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West syndrome with periventricular leukomalacia: a morphometric MRI study
West Syndrome With Periventricular Leukomalacia: A Morphometric MRI Study Hiroshi Ozawa, MD*†, Toshiaki Hashimoto, MD†, Takashi Endo, MD‡, Toshinori Kato, MD‡, Junichi Furusho, MD‡, Yasuyuki Suzuki, MD§, Eiko Takada, MD|, Yunosuke Ogawa, MD|, and Sachio Takashima, MD* A morphometric magnetic resonance imaging study was performed, and the results were compared among three groups (group 1, periventricular leukomalacia patients with West syndrome; group 2, periventricular leukomalacia patients without West syndrome; and group 3, control patients) to clarify the characteristics and cause of West syndrome. This study included 21 infants (11 males and 10 females, 7 months to 2 years 8 months old) born at 24-32 weeks of gestation and weighing 625-1,908 gm. The Evans ratio, ratio of the posterior horns, Cella media index, width of the third ventricle, and the areas of the midbrain, pons, and medulla oblongata were measured and compared among the three groups. There were no differences of gestation or birth weight among the three groups. The Evans ratio, ratio of the posterior horns, Cella media index, and width of the third ventricle were larger in group 1 than in groups 2 and 3. The ratio of the posterior horns and Cella media index were larger in group 2 than in group 3, although the width of the third ventricle was not. Myelination was delayed in all patients in group 1 and in two patients in group 2. In group 1 the areas of the midbrain and pons were smaller than in groups 2 and 3 and the medulla oblongata was smaller than in group 3, although there were no differences in midbrain, pons, and medulla oblongata between groups 2 and 3. Although the infants with periventricular leukomalacia and West syndrome frequently demonstrated marked ventricular dilatation and delayed myelination, the atrophy of midbrain and pons was the most characteristic, and the damage may cause West syndrome. © 1998 by Elsevier Science Inc. All rights reserved.
Ozawa H, Hashimoto T, Endo T, Kato T, Furusho J, Suzuki Y, Takada E, Ogawa Y, Takashima S. West syndrome with periventricular leukomalacia: A morphometric MRI study. Pediatr Neurol 1998;19:358-363.
From the *Departments of Mental Retardation and Birth Defect Research; National Institute of Neuroscience; †Department of Child Neurology; National Center Hospital for Mental, Nervous and Muscular Disorders; National Center of Neurology and Psychiatry; ‡ Department of Pediatrics; Showa General Hospital; §Department of Pediatrics; Tokyo Children’s Rehabilitation Hospital; Tokyo; and \ Department of Pediatrics; Saitama Medical Center; Saitama Medical School; Saitama, Japan.
Communications should be addressed to: Dr. Ozawa; Department of Mental Retardation and Birth Defect Research; National Institute of Neuroscience; 4-1-1 Ogawahigashi; Kodaira, Tokyo 187, Japan. Received February 27, 1998; accepted June 4, 1998.
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Introduction Periventricular leukomalacia (PVL) is an important cause of neurologic sequelae, such as spastic diplegia and intellectual impairment in preterm infants [1-3]. Early medical imaging is indispensable for diagnosis and prognosis. Although ultrasound may demonstrate PVL during the neonatal period, the sensitivity and specificity of this technique have not been demonstrated conclusively. Computed tomography demonstrates characteristic features of PVL in later infancy and childhood [4]. Magnetic resonance imaging (MRI) is superior in demonstrating white matter lesions. The capacity of MRI to detect white matter injury and visualize the cerebral parenchyma also should allow precise delineation of PVL [5-8]. Although the relationships between West syndrome (WS) and term hypoxic-ischemic encephalopathy, intraventricular and subarachnoid hemorrhage, and neonatal hypoglycemia have been well described [9], there have been only a few reports on the relationship between WS and PVL [10,11]. The purposes of this study were to evaluate MRI in patients with PVL and WS and to elucidate the cause of WS with PVL. Materials and Methods This study included 21 infants (11 males, 10 females) born at 24-32 weeks of gestation and weighing 625-1,908 gm. There were three groups:
© 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00081-2 ● 0887-8994/98/$19.00
Table 1.
Clinical course of patients with West syndrome with periventricular leukomalacia
Patient No.
Gestation (wk)
Birth Weight (gm)
Age at onset (mo)
Treatment
Age at MRI (mo)
Perinatal Problem
30 30 32 30 29
982 1,358 752 1,700 1,308
8 11 8 8 6
CZP ACTH, VPA, NZP VPA, CZP ACTH, VPA, CZP VPA, CZP
7 11 14 26 32
Asphyxia, RDS RDS, PDA RDS, convulsion Asphyxia, convulsion Apnea
1 2 3 4 5
Abbreviations: ACTH 5 Adrenocorticotropic hormone CZP 5 Clonazepam MRI 5 Magnetic resonance imaging NZP 5 Nitorazepam
Patient No. 1 2 3 4 5 6 7 8 9 10 11
Spastic Spastic Spastic Spastic Spastic
quadriplegia quadriplegia quadriplegia quadriplegia quadriplegia
Mentality Severe Severe Severe Severe Severe
PDA 5 Patent ductus arteriosus RDS 5 Respiratory distress syndrome VPA 5 Valproic acid
group 1, five PVL patients with WS (Table 1); group 2, 11 PVL patients without WS (Table 2); and group 3, five control patients (Table 3). There were no significant differences in gestation, birth weight, or age at MRI among the three groups of patients by analysis of variance (P , 0.05). The diagnosis of PVL using MRI was based on the following abnormalities: (1) abnormally increased periventricular white matter signal intensity on T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR), most commonly observed in the trigone regions of the lateral ventricles bilaterally; (2) loss of periventricular white matter in the regions of abnormal signal intensity; and (3) focal or widespread ventricular enlargement adjacent to regions of abnormal signal intensity. West syndrome was diagnosed when a patient had a series of spasms and hypsarrhythmia was indicated on interictal electroencephalography. Control patients were determined by no abnormal findings on MRI and normal development. Mentality was assessed by the Denver Developmental Screening Test: normal, intelligence greater than 75; mild retardation, 50-75; moderate, 25-50; and severe, less than 25. MRI was performed, at 7 months to 2 years 8 months of age, with a Siemens, Magneton Impact Expert (Siemens, Erlangen, Germany) with a superconducting magnet operating at 1.0 T (T1-weighted [TR: 570 ms, TE: 12 ms], T2-weighted [TR: 4,200 ms, TE: 99 ms] axial images, FLAIR [TR: 8,000 ms, TE: 105 ms], with 5-mm section thickness), or a General Electric Sigma (General Electric, Milwaukee, WI) with a superconducting magnet operating at 1.5 T (T1-weighted [TR: 500 ms, TE: 19 ms], T2-weighted [TR: 3,500 ms, TE: 102 ms] axial images with 5-mm section thickness). Axial sections were crossed parallel to the anterior commissure-posterior commissures line. Informed consent was
Table 2.
Palsy
obtained from the patients’ parents. All measurements were made with a computer-assisted imaging analyzer (OLYMPUS SP500). The measured portions are illustrated in Figure 1. The Evans ratio (A/B), ratio of the posterior horns (C/B), and Cella media index (E/F) were calculated. The area of the midbrain at the level of the inferior colliculus, the area of the upper pons (isthmus), and the area of the medulla (lower region) were also measured. Myelination was independently assessed by two observers (H.O., S.T.) with T1- and T2-weighted MRI. These findings were compared among the three groups. Statistical analysis was performed using the Student t test.
Results Cerebrum There were no significant differences in gestation, birth weight, and age at MRI among the three groups. In groups 1 and 2, abnormally increased periventricular white matter signal intensity on T2-weighted imaging and FLAIR was observed most commonly in the lateral ventricles bilaterally, and the volumes of periventricular white matter in these regions of abnormal signal intensity were decreased. Also, the walls of the lateral ventricle were irregular (Figs 2 and 3). In group 1 the Evans ratio, ratio of the posterior
Clinical course of patients without West syndrome with periventricular leukomalacia Gestation (wk)
Birth Weight (gm)
Age at MRI (mo)
Perinatal Problem
29 27 27 31 29 31 32 32 29 24 29
894 686 1,148 1,908 1,840 1,544 1,888 1,705 1,616 625 1,228
9 10 13 13 14 14 24 28 29 29 32
RDS RDS RDS, IVH, hyperkalemia RDS RDS, asphyxia RDS RDS RDS RDS RDS, PDA, hyperkalemia Apnea
Palsy Spastic Spastic Spastic Spastic Spastic Spastic Spastic Spastic Spastic Spastic Spastic
diplegia diplegia quadriplegia quadriplegia quadriplegia diplegia diplegia diplegia diplegia diplegia diplegia
Epilepsy
Mentality
2 2 2 2 1 2 2 2 2 2 2
Normal Mild Moderate Mild Mild Normal Normal Mild Normal Normal Mild
Abbreviations: IVH 5 Intraventricular hemorrhage Other abbreviations as in Table 1.
Ozawa et al: PVL and West syndrome 359
Table 3.
bellar fissures was seen in two patients. Abnormal intensity was not seen in groups 1, 2, and 3.
Clinical course of control patients
Patient No. 1 2 3 4 5
Gestation (wk)
Birth Weight (gm)
Age at MRI (mo)
32 27 24 30 32
1,758 866 688 1,239 1,415
7 13 8 18 8
Abbreviations as in Table 1.
horns, Cella media index, and width of the third ventricle were larger than in groups 2 and 3. In group 2 the ratio of the posterior horns and Cella media index were larger than in group 3 but the width of the third ventricle was not (Table 4). Myelination was delayed in all patients in group 1 and in two patients in group 2 (Patients 3 and 5). Brainstem In groups 1 and 2, abnormal intensity was not observed in the midbrain, pons, or medulla oblongata. However, in group 1 the areas of the midbrain and pons were smaller than in groups 2 and 3 and the medulla oblongata was smaller than in group 3. There were no differences in the midbrain, pons, and medulla oblongata between groups 2 and 3 (Table 5) (Fig 4). Cerebellum In group 1, cerebellar atrophy was observed in one patient and slight enlargement of the cerebellar fissures in two patients. In group 2, slight enlargement of the cere-
Discussion PVL has been recognized in infant brains in neuropathologic studies [2,12-16] and by means of imaging techniques [4-8,17] since Banker and Larroche first described it [1]. They attributed the etiology of PVL to perinatal hypoxia, relating this finding to the successive development of spastic diplegia [3,5,6,18], visual and hearing impairment [19-21], and cognitive dysfunction [22-24]. Recently, there have been a few reports of PVL associated with West syndrome [10,11]. Cusmai et al. [10] reported that 12 patients with symptomatic infantile spasms caused by a perinatal insult had PVL, and the outcome of epilepsy appeared to be relatively good. Okumura et al. [11] reported that seven of 27 patients with PVL developed West syndrome and that the volume loss of periventricular white matter extended to the frontal horns in all patients with West syndrome. Also, they observed bilateral parieto-occipital spike-and-wave bursts that could have been a precursor of hypsarrhythmia. Infantile spasms are age-specific and often poorly responsive to conventional antiepileptic drugs [9]. Delayed myelination is reported in infants with West syndrome [25,26]. In all of the authors’ patients with West syndrome with PVL, myelination was delayed. These findings correspond with previous reports. Recently, clinical, physiologic, and pathologic studies have suggested that the brainstem might play an important role in generating infantile spasms [27-32]. Satou et al. [27] performed 22 postmortem examinations on patients with West syndrome and documented the small size of the brainstem tegmen-
Figure 1. (A-C) Measured portions on MRI (TR/TE: 570/12 ms). A, Maximum distance between the anterior horns; B, maximum distance between the internal laminae; C, maximum distance between the posterior horns; D, width of the third ventricle; E, central distance between the level of cella media; and F, maximum distance between the internal laminae at the same level. The authors compared the Evans ratio (A/B), ratio of the posterior horns (C/B), Cella media index (E/F), and width of the third ventricle (D) among the three groups. The area of the midbrain at the level of the inferior colliculus, the area of the upper pons (isthmus), and the area of the medulla (lower region) were also measured.
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Figure 2. MRI of a PVL patient with West syndrome (Patient 5). (A) T2-weighted axial image (TR: 4,200 ms, TE: 99 ms). The lateral ventricle was diffusely enlarged bilaterally, and the wall of the lateral ventricle was irregular. The volume of the periventricular white matter was severely decreased. The periventricular white matter signal intensity was increased, but the border between the lateral ventricle and the white matter could barely be distinguished. Compared with the usual myelination at 2 years, myelination of the frontal lobe was delayed. (B) FLAIR imaging (TR: 8,000 ms, TE: 105 ms). The intensity of the periventricular white matter was increased, and the border between the lateral ventricle and the white matter could easily be distinguished.
tum, the spongy state in and around the central tegmental tract, and a localized periaqueductal glial scarring. Chugani et al. [28] examined positron emission tomography studies in 44 infants with West syndrome and observed increased glucose metabolism in the brainstem and lenticular nuclei region in 21 and 32 of the 44 infants, respectively. In addition, the patients with West syndrome exhibited a marked decrease in rapid eye movement sleep and had a lower total sleep time [29,30]. Furthermore, only
Figure 3. MRI of a PVL patient without West syndrome (Patient 9). This patient is the twin sister of Patient 5. (A) T2-weighted axial image (TR: 4,200 ms, TE: 99 ms). The lateral ventricle of the posterior horn was enlarged bilaterally. The volume of the periventricular white matter in the trigone region was decreased. The periventricular white matter signal intensity of the posterior horn was increased. Myelination was not delayed. (B) FLAIR imaging (TR: 8,000 ms, TE: 105 ms). The intensity of the periventricular white matter was increased, and the border between the lateral ventricle and the white matter could easily be distinguished compared with T2-weighted imaging.
infants whose spasms and hypsarrhythmic pattern on electroencephalography improved with adrenocorticotropic hormone (ACTH) or prednisone demonstrated a reversal of the rapid eye movement sleep abnormality. The site of pathogenesis in West syndrome might be at the pontine level, in close proximity to centers that regulate sleep cycles. Silverstein and Johnston [31] support this hypothesis. They observed lower concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid, in the cerebrospinal fluid of infants with spasms compared with
Ozawa et al: PVL and West syndrome 361
Table 4.
Comparison of width of the cerebrum among the three groups Evans Ratio (A/B)
Group
Ratio of Posterior Horn (C/B)
0.32 6 0.01 0.28 6 0.03 * † 0.26 6 0.03
]
W N-W C
0.68 6 0.09 0.55 6 0.03 0.48 6 0.04
]
] ]
†
]
†
†
Cella Media Index (E/F) 0.50 6 0.07 0.39 6 0.06 0.29 6 0.03
] ]
† †
]
†
Width of Third Ventricle (mm) 8.7 6 3.0 5.1 6 2.2 * * 4.8 6 0.6
]
]
* P , 0.05. † P , 0.01. Abbreviations: C 5 Control patients N-W 5 Patients with PVL without West syndrome W 5 Patients with PVL and West syndrome
age-matched normal infants. They proposed that a state of supersensitivity of serotonin receptors in infants with West syndrome might result in diminished presynaptic serotonin turnover and release from serotonin-containing neurons, which are concentrated in the raphe region of the pons. Coleman et al. [32] reported that the serotonin precursor, 5-hydroxytryptophan, induced infantile spasms when it was administered to patients with Down syndrome. In the authors’ MRI morphometric study the areas of the midbrain and pons were smaller and the width of the third ventricle was larger in patients with WS with PVL than in patients without WS with PVL, as was the Evans ratio, ratio of the posterior horns, and Cella media index. Also, the areas of medulla oblongata were smaller in patients with WS with PVL than in control patients but not in patients without WS with PVL. Therefore, there is a close relationship between WS with PVL and atrophy of the midbrain and pons. Konishi et al. [33] observed that the volumes of the midline structures of the brain, including the pons, cerebellar vermis, and corpus callosum, were decreased in the patients with West syndrome treated with ACTH. Three of the authors’ reported patients with West syndrome were not treated with ACTH; MRI in one patient was performed before ACTH therapy, and in another patient MRI was performed 16 months after ACTH therapy. Thus, in the present MRI study, the effect of ACTH is considered to be small. This study demonstrates that the atrophy of midbrain and pons was the most characteristic and may be a cause of West syndrome. Table 5. groups
Group W N-W C
Comparison of area of the brainstem among the three
Area of midbrain (cm2) 2.3 6 0.4 3.2 6 0.5 3.5 6 0.8
]
†
]
*
Area of pons (cm2) 2.6 6 0.4 3.8 6 0.6 4.0 6 0.6
]
]
† †
PEDIATRIC NEUROLOGY
1.3 6 0.1 1.6 6 0.3 * 1.6 6 0.3
]
Figure 4. (A) T1-weighted axial imaging (TR: 570 ms, TE: 12 ms) of a PVL patient with West syndrome (Patient 5). The volume of the pons was decreased. (B) T1-weighted axial imaging (TR: 570 ms, TE: 12 ms) of a PVL patient without West syndrome (Patient 9). The volume of the pons was not decreased.
* P , 0.05. † P , 0.01. Abbreviations as in Table 4.
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This study was supported by grants from the Ministry of Health and Welfare, and Education of Japan. The authors thank Drs. Masumi Inagaki and Hiroshi Matsuda for their valuable suggestions and advice and Mr. Shougo Kumagai for preparing the manuscript.
References [1] Banker BQ, Larroche JC. Periventricular leukomalacia of infancy: A form of neonatal anoxic encephalopathy. Arch Neurol 1962;7: 386-410. [2] Takashima S, Tanaka K. Development of cerebrovascular architecture and its relationship to periventricular leukomalacia. Arch Neurol 1978;35:11-6. [3] Crawford CL, Hobbs MJ. Anatomy of diplegia: An hypothesis. Dev Med Child Neurol 1994;36:513-7. [4] Flodmark O, Roland EH, Hill A, Whitfield MF. Periventricular leukomalacia: Radiologic diagnosis. Radiology 1987;162:119-24. [5] Koeda T, Suganuma I, Kohno Y, Takamatsu T, Takeshita K. MR imaging of spastic diplegia: Comparative study between preterm and term infants. Neuroradiology 1990;32:187-90. [6] Yokochi K, Aiba K, Horie M, et al. Magnetic resonance imaging in children with spastic diplegia: Correlation with the severity of their motor and mental abnormality. Dev Med Child Neurol 1991;33:18-25. [7] Schouman-Claeys E, Henry-Feugeas M-C, Roswet F, et al. Periventricular leukomalacia: Correlation between MR imaging and autopsy findings during the first 2 months of life. Radiology 1993;189: 59-64. [8] Skanes JS, Vik T, Nilsen G, et al. Cerebral magnetic resonance imaging (MRI) and mental and motor function of very low birth weight infants at one year of corrected age. Neuropediatrics 1993;24:256-62. [9] Jeavons PM, Livet MO. West syndrome: Infantile spasms. In: Roger J, Bureau M, Dravet Ch, Dreifuss FE, Perret A, Wolf P, eds. Epileptic syndrome in infancy, childhood and adolescence, 2nd ed. London: John Libbey, 1992:53-65. [10] Cusmai R, Ricci S, Pinard JM, Plouin P, Fariello G, Dulac O. West syndrome due to perinatal insults. Epilepsia 1993;34:738-42. [11] Okumura A, Hayakawa F, Kuno K, Watanabe K. Periventricular leukomalacia and West syndrome. Dev Med Child Neurol 1996;38: 13-8. [12] Iida K, Takashima S, Takeuchi Y. Etiologies and distribution of neonatal leukomalacia. Pediatr Neurol 1992;8:205-9. [13] Iida K, Takashima S, Takeuchi Y, Ohno T, Ueda K. Neuropathologic study of newborns with prenatal-onset leukomalacia. Pediatr Neurol 1993;9:45-8. [14] Iida K, Takashima S, Ueda K. Immunohistochemical study of myelination and oligodendrocyte in infants with periventricular leukomalacia. Pediatr Neurol 1995;13:296-304. [15] Deguchi K, Mizuguchi M, Takashima S. Immunohistochemical expression of tumor necrosis factor a in neonatal leukomalacia. Pediatr Neurol 1996;14:13-6.
[16] Arai Y, Deguchi K, Mizuguchi M, Takashima S. Expression of b-amyloid precursor protein in axons of periventricular leukomalacia brains. Pediatr Neurol 1995;13:161-3. [17] Baker LL, Stevenson DK, Enzmann DR. End-stage periventricular leukomalacia: MR evaluation. Radiology 1988;168:809-15. [18] Kuban KCK, Leviton A. Cerebral palsy. N Engl J Med 1994;330:188-95. [19] Eken P, de Vries LS, van der Graaf Y, Meiners LC, van Nieuwenhuizen O. Haemorrhagic-ischaemic lesions of the neonatal brain: Correlation between cerebral visual impairment, neurodevelopmental outcome and MRI in infancy. Dev Med Child Neurol 1995;37: 41-55. [20] Scher MS, Table DV, Carpenter NA, Guthrie RD. Visual and neurological outcome in infants with periventricular leukomalacia. Dev Med Child Neurol 1989;31:353-65. [21] van de Bor M, Ens-Dokkum M, Schreuder AM, Veen S, Brand R, Verloove-Vanhorick SP. Outcome of periventricular-intraventricular haemorrhage at five years of age. Dev Med Child Neurol 1993;35:33-41. [22] Fazzi E, Orcesi S, Caffi L, et al. Neurodevelopmental outcome at 5-7 years in preterm infants with periventricular leukomalacia. Neuropediatrics 1994;25:134-9. [23] Volpe JJ. Cognitive deficits in premature infants. N Engl J Med 1991;325:276-8. [24] Fawer CL, Besnier S, Forcada M, Buclin T, Calame A. Influence of perinatal, developmental and environmental factors on cognitive abilities of preterm children without major impairments at 5 years. Early Hum Dev 1995;43:151-64. [25] Schropp C, Staudt M, Staudt F, et al. Delayed myelination in children with West syndrome: An MRI study. Neuropediatrics 1994;25: 116-20. [26] Muroi J, Okuno T, Kuno C, et al. An MRI study of the myelination pattern in West syndrome. Brain Dev 1996;18:179-84. [27] Satou J, Mizutani T, Morimatsu Y. Neuropathology of the brainstem in age-dependent epileptic encephalopathy: Especially of cases with infantile spasms. Brain Dev 1986;8:443-9. [28] Chugani HT, Shewmon DA, Sankar R, Chen BC, Phelps ME. Infantile spasms: II. Lenticular nuclei and brainstem activation on positron emission tomography. Ann Neurol 1992;31:212-9. [29] Hrachovy RA, Frost JD Jr, Kellaway P. Sleep characteristics in infantile spasms. Neurology 1981;31:688-94. [30] Hashimoto T, Ohara K, Hiura K, et al. Sleep polygraphic studies on infantile spasms. Acta Paediatr Jpn 1978;20:1-7. [31] Silverstein F, Johnston MV. Cerebrospinal fluid monoamine metabolites in patients with infantile spasms. Neurology 1984;34:102-5. [32] Coleman M. Infantile spasms associated with 5-hydroxytryptophan administration in patients with Down’s syndrome. Neurology 1971;21:911-9. [33] Konishi Y, Hayakawa K, Kuriyama M, Saito M, Fujii Y, Sudo M. Effects of ACTH on brain midline structures in infants with infantile spasms. Pediatr Neurol 1995;13:134-6.
Ozawa et al: PVL and West syndrome 363
Ozawa H, Hashimoto T, Endo T, Kato T, Furusho J, Suzuki Y, Takada E, Ogawa Y, Takashima S. West syndrome with periventricular leukomalacia: A morphometric MRI study. Pediatr Neurol 1998;19:358-363.
From the *Departments of Mental Retardation and Birth Defect Research; National Institute of Neuroscience; †Department of Child Neurology; National Center Hospital for Mental, Nervous and Muscular Disorders; National Center of Neurology and Psychiatry; ‡ Department of Pediatrics; Showa General Hospital; §Department of Pediatrics; Tokyo Children’s Rehabilitation Hospital; Tokyo; and \ Department of Pediatrics; Saitama Medical Center; Saitama Medical School; Saitama, Japan.
Communications should be addressed to: Dr. Ozawa; Department of Mental Retardation and Birth Defect Research; National Institute of Neuroscience; 4-1-1 Ogawahigashi; Kodaira, Tokyo 187, Japan. Received February 27, 1998; accepted June 4, 1998.
358
PEDIATRIC NEUROLOGY
Vol. 19 No. 5
Introduction Periventricular leukomalacia (PVL) is an important cause of neurologic sequelae, such as spastic diplegia and intellectual impairment in preterm infants [1-3]. Early medical imaging is indispensable for diagnosis and prognosis. Although ultrasound may demonstrate PVL during the neonatal period, the sensitivity and specificity of this technique have not been demonstrated conclusively. Computed tomography demonstrates characteristic features of PVL in later infancy and childhood [4]. Magnetic resonance imaging (MRI) is superior in demonstrating white matter lesions. The capacity of MRI to detect white matter injury and visualize the cerebral parenchyma also should allow precise delineation of PVL [5-8]. Although the relationships between West syndrome (WS) and term hypoxic-ischemic encephalopathy, intraventricular and subarachnoid hemorrhage, and neonatal hypoglycemia have been well described [9], there have been only a few reports on the relationship between WS and PVL [10,11]. The purposes of this study were to evaluate MRI in patients with PVL and WS and to elucidate the cause of WS with PVL. Materials and Methods This study included 21 infants (11 males, 10 females) born at 24-32 weeks of gestation and weighing 625-1,908 gm. There were three groups:
© 1998 by Elsevier Science Inc. All rights reserved. PII S0887-8994(98)00081-2 ● 0887-8994/98/$19.00
Table 1.
Clinical course of patients with West syndrome with periventricular leukomalacia
Patient No.
Gestation (wk)
Birth Weight (gm)
Age at onset (mo)
Treatment
Age at MRI (mo)
Perinatal Problem
30 30 32 30 29
982 1,358 752 1,700 1,308
8 11 8 8 6
CZP ACTH, VPA, NZP VPA, CZP ACTH, VPA, CZP VPA, CZP
7 11 14 26 32
Asphyxia, RDS RDS, PDA RDS, convulsion Asphyxia, convulsion Apnea
1 2 3 4 5
Abbreviations: ACTH 5 Adrenocorticotropic hormone CZP 5 Clonazepam MRI 5 Magnetic resonance imaging NZP 5 Nitorazepam
Patient No. 1 2 3 4 5 6 7 8 9 10 11
Spastic Spastic Spastic Spastic Spastic
quadriplegia quadriplegia quadriplegia quadriplegia quadriplegia
Mentality Severe Severe Severe Severe Severe
PDA 5 Patent ductus arteriosus RDS 5 Respiratory distress syndrome VPA 5 Valproic acid
group 1, five PVL patients with WS (Table 1); group 2, 11 PVL patients without WS (Table 2); and group 3, five control patients (Table 3). There were no significant differences in gestation, birth weight, or age at MRI among the three groups of patients by analysis of variance (P , 0.05). The diagnosis of PVL using MRI was based on the following abnormalities: (1) abnormally increased periventricular white matter signal intensity on T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR), most commonly observed in the trigone regions of the lateral ventricles bilaterally; (2) loss of periventricular white matter in the regions of abnormal signal intensity; and (3) focal or widespread ventricular enlargement adjacent to regions of abnormal signal intensity. West syndrome was diagnosed when a patient had a series of spasms and hypsarrhythmia was indicated on interictal electroencephalography. Control patients were determined by no abnormal findings on MRI and normal development. Mentality was assessed by the Denver Developmental Screening Test: normal, intelligence greater than 75; mild retardation, 50-75; moderate, 25-50; and severe, less than 25. MRI was performed, at 7 months to 2 years 8 months of age, with a Siemens, Magneton Impact Expert (Siemens, Erlangen, Germany) with a superconducting magnet operating at 1.0 T (T1-weighted [TR: 570 ms, TE: 12 ms], T2-weighted [TR: 4,200 ms, TE: 99 ms] axial images, FLAIR [TR: 8,000 ms, TE: 105 ms], with 5-mm section thickness), or a General Electric Sigma (General Electric, Milwaukee, WI) with a superconducting magnet operating at 1.5 T (T1-weighted [TR: 500 ms, TE: 19 ms], T2-weighted [TR: 3,500 ms, TE: 102 ms] axial images with 5-mm section thickness). Axial sections were crossed parallel to the anterior commissure-posterior commissures line. Informed consent was
Table 2.
Palsy
obtained from the patients’ parents. All measurements were made with a computer-assisted imaging analyzer (OLYMPUS SP500). The measured portions are illustrated in Figure 1. The Evans ratio (A/B), ratio of the posterior horns (C/B), and Cella media index (E/F) were calculated. The area of the midbrain at the level of the inferior colliculus, the area of the upper pons (isthmus), and the area of the medulla (lower region) were also measured. Myelination was independently assessed by two observers (H.O., S.T.) with T1- and T2-weighted MRI. These findings were compared among the three groups. Statistical analysis was performed using the Student t test.
Results Cerebrum There were no significant differences in gestation, birth weight, and age at MRI among the three groups. In groups 1 and 2, abnormally increased periventricular white matter signal intensity on T2-weighted imaging and FLAIR was observed most commonly in the lateral ventricles bilaterally, and the volumes of periventricular white matter in these regions of abnormal signal intensity were decreased. Also, the walls of the lateral ventricle were irregular (Figs 2 and 3). In group 1 the Evans ratio, ratio of the posterior
Clinical course of patients without West syndrome with periventricular leukomalacia Gestation (wk)
Birth Weight (gm)
Age at MRI (mo)
Perinatal Problem
29 27 27 31 29 31 32 32 29 24 29
894 686 1,148 1,908 1,840 1,544 1,888 1,705 1,616 625 1,228
9 10 13 13 14 14 24 28 29 29 32
RDS RDS RDS, IVH, hyperkalemia RDS RDS, asphyxia RDS RDS RDS RDS RDS, PDA, hyperkalemia Apnea
Palsy Spastic Spastic Spastic Spastic Spastic Spastic Spastic Spastic Spastic Spastic Spastic
diplegia diplegia quadriplegia quadriplegia quadriplegia diplegia diplegia diplegia diplegia diplegia diplegia
Epilepsy
Mentality
2 2 2 2 1 2 2 2 2 2 2
Normal Mild Moderate Mild Mild Normal Normal Mild Normal Normal Mild
Abbreviations: IVH 5 Intraventricular hemorrhage Other abbreviations as in Table 1.
Ozawa et al: PVL and West syndrome 359
Table 3.
bellar fissures was seen in two patients. Abnormal intensity was not seen in groups 1, 2, and 3.
Clinical course of control patients
Patient No. 1 2 3 4 5
Gestation (wk)
Birth Weight (gm)
Age at MRI (mo)
32 27 24 30 32
1,758 866 688 1,239 1,415
7 13 8 18 8
Abbreviations as in Table 1.
horns, Cella media index, and width of the third ventricle were larger than in groups 2 and 3. In group 2 the ratio of the posterior horns and Cella media index were larger than in group 3 but the width of the third ventricle was not (Table 4). Myelination was delayed in all patients in group 1 and in two patients in group 2 (Patients 3 and 5). Brainstem In groups 1 and 2, abnormal intensity was not observed in the midbrain, pons, or medulla oblongata. However, in group 1 the areas of the midbrain and pons were smaller than in groups 2 and 3 and the medulla oblongata was smaller than in group 3. There were no differences in the midbrain, pons, and medulla oblongata between groups 2 and 3 (Table 5) (Fig 4). Cerebellum In group 1, cerebellar atrophy was observed in one patient and slight enlargement of the cerebellar fissures in two patients. In group 2, slight enlargement of the cere-
Discussion PVL has been recognized in infant brains in neuropathologic studies [2,12-16] and by means of imaging techniques [4-8,17] since Banker and Larroche first described it [1]. They attributed the etiology of PVL to perinatal hypoxia, relating this finding to the successive development of spastic diplegia [3,5,6,18], visual and hearing impairment [19-21], and cognitive dysfunction [22-24]. Recently, there have been a few reports of PVL associated with West syndrome [10,11]. Cusmai et al. [10] reported that 12 patients with symptomatic infantile spasms caused by a perinatal insult had PVL, and the outcome of epilepsy appeared to be relatively good. Okumura et al. [11] reported that seven of 27 patients with PVL developed West syndrome and that the volume loss of periventricular white matter extended to the frontal horns in all patients with West syndrome. Also, they observed bilateral parieto-occipital spike-and-wave bursts that could have been a precursor of hypsarrhythmia. Infantile spasms are age-specific and often poorly responsive to conventional antiepileptic drugs [9]. Delayed myelination is reported in infants with West syndrome [25,26]. In all of the authors’ patients with West syndrome with PVL, myelination was delayed. These findings correspond with previous reports. Recently, clinical, physiologic, and pathologic studies have suggested that the brainstem might play an important role in generating infantile spasms [27-32]. Satou et al. [27] performed 22 postmortem examinations on patients with West syndrome and documented the small size of the brainstem tegmen-
Figure 1. (A-C) Measured portions on MRI (TR/TE: 570/12 ms). A, Maximum distance between the anterior horns; B, maximum distance between the internal laminae; C, maximum distance between the posterior horns; D, width of the third ventricle; E, central distance between the level of cella media; and F, maximum distance between the internal laminae at the same level. The authors compared the Evans ratio (A/B), ratio of the posterior horns (C/B), Cella media index (E/F), and width of the third ventricle (D) among the three groups. The area of the midbrain at the level of the inferior colliculus, the area of the upper pons (isthmus), and the area of the medulla (lower region) were also measured.
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Figure 2. MRI of a PVL patient with West syndrome (Patient 5). (A) T2-weighted axial image (TR: 4,200 ms, TE: 99 ms). The lateral ventricle was diffusely enlarged bilaterally, and the wall of the lateral ventricle was irregular. The volume of the periventricular white matter was severely decreased. The periventricular white matter signal intensity was increased, but the border between the lateral ventricle and the white matter could barely be distinguished. Compared with the usual myelination at 2 years, myelination of the frontal lobe was delayed. (B) FLAIR imaging (TR: 8,000 ms, TE: 105 ms). The intensity of the periventricular white matter was increased, and the border between the lateral ventricle and the white matter could easily be distinguished.
tum, the spongy state in and around the central tegmental tract, and a localized periaqueductal glial scarring. Chugani et al. [28] examined positron emission tomography studies in 44 infants with West syndrome and observed increased glucose metabolism in the brainstem and lenticular nuclei region in 21 and 32 of the 44 infants, respectively. In addition, the patients with West syndrome exhibited a marked decrease in rapid eye movement sleep and had a lower total sleep time [29,30]. Furthermore, only
Figure 3. MRI of a PVL patient without West syndrome (Patient 9). This patient is the twin sister of Patient 5. (A) T2-weighted axial image (TR: 4,200 ms, TE: 99 ms). The lateral ventricle of the posterior horn was enlarged bilaterally. The volume of the periventricular white matter in the trigone region was decreased. The periventricular white matter signal intensity of the posterior horn was increased. Myelination was not delayed. (B) FLAIR imaging (TR: 8,000 ms, TE: 105 ms). The intensity of the periventricular white matter was increased, and the border between the lateral ventricle and the white matter could easily be distinguished compared with T2-weighted imaging.
infants whose spasms and hypsarrhythmic pattern on electroencephalography improved with adrenocorticotropic hormone (ACTH) or prednisone demonstrated a reversal of the rapid eye movement sleep abnormality. The site of pathogenesis in West syndrome might be at the pontine level, in close proximity to centers that regulate sleep cycles. Silverstein and Johnston [31] support this hypothesis. They observed lower concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid, in the cerebrospinal fluid of infants with spasms compared with
Ozawa et al: PVL and West syndrome 361
Table 4.
Comparison of width of the cerebrum among the three groups Evans Ratio (A/B)
Group
Ratio of Posterior Horn (C/B)
0.32 6 0.01 0.28 6 0.03 * † 0.26 6 0.03
]
W N-W C
0.68 6 0.09 0.55 6 0.03 0.48 6 0.04
]
] ]
†
]
†
†
Cella Media Index (E/F) 0.50 6 0.07 0.39 6 0.06 0.29 6 0.03
] ]
† †
]
†
Width of Third Ventricle (mm) 8.7 6 3.0 5.1 6 2.2 * * 4.8 6 0.6
]
]
* P , 0.05. † P , 0.01. Abbreviations: C 5 Control patients N-W 5 Patients with PVL without West syndrome W 5 Patients with PVL and West syndrome
age-matched normal infants. They proposed that a state of supersensitivity of serotonin receptors in infants with West syndrome might result in diminished presynaptic serotonin turnover and release from serotonin-containing neurons, which are concentrated in the raphe region of the pons. Coleman et al. [32] reported that the serotonin precursor, 5-hydroxytryptophan, induced infantile spasms when it was administered to patients with Down syndrome. In the authors’ MRI morphometric study the areas of the midbrain and pons were smaller and the width of the third ventricle was larger in patients with WS with PVL than in patients without WS with PVL, as was the Evans ratio, ratio of the posterior horns, and Cella media index. Also, the areas of medulla oblongata were smaller in patients with WS with PVL than in control patients but not in patients without WS with PVL. Therefore, there is a close relationship between WS with PVL and atrophy of the midbrain and pons. Konishi et al. [33] observed that the volumes of the midline structures of the brain, including the pons, cerebellar vermis, and corpus callosum, were decreased in the patients with West syndrome treated with ACTH. Three of the authors’ reported patients with West syndrome were not treated with ACTH; MRI in one patient was performed before ACTH therapy, and in another patient MRI was performed 16 months after ACTH therapy. Thus, in the present MRI study, the effect of ACTH is considered to be small. This study demonstrates that the atrophy of midbrain and pons was the most characteristic and may be a cause of West syndrome. Table 5. groups
Group W N-W C
Comparison of area of the brainstem among the three
Area of midbrain (cm2) 2.3 6 0.4 3.2 6 0.5 3.5 6 0.8
]
†
]
*
Area of pons (cm2) 2.6 6 0.4 3.8 6 0.6 4.0 6 0.6
]
]
† †
PEDIATRIC NEUROLOGY
1.3 6 0.1 1.6 6 0.3 * 1.6 6 0.3
]
Figure 4. (A) T1-weighted axial imaging (TR: 570 ms, TE: 12 ms) of a PVL patient with West syndrome (Patient 5). The volume of the pons was decreased. (B) T1-weighted axial imaging (TR: 570 ms, TE: 12 ms) of a PVL patient without West syndrome (Patient 9). The volume of the pons was not decreased.
* P , 0.05. † P , 0.01. Abbreviations as in Table 4.
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This study was supported by grants from the Ministry of Health and Welfare, and Education of Japan. The authors thank Drs. Masumi Inagaki and Hiroshi Matsuda for their valuable suggestions and advice and Mr. Shougo Kumagai for preparing the manuscript.
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