PET performed at 10 and 18 months of age after the cessation o f tonic spasms. PET at 10 months displayed hypometabolism in the left temporal region (arrows), but PET at 18 months revealed improvement. The images are not shown to the same scale.
Maeda et al: Idiopathic West Syndrome 433
L o c a l i z e d P E T a b n o r m a l i t i e s are f r e q u e n t e v e n in nonrefractory idiopathic West s y n d r o m e ; h o w e v e r , t h e s e P E T a b n o r m a l i t i e s are transient and do not n e c e s s a r i l y represent focal organic lesions. F o c a l cortical d y s f u n c t i o n may play an i m p o r t a n t role in the d e v e l o p m e n t o f idiopathic West s y n d r o m e .
We thank Dr. Nuguri Shyraja for her assistance in writing the manuscript. This study was supported in part by grants from the Japan Epilepsy Research Foundation, and a grant for Nervous and Mental Disorders from the Ministry of Health and Welfare.
References [1] Commission on Pediatric Epilepsy of the International League Against Epilepsy. Workshop on infantile spasms. Epilepsia 1992;33:195. [2] Riikonen RA. Long-term follow-up study of 214 children with the syndrome of infantile spasms. Neuropediatrics 1982;13:14-23. [3] Matumoto M, Watanabe K, Negoro T, et al. Long-term prognosis after infantile spasms: A statistical study of prognostic factor in 200 cases. Dev Med Child Neurol 1981;23:51-65. [4] Jeavons PM, Bower BD, Dimitrakoudi M. Long-term prognosis of 150 cases of "West syndrome." Epilepsia 1973;14:153-64.
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PEDIATRIC NEUROLOGY
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[5] Chugani HT, Shiels WD, Shewmen DA, Olson DM, Phelps ME. Peacock WJ. Infantile spasms: 1. PET identifies tk~calcortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990;27:406-13. [6] Chugani HT, Shewmen DA, Sankar R, Chen BC, Phelps ME, Infantile spasms: 11. Lenticular nuclei and brain stem acliwltion on positron emission tomography. Ann Neurol 1992;31:212-9. 17] Matsumoto A, Kumagai T, Takeuchi T, Miyazaki S, Watanabe K. Clinical effects of thyrotropin-releasing hormone for severe epilepsy in childhood: A comparative study with ACTH. Epilepsia 1987;28: 49-55. [8] Barkovich AJ, Truwit CL. Practical MRI atlas of neonatal brain development. New York: Raven Press, 1990; 1-52. [9] Barr ML, Sergovich FR, Can" DH, Shaver EL. The triplo-X female: An appraisal based on a study of 12 cases and a review of the literature. Can Med Assoc J 1969;I 01:247-58. [10] Tennes K, Puck M, Bryant K, Frankenburg W, Robinson A. A development study of girls with trisomy X. Am J Genet 1975;27:71-80. [11] Linden MG, Bender BG, Harmon RJ, Mrazek DA, Robinson A. 47,XXX: What is prognosis'? Pediatrics 1988;82:619-31). [12] Yamamoto N, Watanabe K, Negoro T, et al. Partial seizure evolving to infantile spasms. Epilepsia 1988;29:34-40. [13] Branch CE, Dyken PR. Chornid plexus papilloma and infantile spasms. Ann Neurol 1979;5:302-4. [14] Mimaki T, Ono J, Yabuuchi H. Temporal lobe astrocytoma with infantile spurns. Ann Neurol 1983;14:695-6. [15] Uthman BM, Reid SA, Wilder BJ, Andriola MR, Beydoun AA. Outcome for West syndrome following surgical treatment. Epilepsia 1991 ;32:668-71.
Positron emission tomography (PET) using 18F-labeled 2-deoxy-D-glucose was performed serially in 5 infants with idiopathic West syndrome. While tonic spasms persisted, 2 infants had hypometabolism in the bilateral temporo-parieto-occipital regions, which disappeared after cessation of spasms. In 2 other infants, PET revealed focal hypometabolism in the temporal region a few months after the disappearance of tonic spasms, but subsequent PET studies were normal. PET can detect transient metabolic abnormalities of the cerebral cortex which may be associated with the pathophysiology of West syndrome. Maeda N, Watanabe K, Negoro T, Aso K, Haga Y, Kito M, Ohki T, Ito K, Kato T. Transient focal cortical hypometabolism in idiopathic West syndrome. Pediatr Neurol 1993;9:430-4.
Introduction West syndrome is an epileptic encephalopathy of infancy characterized by clusters of tonic spasms and hypsarrhythmia on electroencephalography (EEG). This syndrome can be caused by a variety of brain lesions; however, some infants exhibit normal development before the onset of West syndrome and current diagnostic techniques cannot identify any etiology. A recent workshop on infantile spasms identified these infants as having idiopathic West syndrome [1]. The prognosis is better for patients with the idiopathic type of West syndrome [2-4], but the clinical course varies even among these patients. Some do not respond to treatment and demonstrate developmental retardation while others respond well to treatment and exhibit normal psychomotor development. The reason for these differences in outcome remains unknown at present. It is also unclear why epileptic encephalopathy accompanied by marked EEG abnormalities occurs in infants without any apparent abnormalities of the central nervous system.
From the Departments of *Pediatrics and *Radiology; Nagoya University School of Medicine; Nagoya, Japan.
430
PEDIATRIC NEUROLOGY
Vol. 9 No. 6
Studies of West syndrome by positron emission tomography (PET) demonstrated brain abnormalities that could not be detected by computed tomography (CT) or magnetic resonance imaging (MRI) [5,6]; however, there has been no study in which serial PET was used to evaluate infants with idiopathic West syndrome. In order to investigate the etiology and pathophysiology of this syndrome, we performed a prospective PET study of 5 newly diagnosed patients with idiopathic West syndrome.
Methods Between April, 1991 and March, 1993, serial 18F-labeled 2-deoxy-Dgluco~ 08F-FDG) PET was performed in 17 infants who developed clusters of tonic spasms. Among them, 5 patients were diagnosed as having idiopathic West syndrome. The criteria for making this diagnosis were as follows: (1) Onset of spasms before 1 year of age; (2) Normal birth and the absence of any probable or definite etiologic factors related to tonic spasms; (3) Normal development before onset and no neurologic abnormalities at the onset of seizures; (4) The occurrence of clusters of symmetric tonic spasms without any other types of seizures before the onset of tonic spasms; (5) Hypsarrhythmia in the interictal EEG without any focal abnormalities; and, (6) Normal CT and MRI findings at onset. On admission, the following laboratory investigations were performed: complete blood count, serum lactate, pyruvate, copper, ceruloplasmin, ammonia, and amino acid levels, viral antibody titers, urinalysis, cerebrospinal fluid analysis, and karyotyping. Neurologic evaluation included a physical examination, fundoscopy, EEG, auditory brainstem responds, cranial CT and MRI, and 18F-FDG PET. All patients were treated by the following protocol. Initially, sodium valproate or clonazepam was administered for 1 week. If no respon~ were obtained, pyridoxine would be administered at 30 mg/kg/day for 3 days and at 50 mg/kg/day for another 3 days. If pyridoxine could not control the spasms, thyrotropin-releasing hormone (TRH) was administered intramu~ularly at 1 mg/day for 2 weeks [7]. If TRH failed to control the seizures, adrenocorticotropic hormone was given intramuscularly at 0.015 mg/kg/day for 2 weeks. The effectiveness of each drug was evaluated on the basis of the frequency and intensity of spasms and the interictal EEG findings. During follow-up, neurologic examination was performed at 2-month intervals. Interictal EEGs were performed at l-month intervals until the age of I year and at 3-month intervals thereafter. In addition, develop-
Communications should be addressed to: Dr. Maeda; Department of Pediatrics; Nagoya University School of Medicine; 65 Turuma-cho, Showa-ku; Nagoya 466, Japan. Received June 29, 1993; accepted September 21, 1993.
Table 1. Clinical profiles of the patients Pt.
No.
Sex
1
M
2
M
Age (mos) at OTS 6
6
Age (mos) at CTS 8
7
Medkafion PET
Interictal EEG Findings at PET
Development at Follow-up
7 mos: Normal
CZP
Hypsarrhythmia
22 mos: Normal
10 mos: Normal
CZP
Normal
7 mos: Bilateral temporo-parieto-occipital hypometabolism
TRH
Hypsarrhythmia
PET Findings
Normal
10 mos: Normal 3
4
5
F
M
M
4
4
4
Abbreviations: CTS = Cessation of tonic spasms CZP = Clonazepam HVS = High-voltage slow waves
5
5
5
5 mos: Bilateral temporo-parieto-occipital hypometabolism
21 mos: Normal
Pyfidoxine
Hypsarrhythmia
10 mos: Normal
Normal
4 mos: Normal
Hypsarrhythmia
10 mos: Bilateral temporal hypometabolism (L > R)
CZP
Sporadic R posterior HVS
21 mos: Normal
CZP
Normal
10 mos: L temporal hypometabolism
VPA, CZP
Bilateral temporal HVS with spikes or polyspikes (L > R)
18 mos: Normal
VPA, CZP
Sporadic R frontal sharp waves
28 mos: Normal
30 mos: Mild delay
35 mos: Mild delay
OTS = Onset of tonic spasms TRH = Thyrotropin-releasing hormone VPA = Valproic acid
ment was evaluated by the Tsumori-Inage developmental quotient (DQ) at the age of 10 months and at 6-month intervals after age 1 year. PET and MRI were performed both at the onset of seizures and at age 10 months. Infants with MRI or PET abnormalities at 10 months were re-examined a few months later. MRI was performed using a 1.5 T superconducting MRI unit (Signa, General Electric Medical). Axial scans were obtained parallel to and from the level of the orbito-meatal line with a slice thickness of 5 mm and an interslice gap of 1.5 mm. In addition, coronal and sagittal scans were obtained. With axial and coronal scanning, Tl-weighted images (TR: 500, TE: 20), proton-density images (TR: 2,000, TE: 30), and T2-weighted images (TR: 2,000, TE :80) were obtained, while TIweighted images were obtained with sagittal scanning. Myelination was considered to be delayed when it was at least 2 months later than the standards given in the atlas by Barkovich et al. [8]. After informed consent was obtained, PET was performed using a Headtome IV scanner (Shimadzu) with an in-plane spatial resolution of 4.5 mm full width at half maximum. Before PET, an intravenous line was established to infuse normal saline and a chloral hydrate suppository (30-50 mg/kg) was administered to induce sleep. After transmission scanning, 31-61 MBq of 18F-FDG was injected intravenously through the intravenous line. After 50 min, 14 axial images (11 mm thick) were collected at 6.5 mm intervals in parallel to and starting from the orbitomeatal line. PET scans were compared to MRI in the same plane and were considered abnormal if decreased 18F-FDG accumulation was observed in 2 or more slices of 2 or more gyri.
Results The data of the 5 patients (4 males, 1 female) are summarized in Table 1. The age of onset ranged from 4-6 months (mean: 5 months). Patient 3 had the 47-XXX chromosomal abnormality. In the other 4 patients, no abnormalities were demonstrated by either laboratory tests or CT and MRI. Experienced pediatric neurologists confirmed the occurrence of symmetric tonic spasms in all patients. Simultaneous video-EEG recordings were obtained in 3 patients (Patients 2-4). With various treatments, the tonic spasms disappeared within 8 weeks of onset in all patients and did not recur. In Patients 1 and 5, administration of clonazepam or valproate was effective and was continued after the cessation of spasms. In the other 3 patients, the tonic spasms disappeared after administration of TRH (Patient 3) or adrenocorticotropic hormone (Patients 2,4), and no drugs were administered thereafter. Patient 4 developed complex partial seizures 20 days after the disappearance of tonic spasms, but these seizures were easily controlled with clonazepam.
Maeda et al: Idiopathic West Syndrome 431
Interictal EEGs at the onset of spasms revealed hypsarrhythmia in all patients; in Patients 1-3, EEG was normalized when the spasms disappeared. In Patients 4 and 5, however, focal epileptic discharges persisted up to 20 months of age after the disappearance of hypsarrhythmia, and one of them had partial seizures as mentioned above. In all patients, neurologic examination detected no significant abnormalities throughout the follow-up period. In 3 patients, the DQ remained above 100. In the other 2 patients, the DQ was 70-80 at age 10 months and mild developmental retardation was observed at the most recent evaluation. MRI at the onset of seizures and during follow-up revealed no morphologic abnormalities, such as atrophy, deformities, migration disorders, or foreign tissue lesions; however, myelination appeared to be delayed at age 10 months in Patients 4 and 5 with mild developmental retardation. No tonic spasms occurred during PET or in the 2 hours before the procedure; therefore, all PET images obtained in this study were regarded as interictal. PET images were abnormal in 4 of 5 patients during the follow-up period, but subsequently became normal in all of them. In 4 patients, the initial PET was performed while they still had tonic spasms and the interictal EEG disclosed hypsarrhythmia. In 2 of these 4 patients, PET demonstrated a decrease in 18F-FDG accumulation in the bilateral temporo-parieto-occipital regions, which were normal at age 10 months (Fig 1). After the disappearance of spasms, PET displayed a decrease in 18F-FDG accumulation limited to the temporal lobe in the other 2 patients (Patients 4,5), but later demonstrated normal findings (Figs 2,3). In these 2 patients, EEG revealed localized epileptic discharges after the disappearance of spasms, and development was slightly delayed. Discussion All 5 of our patients fulfilled the criteria for idiopathic West syndrome. Patient 3 had the 47-XXX chromosomal aberration, but 47-XXX superfemales often exhibit normal mental development and lead a normal life [9-11 ]. In this patient, development during the follow-up period was normal and the chromosomal aberration may have been an incidental finding. Chugani et al. performed 18F-FDG PET in 13 patients with infantile spasms in whom CT and MRI findings were normal, and found hypometabolic areas in the cerebral cortex in 5 patients [5]. Four of these 5 patients underwent resection of the hypometabolic cortical areas, and the surgical specimens revealed microscopic dysgenesis; however, the clinical courses of their 5 patients were different from those of our patients. When PET was performed, the patients reported by Chugani et al. had neurologic deficits and intractable partial seizures or infantile spasms [5]. Although Chugani et al. concluded that these patients had "cryptogenic" West syndrome [5], it is uncertain whether developmental retardation was present
432 PEDIATRICNEUROLOGY Vol.9 No. 6
before the onset of infantile spasms. In contrast, our patients did not exhibit any developmental delay before the onset of spasms, and there were no neurologic deficits detected throughout the follow-up period. In addition, tonic spasms and partial seizures were easily controlled by treatment, and the PET abnormalities were transient and disappeared before the last evaluation. In contrast to the changes reported by Chugani et al. 15], the focal cortical hypometabolic areas observed in our patients may have reflected functional changes rather than organic lesions. Involvement of the cortex in the development of tonic spasms has been suggested by several studies. Yamamoto et al. reported infants who had tonic spasms preceded by partial seizures [12]; there have been several reports of infantile spasms due to brain tumors or porencephalic cysts [13-15]. These studies, however, were mainly concerned with symptomatic patients. Conversely, all of our patients fulfilled the strict criteria for idiopathic West syndrome; therefore, the PET abnormalities detected in our patients are more likely to be related to the pathophysiology of infantile spasms than the changes observed in patients with symptomatic West syndrome; however, it is still unclear whether the transient cortical hypometabolism observed in our patients was directly related to the development of tonic spasms. While tonic spasms persisted, 2 patients demonstrated focal hypometabolism on PET, but no abnormalities occurred in another 2. After the cessation of spasms, PET revealed hypometabolic areas in the temporal lobes of 2 patients but not in the other 3. The following factors could have been responsible for these differences among the patients: (1) Some patients with idiopathic West syndrome may not have functional abnormalities of the cerebral cortex; (2) Functional cortical abnormalities may not have been demonstrated in some patients because of fluctuation; and, (3) The imaging technique used may have missed some patients with focal or generalized cortical hypometabolism. In order to elucidate the actual cause of these differences, further studies involving multiple evaluations or quantitative PET may be needed. The 3 patients with normal PET studies after the cessation of tonic spasms exhibited normal development, while the 2 patients who displayed focal cortical hypometabolism after the disappearance of spasms had developmental delay. The reason for this difference is unknown. One possible explanation may be that the persistence of focal hypometabolism reflected a more severe functional abnormality in 2 patients with delay. It is also uncertain whether the detection of focal cortical hypometabolism after the cessation of tonic spasms is an indicator of a worse prognosis for mental function in idiopathic West syndrome. Further studies are needed to demonstrate the value of PET for prognostic evaluation.
Figure 1. PET findings of Patient 2. lnterictal PET performed at ages 7 and 10 months. PET at 7 months displayed hypometabolism in the bilateral temporo-parieto-occipital regions (arrows), but PET at 10 months demonstrated improvement. The images are not shown to the same scale.
Figure 2. PET findings of Patient 4. lnterictal PET performed at 4, 10, and 21 months o f age. PET at 4 months disclosed no abnormalities, but PET at 10 months revealed hypometabolic regions in the bilateral temporal lobes (left > right, arrows). PET at 21 months demonstrated improvement of these changes. The images are not shown to the same scale.
Figure 3. PET findings of Patient 5. lnterictal PET performed at 10 and 18 months of age after the cessation o f tonic spasms. PET at 10 months displayed hypometabolism in the left temporal region (arrows), but PET at 18 months revealed improvement. The images are not shown to the same scale.
Maeda et al: Idiopathic West Syndrome 433
L o c a l i z e d P E T a b n o r m a l i t i e s are f r e q u e n t e v e n in nonrefractory idiopathic West s y n d r o m e ; h o w e v e r , t h e s e P E T a b n o r m a l i t i e s are transient and do not n e c e s s a r i l y represent focal organic lesions. F o c a l cortical d y s f u n c t i o n may play an i m p o r t a n t role in the d e v e l o p m e n t o f idiopathic West s y n d r o m e .
We thank Dr. Nuguri Shyraja for her assistance in writing the manuscript. This study was supported in part by grants from the Japan Epilepsy Research Foundation, and a grant for Nervous and Mental Disorders from the Ministry of Health and Welfare.
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