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Clinical study of catastrophic infantile epilepsy with focal seizures
Clinical Study of Catastrophic Infantile Epilepsy With Focal Seizures Kayano Ishii, MD, Hirokazu Oguni, MD, Kitami Hayashi, MD, Seigo Shirakawa, MD, Yasushi Itoh, MD, and Makiko Osawa, MD This study investigated clinico-electrical and etiologic characteristics of catastrophic infantile epilepsy with focal seizures developed in early infancy. The patients included 15 children who fulfilled the following criteria: seizure onset before 12 months of age, presence of daily focal or secondarily generalized seizures resistant to antiepileptic drugs for at least 3 months, and exclusion of Ohtahara and West syndromes. Patients were classified into three subgroups. Three patients demonstrated progressively deteriorating neurologic symptoms associated with progressive cerebral atrophy and multifocal seizure onset. Three other children were characterized by hemiparesis and exclusively lateralized seizure onset because of focal cortical dysplasia in the contralateral hemisphere. The remaining nine children did not demonstrate any rapidly progressive neurologic deterioration or increasing cerebral atrophy and exhibited multifocal seizure onset. At the last examinations, all except one patient demonstrated moderate to severe psychomotor retardation. Catastrophic infantile epilepsy with focal seizures tended to demonstrate multifocal seizure onset and a deleterious clinical course with numerous focal seizures regardless of etiology. Because migratory focal seizures appear to be common in these infants, we have to search for the underlying etiopathogenesis of these patients, including not only metabolic errors but also localized or lateralized structural abnormality. © 2002 by Elsevier Science Inc. All rights reserved. Ishii K, Oguni H, Hayashi K, Shirakawa S, Itoh Y, Osawa M. Clinical study of catastrophic infantile epilepsy with focal seizures. Pediatr Neurol 2002;27:369-377.
Introduction The onset of epilepsy during infancy is one of the crucial factors for prognosis because epileptic seizures tend to develop in association with critical developmental abnormalities of the brain. There have been several reports analyzing patients with convulsive disorders developing in the first year of life [1-4]. The findings were largely consistent with the conclusion that febrile seizures, West syndrome, and status epilepticus were the most frequent causes of seizures in this age group. However, although the number of patients remains small, there have been sporadic reports of infants who have frequent exclusively focal motor seizures and status epilepticus, and these infants follow a catastrophic clinical course [1,2,5-7]. These patients sometimes require long-term anesthesia for the treatment of incapacitating status epilepticus resistant to conventional antiepileptic drugs. The etiology in these cases remains largely unknown, although recent progress in epilepsy surgery has identified underlying cortical dysplasia in some infants demonstrating lateralized or localized neuroimaging abnormality responsible for these catastrophic seizures [8,9]. Although these infants with catastrophic focal seizures have sporadically been reported worldwide, there have not been any systematic studies conducted regarding these patients. In the present study, we described the result of investigations into the etiology and clinical, electroencephalogram (EEG), and neuroimaging pictures of catastrophic infantile epilepsy with focal seizures and discuss the nosology of epilepsy. Patients and Methods Among patients with intractable epileptic seizures admitted to our hospital between January 1985 and December 1999, we selected patients according to the following criteria: (1) seizure onset before 12 months of age and (2) presence of daily focal or secondarily generalized seizures
From the Department of Pediatrics; Tokyo Women’s Medical University; Tokyo, Japan.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(02)00449-6 ● 0887-8994/02/$—see front matter
Communications should be addressed to: Dr. Oguni; Department of Pediatrics; Tokyo Women’s Medical University; 8-1 Kawada-cho; Shinjuku-ku; Tokyo 162, Japan. Received February 19, 2002; accepted May 8, 2002.
Ishii et al: Catastrophic Infantile Epilepsy 369
resistant to conventional antiepileptic drugs for at least 3 months. Patients with early infantile epileptic encephalopathy (also known as Ohtahara syndrome) and West syndrome who developed focal seizures followed by epileptic spasms or by combined focal seizures and epileptic spasms were excluded from the study. The clinical, EEG, and laboratory findings, as well as neuroimaging data, were retrospectively studied from the clinical records. The seizure frequencies were evaluated at daily and monthly intervals by seizure records, in which parents or caregivers documented the number of seizures per day. Because of the large number of daily seizures in many patients, the average seizure frequencies were sometimes recorded per hour and the frequency per day was calculated. The seizure types were determined by analysis of simultaneous video electroencephalogram documentation. The etiology of epilepsy in patients fulfilling the criteria was speculated largely based on the findings of computed tomography, magnetic resonance imaging, and the following laboratory data when the specific etiology was not identified: cerebrospinal fluid glucose, protein, and IgG index, serum and cerebrospinal fluid lactic acid, urinary amino acid and organic acid, long-chain fatty acid, serum copper, ceruloplasmin and selen, lysosomal storage enzyme, muscle biopsy (three patients), and ophthalmologic examinations. We tentatively classified the patients into progressive and nonprogressive groups according to the presence or absence of both progressive neurologic deterioration (i.e., appearance of spasticity or rigidity, progressive loss of acquired skill) and progressive atrophy of the brain on neuroimaging studies performed at intervals of several months. Interictal and ictal EEG findings were also reviewed in all patients to identify lateralization and localization of epileptogenic EEG foci. The effectiveness of the treatments was estimated by the following criteria: excellent response, more than 80% reduction; moderate response, more than 50% reduction; poor response, less than 50% reduction; and aggravated, more than 50% increase of focal or secondarily generalized seizures.
Results Fifteen patients met the criteria and were included in the study (Table 1). There were five males and 10 females. The median age at onset of the first seizure was 21 days of age (range ⫽ 1 day to 7 months of age). The age at the first consultation at our hospital ranged from 20 days to 2 years, 8 months of age, with a mean of 7.8 months. The mean follow-up period was 5 years and 1 month. During the follow-up, three patients demonstrated progressively deteriorating neurologic symptoms associated with progressive cerebral atrophy on magnetic resonance imaging or computed tomography scan at intervals of several months (progressive group ⫽ P group). The remaining 12 infants did not demonstrate such a rapidly progressive neurologic deterioration or increasing cerebral atrophy, although the frequent seizures or status epilepticus appeared to stagnate their development or to cause some neurologic deterioration (nonprogressive group ⫽ NP group). Among the 12 patients, three patients always had lateralized seizure onset (nonprogressive unilateral group ⫽ NPU group), and the remaining nine patients had manifested bilateral or independent multifocal seizure onset on repeated EEG examinations (nonprogressive diffuse group ⫽ NPD group). The three patients in the NPU group demonstrated worsening of pre-existing hemiplegia or slowly progressive hemiparesis along with fre-
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quent seizures. The clinical details of these three NPU patients has been described previously [10]. Perinatal Abnormalities In five of the 15 patients, perinatal abnormalities, including fetal distress in three patients and severe asphyxia in one patient, were documented. Two of these five infants had also demonstrated in utero growth retardation with oligohydramnois. One other patient had received maternal-fetal transfusion. In the remaining infant, regular fetal echo investigations identified hydrocephalus, which was identified as severe cerebral atrophy on postnatal magnetic resonance imaging. Multiple anomalies had been identified in three infants at birth (two in the P group, and one in the NPD group) (Table 1). Development Before the Onset of Epilepsy Because seizure onset was early in all patients, development before seizure onset is difficult to evaluate precisely. One patient demonstrated profound hypotonia and gross developmental delay at 7 months of age when focal motor seizures developed (Patient 2, Table 1). The other six infants, including one in the P group (Patient 3), three in the NPU group, and two in the NPD group (Patients 9 and 15) achieved appropriate developmental milestones at 2-3 months of age based either on documentation of regular developmental checkup at 3 months of age or on our own neurologic examinations. The development had already become significantly retarded in all patients except one in the NP group at the time of the first consultation. In addition, pyramidal signs and cerebral hypotonia were observed at the first examinations in nine and 10 patients, respectively. Seizure Types and Frequency The seizures in all 15 cases consisted of focal seizures with motor symptoms involving the face, arm, and legs simultaneously or independently. In addition, versive and postural symptoms were also mixed during the seizures. The three infants in the P group and the nine infants in the NPD group demonstrated focal motor seizures of multifocal onset at times appearing on one or both sides of the body or changing sides during a single seizure, or successively occurring on alternating sides of the body, whereas three infants in the NPU group had lateralized focal motor or unilateral seizures. In all 15 infants the seizures progressively increased in frequency and occurred at least 10 or more times/day at the peak of the clinical course. All three patients in the P group demonstrated almost continuous attacks during wakefulness, requiring prolonged pentobarbital anesthesia at the peak of the clinical course, and two infants finally died of status epilepticus at 14 months and 29 months of age, respectively. In addition, six of the nine infants in the
Figure 1. Interictal electroencephalogram study of Patient 1 (P group) is presented. Electroencephalogram during sleep revealed diffuse irregular mixed theta and delta activity at 8 months of age (A), which changed to diffuse depressed activity 7 months later (B).
NPD group also demonstrated status epilepticus or almost continuous focal seizures occurring every 3-5 minutes. All six of these infants also received pentobarbital anesthesia at some time during the clinical course. The three patients in the NPU group also had frequent daily attacks, although none of them culminated in status epilepticus.
lateralized in one hemisphere, which was consistent with the side demonstrating abnormal neuroradiologic findings (i.e., right frontocentrotemporal region in one patient, right frontocentral region in another patient, and the left centroparietal region in the remaining patient). Etiology and Neuroradiologic Findings
Electroencephalogram Findings On interictal EEGs, three patients in the P group and nine patients in the NPD group demonstrated frequent intermittent multifocal spikes or sharp waves with markedly disorganized background activity during both wakefulness and sleep. The interictal EEGs of the three patients in the P group changed from multifocal spikes with disorganized background activity in the early stage to disappearance of spike discharges with continuous depressed background activity when they were more than 1 year of age (Fig 1). In the ictal EEGs the three patients in the P group and the nine patients in the NPD group exhibited the onset of the seizures shifting from one hemisphere to the other (Fig 2). When the clustering of seizures occurred the EEG seizure foci changed, alternating in both hemispheres. The EEG seizure foci were multifocal and sometimes different in localization in both hemispheres. However, the three patients in the NPU group demonstrated the ictal EEG onset, and predominant interictal EEG spike foci were
The three patients in the P group were diagnosed clinically as having Alpers syndrome based on progressive deterioration of clinical and neuroimaging findings and the exclusion of other known causes of degenerative or metabolic encephalopathy. On sequential computed tomography investigation performed at 3-6-month intervals, these infants demonstrated progressive cerebral atrophy consistent with the progressive nature of neurologic deterioration in these cases (Fig 3). Two infants died of status epilepticus and were examined postmortem. In the one patient who manifested cytochrome C oxidase deficiency on previous muscle biopsy, the brain specimen demonstrated status spongiosus, pseudolaminar destruction of the neurons in the cerebral cortex, and marked astrocytic gliosis involving both cerebral cortex and white matter, which is consistent with the pathologic findings of Alpers syndrome [11]. In another patient with severe brain atrophy, high cerebrospinal fluid lactate values, and marked liver dysfunction, the brain specimen also revealed the pathologic features of Alpers syndrome and fatty and
Ishii et al: Catastrophic Infantile Epilepsy 371
Table 1.
Clinical findings in 15 patients
Sex
Onset of Seizures (mo)
P 1
M
1 day
5
Asphyxia, hydrocephalus on fetal ultrasonography
2
F
7
5
IUGR, hypoammniosis
3
M
1
3
31
Equivalent to 2-3 months
Hypotonia, mild paraplegia
NPU 4
M
2.5
7
126
DQ⫽87
Hypotonia, Lt hemiparesis
5
M
2
12
102
DQ⫽150
No abnormality
6
F
2
32
102
DQ⫽24
Hypotonia, Lt hemiplegia
NPD 7 8
F F
120 69
DQ⫽120 DQ⫽1
Mild quadriplegia Mild quadriplegia
9
F
3
7
DQ⫽1
Hypotonia, mild quadriplegia
10
M
1 day
1
11 12
F F
20 days 10 days
6 24 days
13 14
M F
13 days 2 days
20 days 7
15
M
Patient No.
21 days 21 days
3
Age at First Examination (mo)
2 4
5
Perinatal History
SFD, fetal distress
—
24
DQ⫽10
Hypotonia
9
DQ⫽30
Hypotonia
15
SFD IUGR, fetal distress, hypoammniosis — —
Maternal-fetal blood transfusion, fetal distress, severe asphyxia
NPD NPU P PAS Rt SE SFD SG TIQ
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
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—
Neurological Abnormality at First Examination
Hypotonia, mild quadriplegia
156 99
DQ⫽65 —
Mild quadriplegia Hypotonia
30 7
— DQ⫽3
No abnormality Hypotonia, mild quadriplegia
7
DQ⫽59
Hypotonia
Nonprogressive diffuse group Nonprogressive unilateral group Progressive group Prolonged atonic seizure Right Status epilepticus Small for date infant Secondary generalization Total intelligence quotient
vacuolar degeneration of the liver. In the remaining patient, various laboratory studies including muscle biopsy, lysosomal enzyme, long-chain fatty acid, urinary organic and amino acid, serum Cu, and ceruloplasmin failed to demonstrate abnormality. Although serum selenium was low in this patient, supplementation with selenium did not improve the clinical findings [12]. The selenium deficiency in this patient was likely secondary to deficient nutrition. In the three patients in the NPU group, lateralized cerebral dysgenesis was strongly suspected on magnetic
PEDIATRIC NEUROLOGY
Development at First Examination
32
Abbreviations: Bil ⫽ Bilateral CD ⫽ Cortical dysplasia DQ ⫽ Developmental quotient estimated by Japanese Tsumori-Inage method FMS ⫽ Focal motor seizures IUGR ⫽ Intrauterine growth retardation Lt ⫽ Left MFS ⫽ Multifocal spikes MR ⫽ Mental retardation
372
Follow-up Period (mo)
resonance imaging and single-photon emission computed tomography findings together with contralateral hemiplegia, and lateralized seizure and EEG manifestations. The diagnosis of cortical dysplasia was confirmed by pathologic investigation of brain tissues after epilepsy surgery in all patients. In the remaining nine patients in the NPD group the etiology was only identified in two patients. One patient had diffuse cortical dysplasia caused by congenital Cytomegalovirus infection. In one other patient with a history of severe perinatal asphyxia the magnetic resonance im-
Seizure Type
MRI/CT
EEG Findings
Bil FMS, SE
Progressive atrophy
MFS, progressive worsening
Bil FMS, SE
Progressive atrophy
MFS, progressive worsening
Bil FMS, SE
Progressive atrophy
MFS, progressive worsening
Lt FMS, SG
Rt CD
Rt FMS
Mental and Neurologic Outcomes
Others
Progressive mental and neurologic deterioration, quadriplegia, profound psychomotor retardation Progressive mental and neurologic deterioration, quadriplegia, profound psychomotor retardation Progressive mental and neurologic deterioration, quadriplegia, profound psychomotor retardation
Multiple anomalies, high CSF lactate, died of hepatic failure, pathologically confirmed Alpers syndrome Multiple anomalies, died of SE, pathologically confirmed Alpers syndrome
Rt frontocentrotemporal
Lt hemiplegia, moderate MR
Lt focal CD
Lt centroparietal focus
Rt hemiparesis, TIQ⫽96
Lt FMS, SG
Rt CD
Rt frontocentral focus
Lt hemiplegia, severe MR
Rt hemispherectomy at age 6 yr, 5 mo Lt centroparietal resection at age 4 yr, 8 mo Lt hemispherectomy at age 8 yr, 7 mo
Bil FMS Bil FMS, SE
MFS MFS
Bil FMS
Normal Cerebral atrophy, calcification Normal
Bil FMS
Normal
MFS
Bil FMS Bil FMS
Normal Normal
MFS MFS
Quadriplegia, severe MR Quadriplegia, profound psychomotor retardation Quadriplegia, profound psychomotor retardation Quadriplegia, severe psychomotor retardation Quadriplegia, moderate MR Severe MR
Bil FMS, PAS, SE Bil FMS, PAS, SE
Normal Hypoplasia of corpus callosum, Bil frontal atrophy Cerebral atrophy with parieto-occipital predominance
MFS MFS
Severe MR Quadriplegia, profound psychomotor retardation
MFS
Moderate psychomotor retardation
Bil FMS, PAS
MFS
aging scan revealed moderate cerebral atrophy involving both occipitoparietal regions typical for the magnetic resonance imaging picture of partial asphyxia in the term neonate [13]. In the remaining seven patients in the NPD group the etiology has remained unclear in the present investigations, including one infant who demonstrated hypoplasia of the corpus callosum and bilateral frontal lobe atrophy, although brain magnetic resonance imaging was not able to visualize any sign of cerebral dysgenesis at 8 months of age.
Low serum selenium
Multiple anomalies
Sudden death
(blood concentration was more than 80 mol/L) exerted moderate responses, although the effect was not satisfactory because of the persistence of daily seizures. Surgical treatment was finally performed successfully in these three patients (hemispherectomy in two patients and partial resection in one patient), resulting in significant seizure reductions in all three patients. In the nine patients in the NPD group, high-dose phenytoin was moderately effective in four patients and potassium bromide was moderately effective in three patients. Clorazepate was also moderately effective in two patients.
Treatment Prognosis The three patients in the P group had daily seizures completely refractory to all available antiepileptic drugs. In addition, ketogenic diet treatment was tried without success in one patient. In the NP group, several antiepileptic drugs were partially effective. In the three patients in the NPU group, valproic acid or high-dose phenytoin
The seizure frequencies were evaluated at monthly intervals throughout the follow-up period ranging from 7 months to 126 months, with a median of 32 months. The three patients in the P group continued to have daily numerous focal motor seizures throughout the clinical
Ishii et al: Catastrophic Infantile Epilepsy 373
Figure 2. Ictal electroencephalogram study of Patient 15 with a history of perinatal hypoxic-ischemic brain damage (nonprogressive diffuse group) is illustrated. (1) The electroencephalogram revealed onset of rhythmic theta discharges arising from the left centrotemporal regions (A, indicated by arrow), gradually involving the entire right hemisphere (B). (2) The other seizure began from the right centrotemporoparietal regions in the form of low-amplitude rhythmic beta discharges (A, indicated by arrows), which gradually increased in amplitude and slowed down in frequency (B), then disappeared in the right temporal region (C).
course. In the three patients in the NPU group, daily seizures were significantly reduced to weekly or monthly seizures in two patients, and markedly fewer daily seizures
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in one patient after surgical intervention. The nine patients in the NPD group demonstrated a gradual reduction of seizure frequency over the years, although seven patients
Figure 3. Progressive diffuse brain atrophy identified by computed tomography in Patient 1 (progressive group) is presented. The computed tomography revealed moderate diffuse atrophy at 10 months of age (A), which became more severely atrophic 5 months later (B).
continued to have daily seizures at the last examinations. Mental and neurologic outcomes demonstrated profound to severe mental or psychomotor retardation in 11 patients and spastic quadriplegia in nine patients, respectively (Table 1). Discussion Wyllie designated the term catastrophic infantile epilepsy to describe infants who develop epileptic seizures during early infancy and have an unfavorable clinical course with frequent seizures and stagnated development [14,15]. The catastrophic infantile epilepsy comprises both generalized epilepsies, including Ohtahara syndrome, West syndrome, severe myoclonic epilepsy in infants or other symptomatic generalized epilepsies, and localization-related epilepsies produced by localized structural abnormality of the brain. We described catastrophic infantile epilepsy with focal seizures regardless of etiology, which shares similar clinical and EEG manifestations. In the present study, we were able to subclassify 15 infants with catastrophic infantile epilepsy with focal seizures into three subgroups based on clinico-electrical and etiopathogenic features, as well as clinical evolution. However, the short-term and long-term seizure and intellectual outcomes were generally poor in all patients. The clinical and EEG seizure manifestations were also similar, exhibiting frequent focal motor seizures appearing singly and consecutively involving alternating sides of the body, and arising from multifocal regions in both hemispheres in the P and NPD groups regardless of etiology. At the peak of the clinical course the seizures frequently appeared in
clusters and evolved to status epilepticus, at times requiring generalized pentobarbital anesthesia. Although we performed all available laboratory examinations, including urinary amino acid and organic acid screenings and muscle biopsy to exclude such rare metabolic disorders, we could not identify the etiology in approximately one half of the infants. Regarding known metabolic encephalopathies capable of causing intractable infantile focal epilepsies, there have been an increasing number of case reports attributed to newly identified causes, including mitochondrial disorders [16], peroxisomal disease [17], selenium deficiency [12], glutathione synthetase deficiency [18], glucose transporter deficiency syndrome [19], and sulfite oxidase deficiency [20]. In two of the three patients in the P group, Alpers syndrome was pathologically confirmed. One patient demonstrated cytochrome C oxidase deficiency, whereas the etiology of the other patient remained biochemically undetermined. Although the underlying metabolic abnormality is difficult to confirm in this group, progressive brain atrophy and deterioration of EEG background activity within a several-month interval in addition to rapidly progressive neurologic deterioration strongly suggested the degenerative nature of the etiology. Although the remaining 12 patients in the NP group did not demonstrate such rapidly progressive neurologic deterioration, most of the NPD patients had already exhibited arrested development at an early infant period. The underlying cerebral abnormality was so severe that it would significantly disturb early development in addition to producing catastrophic focal seizures. Thus observation by
Ishii et al: Catastrophic Infantile Epilepsy 375
periodic neuroradiologic, EEG, and clinical examinations at intervals of several months would help to distinguish the P group from the NPD group. Coppola et al. [5] described the epileptic condition characterized by seizure onset at less than 6 months of age, nearly continuous electrographic seizures involving multiple independent areas whose onset migrated across both hemispheres, absence of identifiable cause, and poor seizure and intellectual outcomes. They designate this condition as migrating partial seizure in infancy based on the clinical and EEG characteristics in addition to the inability to identify the specific pathology in two patients who underwent postmortem examination. Although there was no further pathologic proof, subsequent reports of this syndrome have been sporadically published worldwide [6-8]. However, it is not easy to establish a diagnosis of this syndrome without pathologic examinations because there are so many possible underlying causes that could induce similar focal seizures in this age range. In addition, we are not always able to identify the cause by currently available laboratory examinations because of clinical and technical limitations. Although a number of our patients in the NPD group clinically and electroencephalographically resemble this syndrome, we cannot exclude diffuse microscopic cortical dysplasia. As evident in our series, medical treatment, including all available antiepileptic drugs, was not effective in every infant, with pentobarbital anesthesia being required in seven infants. However, high-dose phenytoin, valproic acid, and potassium bromide appeared to be partially effective in a few patients with a nonprogressive clinical course. There have recently been several sporadic reports from Japan regarding the successful treatment using potassium bromide in infants with intractable focal seizures [7,21,22]. The clinical details of these infants did not reveal any metabolic or structural abnormality, although there were intractable multifocal and shifting foci with numerous focal or secondarily generalized seizures, consistent with the diagnosis of migrating partial seizures in infancy. Thus potassium bromide should be tried for these patients as early as possible after confirming the inefficacy of conventional antiepileptic drugs, including high-dose valproic acid and phenytoin treatment. Wyllie and other investigators in the United States appear to take a more practical approach for analyzing catastrophic infantile epilepsies, searching for a therapeutic strategy in individual cases [14,15,23-25]. She recommends extensive neuroradiologic examinations to identify surgically remediable catastrophic focal epilepsy because early surgical intervention may alter the long-term prognosis. Increasing numbers of infants with catastrophic epilepsy have recently been considered for surgical treatment because of the recent progress in neuroimaging devices. Our three patients in the NPU group should be included as representative of surgically remediable catastrophic infantile focal epilepsy. In catastrophic infantile epilepsy with focal seizures, we must carefully evaluate all
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the seizures electrographically and clinically to establish that they arise from one hemisphere or both hemispheres independently even if magnetic resonance imaging does not identify the abnormality. We should repeat magnetic resonance imaging examinations on patients with lateralized EEG epileptogenic foci because the poor myelination of this age may obscure subtle magnetic resonance imaging abnormalities. However, as we have reported in this study, a significant number of infants appear to have diffuse cortical pathology without any identifiable cause, as well as resectable lesions and these cases run a pessimistic clinical course even in nonprogressive patients. Although the shifting or migrating nature of the seizures has received attention since the reports by Coppla, this phenomenon itself appears to be nonspecific, as demonstrated in this study, and may be attributed to nonspecific electrophysiologic responses in the immature brain to multifocal severe brain abnormality caused by any pathologic process. Accumulating rare metabolic cases, as well as pathologically proven cases of catastrophic infantile focal epilepsy or migrating partial seizures in infancy, should be encouraged to build up the classification of intractable infantile epilepsy.
We thank Dr. Shibata, Department of Pathology, Tokyo Women’s Medical University, for valuable comments on the pathologic findings of Alpers syndrome.
References [1] Chevrie JJ, Aicardi J. Convulsive disorders in the first year of life: Etiologic factors. Epilepsia 1977;18:489-98. [2] Chevrie JJ, Aicardi J. Convulsive disorders in the first year of life: neurological and mental outcome and mortality. Epilepsia 1978;19: 67-74. [3] Matsumoto A, Watanabe K, Sugiura M, Negoro T, Takaesu E, Iwase K. Etiologic factors and long-term prognosis of convulsive disorders in the first year of life. Neuropediatrics 1983;14:231-4. [4] Cavazzuti GB, Ferrari P, Lalla M. Follow-up study of 482 cases with convulsive disorders in the first year of life. Dev Med Child Neurol 1984;26:425-37. [5] Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: A malignant disorder with developmental arrest. Epilepsia 1995;36:1017-24. [6] Wilmshurst JM, Appleton DB, Grattan-Smith PJ. Migrating partial seizures in infancy: Two new cases. J Child Neurol 2000;15:71722. [7] Okuda K, Yasuhara A, Kamei A, Araki A, Kitamura N, Kobayashi Y. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain Dev 2000;22:56-9. [8] Veneselli E, Perrone MV, Di Rocco M, Gaggero R, Biancheri R. Malignant migrating partial seizures in infancy. Epilepsy Res 2001;46: 27-32. [9] Vigevano F, Bertini E, Boldrini R, et al. Hemimegalencehaly and intractable epilepsy: Benefits of hemispherectomy. Epilepsia 1989;30: 833-43.
[10] Mukahira K, Oguni H, Awaya Y, et al. Study on surgical treatment of intractable childhood epilepsy. Brain Dev 1998;20:154-64. [11] Jellinger K, Seitelberger F. Spongy glio-neuronal dystrophy in infancy and childhood. Acta Neuropathol (Berl) 1970;16:125-40. [12] Ramaekers VT, Calomme M, Vanden Berghe D, Makropoulos W. Selenium deficiency triggering intractable seizures. Neuropediatrics 1994;25:217-23. [13] Barkovich AJ. Hypoxic-ischemic brain injury. In: Barkovich AJ, ed. Pediatric neuroimaging, 2nd ed. New York: Raven Press, 1995:11341. [14] Wyllie E, Comair Y, Kotagal P, Raja S, Rugieri P. Epilepsy surgery in infants. Epilepsia 1996;37:625-37. [15] Wyllie E. Surgery for catastrophic localization-related epilepsy in infants. Epilepsia 1996;37(Suppl):22-5. [16] Gauthier-Villars M, Landrieu P, Cormier-Daire V, et al. Respiratory chain deficiency in Alpers syndrome. Neuropediatrics 2001; 32:150-2. [17] Takahashi Y, Suzuki Y, Kumazaki K, et al. Epilepsy in peroxisomal diseases. Epilepsia 1997;38:182-8. [18] Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr 2001;139:79-84.
[19] Brockmann K, Wang D, Korenke CG, et al. Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Ann Neurol 2001;50:476-85. [20] Slot HM, Overweg-Plandsoen WC, Bakker HD, et al. Molybdenum-cofactor deficiency: an easily missed cause of neonatal convulsions. Neuropediatrics 1993;24:139-42. [21] Takayanagi M, Tobisihi M, Kitamura T, Yamamoto K. A case with intractable symptomatic localization-related epilepsy responded dramatically to BrK. No to Hattatsu 1998;30:S244. [22] Takaya K, Kanou H, Tanaka M, et al. A case with migrating partial seizures in infancy. No to Hattatsu 1999;31:S298. [23] Duchowny MS, Resnick TJ, Alvarez LA, Morrison G. Focal resection for malignant partial seizures in infancy. Neurology 1990;40: 980-4. [24] Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. Infantile spasms: PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990;27: 406-13. [25] Shields WD, Duchowny MS, Holmes GL. Surgical remediable syndromes of infancy and early childhood. In: Engel J, ed. Surgical treatment of the epilepsies, 2nd ed. New York: Raven Press, 1993:35-48.
Ishii et al: Catastrophic Infantile Epilepsy 377
Introduction The onset of epilepsy during infancy is one of the crucial factors for prognosis because epileptic seizures tend to develop in association with critical developmental abnormalities of the brain. There have been several reports analyzing patients with convulsive disorders developing in the first year of life [1-4]. The findings were largely consistent with the conclusion that febrile seizures, West syndrome, and status epilepticus were the most frequent causes of seizures in this age group. However, although the number of patients remains small, there have been sporadic reports of infants who have frequent exclusively focal motor seizures and status epilepticus, and these infants follow a catastrophic clinical course [1,2,5-7]. These patients sometimes require long-term anesthesia for the treatment of incapacitating status epilepticus resistant to conventional antiepileptic drugs. The etiology in these cases remains largely unknown, although recent progress in epilepsy surgery has identified underlying cortical dysplasia in some infants demonstrating lateralized or localized neuroimaging abnormality responsible for these catastrophic seizures [8,9]. Although these infants with catastrophic focal seizures have sporadically been reported worldwide, there have not been any systematic studies conducted regarding these patients. In the present study, we described the result of investigations into the etiology and clinical, electroencephalogram (EEG), and neuroimaging pictures of catastrophic infantile epilepsy with focal seizures and discuss the nosology of epilepsy. Patients and Methods Among patients with intractable epileptic seizures admitted to our hospital between January 1985 and December 1999, we selected patients according to the following criteria: (1) seizure onset before 12 months of age and (2) presence of daily focal or secondarily generalized seizures
From the Department of Pediatrics; Tokyo Women’s Medical University; Tokyo, Japan.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(02)00449-6 ● 0887-8994/02/$—see front matter
Communications should be addressed to: Dr. Oguni; Department of Pediatrics; Tokyo Women’s Medical University; 8-1 Kawada-cho; Shinjuku-ku; Tokyo 162, Japan. Received February 19, 2002; accepted May 8, 2002.
Ishii et al: Catastrophic Infantile Epilepsy 369
resistant to conventional antiepileptic drugs for at least 3 months. Patients with early infantile epileptic encephalopathy (also known as Ohtahara syndrome) and West syndrome who developed focal seizures followed by epileptic spasms or by combined focal seizures and epileptic spasms were excluded from the study. The clinical, EEG, and laboratory findings, as well as neuroimaging data, were retrospectively studied from the clinical records. The seizure frequencies were evaluated at daily and monthly intervals by seizure records, in which parents or caregivers documented the number of seizures per day. Because of the large number of daily seizures in many patients, the average seizure frequencies were sometimes recorded per hour and the frequency per day was calculated. The seizure types were determined by analysis of simultaneous video electroencephalogram documentation. The etiology of epilepsy in patients fulfilling the criteria was speculated largely based on the findings of computed tomography, magnetic resonance imaging, and the following laboratory data when the specific etiology was not identified: cerebrospinal fluid glucose, protein, and IgG index, serum and cerebrospinal fluid lactic acid, urinary amino acid and organic acid, long-chain fatty acid, serum copper, ceruloplasmin and selen, lysosomal storage enzyme, muscle biopsy (three patients), and ophthalmologic examinations. We tentatively classified the patients into progressive and nonprogressive groups according to the presence or absence of both progressive neurologic deterioration (i.e., appearance of spasticity or rigidity, progressive loss of acquired skill) and progressive atrophy of the brain on neuroimaging studies performed at intervals of several months. Interictal and ictal EEG findings were also reviewed in all patients to identify lateralization and localization of epileptogenic EEG foci. The effectiveness of the treatments was estimated by the following criteria: excellent response, more than 80% reduction; moderate response, more than 50% reduction; poor response, less than 50% reduction; and aggravated, more than 50% increase of focal or secondarily generalized seizures.
Results Fifteen patients met the criteria and were included in the study (Table 1). There were five males and 10 females. The median age at onset of the first seizure was 21 days of age (range ⫽ 1 day to 7 months of age). The age at the first consultation at our hospital ranged from 20 days to 2 years, 8 months of age, with a mean of 7.8 months. The mean follow-up period was 5 years and 1 month. During the follow-up, three patients demonstrated progressively deteriorating neurologic symptoms associated with progressive cerebral atrophy on magnetic resonance imaging or computed tomography scan at intervals of several months (progressive group ⫽ P group). The remaining 12 infants did not demonstrate such a rapidly progressive neurologic deterioration or increasing cerebral atrophy, although the frequent seizures or status epilepticus appeared to stagnate their development or to cause some neurologic deterioration (nonprogressive group ⫽ NP group). Among the 12 patients, three patients always had lateralized seizure onset (nonprogressive unilateral group ⫽ NPU group), and the remaining nine patients had manifested bilateral or independent multifocal seizure onset on repeated EEG examinations (nonprogressive diffuse group ⫽ NPD group). The three patients in the NPU group demonstrated worsening of pre-existing hemiplegia or slowly progressive hemiparesis along with fre-
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quent seizures. The clinical details of these three NPU patients has been described previously [10]. Perinatal Abnormalities In five of the 15 patients, perinatal abnormalities, including fetal distress in three patients and severe asphyxia in one patient, were documented. Two of these five infants had also demonstrated in utero growth retardation with oligohydramnois. One other patient had received maternal-fetal transfusion. In the remaining infant, regular fetal echo investigations identified hydrocephalus, which was identified as severe cerebral atrophy on postnatal magnetic resonance imaging. Multiple anomalies had been identified in three infants at birth (two in the P group, and one in the NPD group) (Table 1). Development Before the Onset of Epilepsy Because seizure onset was early in all patients, development before seizure onset is difficult to evaluate precisely. One patient demonstrated profound hypotonia and gross developmental delay at 7 months of age when focal motor seizures developed (Patient 2, Table 1). The other six infants, including one in the P group (Patient 3), three in the NPU group, and two in the NPD group (Patients 9 and 15) achieved appropriate developmental milestones at 2-3 months of age based either on documentation of regular developmental checkup at 3 months of age or on our own neurologic examinations. The development had already become significantly retarded in all patients except one in the NP group at the time of the first consultation. In addition, pyramidal signs and cerebral hypotonia were observed at the first examinations in nine and 10 patients, respectively. Seizure Types and Frequency The seizures in all 15 cases consisted of focal seizures with motor symptoms involving the face, arm, and legs simultaneously or independently. In addition, versive and postural symptoms were also mixed during the seizures. The three infants in the P group and the nine infants in the NPD group demonstrated focal motor seizures of multifocal onset at times appearing on one or both sides of the body or changing sides during a single seizure, or successively occurring on alternating sides of the body, whereas three infants in the NPU group had lateralized focal motor or unilateral seizures. In all 15 infants the seizures progressively increased in frequency and occurred at least 10 or more times/day at the peak of the clinical course. All three patients in the P group demonstrated almost continuous attacks during wakefulness, requiring prolonged pentobarbital anesthesia at the peak of the clinical course, and two infants finally died of status epilepticus at 14 months and 29 months of age, respectively. In addition, six of the nine infants in the
Figure 1. Interictal electroencephalogram study of Patient 1 (P group) is presented. Electroencephalogram during sleep revealed diffuse irregular mixed theta and delta activity at 8 months of age (A), which changed to diffuse depressed activity 7 months later (B).
NPD group also demonstrated status epilepticus or almost continuous focal seizures occurring every 3-5 minutes. All six of these infants also received pentobarbital anesthesia at some time during the clinical course. The three patients in the NPU group also had frequent daily attacks, although none of them culminated in status epilepticus.
lateralized in one hemisphere, which was consistent with the side demonstrating abnormal neuroradiologic findings (i.e., right frontocentrotemporal region in one patient, right frontocentral region in another patient, and the left centroparietal region in the remaining patient). Etiology and Neuroradiologic Findings
Electroencephalogram Findings On interictal EEGs, three patients in the P group and nine patients in the NPD group demonstrated frequent intermittent multifocal spikes or sharp waves with markedly disorganized background activity during both wakefulness and sleep. The interictal EEGs of the three patients in the P group changed from multifocal spikes with disorganized background activity in the early stage to disappearance of spike discharges with continuous depressed background activity when they were more than 1 year of age (Fig 1). In the ictal EEGs the three patients in the P group and the nine patients in the NPD group exhibited the onset of the seizures shifting from one hemisphere to the other (Fig 2). When the clustering of seizures occurred the EEG seizure foci changed, alternating in both hemispheres. The EEG seizure foci were multifocal and sometimes different in localization in both hemispheres. However, the three patients in the NPU group demonstrated the ictal EEG onset, and predominant interictal EEG spike foci were
The three patients in the P group were diagnosed clinically as having Alpers syndrome based on progressive deterioration of clinical and neuroimaging findings and the exclusion of other known causes of degenerative or metabolic encephalopathy. On sequential computed tomography investigation performed at 3-6-month intervals, these infants demonstrated progressive cerebral atrophy consistent with the progressive nature of neurologic deterioration in these cases (Fig 3). Two infants died of status epilepticus and were examined postmortem. In the one patient who manifested cytochrome C oxidase deficiency on previous muscle biopsy, the brain specimen demonstrated status spongiosus, pseudolaminar destruction of the neurons in the cerebral cortex, and marked astrocytic gliosis involving both cerebral cortex and white matter, which is consistent with the pathologic findings of Alpers syndrome [11]. In another patient with severe brain atrophy, high cerebrospinal fluid lactate values, and marked liver dysfunction, the brain specimen also revealed the pathologic features of Alpers syndrome and fatty and
Ishii et al: Catastrophic Infantile Epilepsy 371
Table 1.
Clinical findings in 15 patients
Sex
Onset of Seizures (mo)
P 1
M
1 day
5
Asphyxia, hydrocephalus on fetal ultrasonography
2
F
7
5
IUGR, hypoammniosis
3
M
1
3
31
Equivalent to 2-3 months
Hypotonia, mild paraplegia
NPU 4
M
2.5
7
126
DQ⫽87
Hypotonia, Lt hemiparesis
5
M
2
12
102
DQ⫽150
No abnormality
6
F
2
32
102
DQ⫽24
Hypotonia, Lt hemiplegia
NPD 7 8
F F
120 69
DQ⫽120 DQ⫽1
Mild quadriplegia Mild quadriplegia
9
F
3
7
DQ⫽1
Hypotonia, mild quadriplegia
10
M
1 day
1
11 12
F F
20 days 10 days
6 24 days
13 14
M F
13 days 2 days
20 days 7
15
M
Patient No.
21 days 21 days
3
Age at First Examination (mo)
2 4
5
Perinatal History
SFD, fetal distress
—
24
DQ⫽10
Hypotonia
9
DQ⫽30
Hypotonia
15
SFD IUGR, fetal distress, hypoammniosis — —
Maternal-fetal blood transfusion, fetal distress, severe asphyxia
NPD NPU P PAS Rt SE SFD SG TIQ
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
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—
Neurological Abnormality at First Examination
Hypotonia, mild quadriplegia
156 99
DQ⫽65 —
Mild quadriplegia Hypotonia
30 7
— DQ⫽3
No abnormality Hypotonia, mild quadriplegia
7
DQ⫽59
Hypotonia
Nonprogressive diffuse group Nonprogressive unilateral group Progressive group Prolonged atonic seizure Right Status epilepticus Small for date infant Secondary generalization Total intelligence quotient
vacuolar degeneration of the liver. In the remaining patient, various laboratory studies including muscle biopsy, lysosomal enzyme, long-chain fatty acid, urinary organic and amino acid, serum Cu, and ceruloplasmin failed to demonstrate abnormality. Although serum selenium was low in this patient, supplementation with selenium did not improve the clinical findings [12]. The selenium deficiency in this patient was likely secondary to deficient nutrition. In the three patients in the NPU group, lateralized cerebral dysgenesis was strongly suspected on magnetic
PEDIATRIC NEUROLOGY
Development at First Examination
32
Abbreviations: Bil ⫽ Bilateral CD ⫽ Cortical dysplasia DQ ⫽ Developmental quotient estimated by Japanese Tsumori-Inage method FMS ⫽ Focal motor seizures IUGR ⫽ Intrauterine growth retardation Lt ⫽ Left MFS ⫽ Multifocal spikes MR ⫽ Mental retardation
372
Follow-up Period (mo)
resonance imaging and single-photon emission computed tomography findings together with contralateral hemiplegia, and lateralized seizure and EEG manifestations. The diagnosis of cortical dysplasia was confirmed by pathologic investigation of brain tissues after epilepsy surgery in all patients. In the remaining nine patients in the NPD group the etiology was only identified in two patients. One patient had diffuse cortical dysplasia caused by congenital Cytomegalovirus infection. In one other patient with a history of severe perinatal asphyxia the magnetic resonance im-
Seizure Type
MRI/CT
EEG Findings
Bil FMS, SE
Progressive atrophy
MFS, progressive worsening
Bil FMS, SE
Progressive atrophy
MFS, progressive worsening
Bil FMS, SE
Progressive atrophy
MFS, progressive worsening
Lt FMS, SG
Rt CD
Rt FMS
Mental and Neurologic Outcomes
Others
Progressive mental and neurologic deterioration, quadriplegia, profound psychomotor retardation Progressive mental and neurologic deterioration, quadriplegia, profound psychomotor retardation Progressive mental and neurologic deterioration, quadriplegia, profound psychomotor retardation
Multiple anomalies, high CSF lactate, died of hepatic failure, pathologically confirmed Alpers syndrome Multiple anomalies, died of SE, pathologically confirmed Alpers syndrome
Rt frontocentrotemporal
Lt hemiplegia, moderate MR
Lt focal CD
Lt centroparietal focus
Rt hemiparesis, TIQ⫽96
Lt FMS, SG
Rt CD
Rt frontocentral focus
Lt hemiplegia, severe MR
Rt hemispherectomy at age 6 yr, 5 mo Lt centroparietal resection at age 4 yr, 8 mo Lt hemispherectomy at age 8 yr, 7 mo
Bil FMS Bil FMS, SE
MFS MFS
Bil FMS
Normal Cerebral atrophy, calcification Normal
Bil FMS
Normal
MFS
Bil FMS Bil FMS
Normal Normal
MFS MFS
Quadriplegia, severe MR Quadriplegia, profound psychomotor retardation Quadriplegia, profound psychomotor retardation Quadriplegia, severe psychomotor retardation Quadriplegia, moderate MR Severe MR
Bil FMS, PAS, SE Bil FMS, PAS, SE
Normal Hypoplasia of corpus callosum, Bil frontal atrophy Cerebral atrophy with parieto-occipital predominance
MFS MFS
Severe MR Quadriplegia, profound psychomotor retardation
MFS
Moderate psychomotor retardation
Bil FMS, PAS
MFS
aging scan revealed moderate cerebral atrophy involving both occipitoparietal regions typical for the magnetic resonance imaging picture of partial asphyxia in the term neonate [13]. In the remaining seven patients in the NPD group the etiology has remained unclear in the present investigations, including one infant who demonstrated hypoplasia of the corpus callosum and bilateral frontal lobe atrophy, although brain magnetic resonance imaging was not able to visualize any sign of cerebral dysgenesis at 8 months of age.
Low serum selenium
Multiple anomalies
Sudden death
(blood concentration was more than 80 mol/L) exerted moderate responses, although the effect was not satisfactory because of the persistence of daily seizures. Surgical treatment was finally performed successfully in these three patients (hemispherectomy in two patients and partial resection in one patient), resulting in significant seizure reductions in all three patients. In the nine patients in the NPD group, high-dose phenytoin was moderately effective in four patients and potassium bromide was moderately effective in three patients. Clorazepate was also moderately effective in two patients.
Treatment Prognosis The three patients in the P group had daily seizures completely refractory to all available antiepileptic drugs. In addition, ketogenic diet treatment was tried without success in one patient. In the NP group, several antiepileptic drugs were partially effective. In the three patients in the NPU group, valproic acid or high-dose phenytoin
The seizure frequencies were evaluated at monthly intervals throughout the follow-up period ranging from 7 months to 126 months, with a median of 32 months. The three patients in the P group continued to have daily numerous focal motor seizures throughout the clinical
Ishii et al: Catastrophic Infantile Epilepsy 373
Figure 2. Ictal electroencephalogram study of Patient 15 with a history of perinatal hypoxic-ischemic brain damage (nonprogressive diffuse group) is illustrated. (1) The electroencephalogram revealed onset of rhythmic theta discharges arising from the left centrotemporal regions (A, indicated by arrow), gradually involving the entire right hemisphere (B). (2) The other seizure began from the right centrotemporoparietal regions in the form of low-amplitude rhythmic beta discharges (A, indicated by arrows), which gradually increased in amplitude and slowed down in frequency (B), then disappeared in the right temporal region (C).
course. In the three patients in the NPU group, daily seizures were significantly reduced to weekly or monthly seizures in two patients, and markedly fewer daily seizures
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in one patient after surgical intervention. The nine patients in the NPD group demonstrated a gradual reduction of seizure frequency over the years, although seven patients
Figure 3. Progressive diffuse brain atrophy identified by computed tomography in Patient 1 (progressive group) is presented. The computed tomography revealed moderate diffuse atrophy at 10 months of age (A), which became more severely atrophic 5 months later (B).
continued to have daily seizures at the last examinations. Mental and neurologic outcomes demonstrated profound to severe mental or psychomotor retardation in 11 patients and spastic quadriplegia in nine patients, respectively (Table 1). Discussion Wyllie designated the term catastrophic infantile epilepsy to describe infants who develop epileptic seizures during early infancy and have an unfavorable clinical course with frequent seizures and stagnated development [14,15]. The catastrophic infantile epilepsy comprises both generalized epilepsies, including Ohtahara syndrome, West syndrome, severe myoclonic epilepsy in infants or other symptomatic generalized epilepsies, and localization-related epilepsies produced by localized structural abnormality of the brain. We described catastrophic infantile epilepsy with focal seizures regardless of etiology, which shares similar clinical and EEG manifestations. In the present study, we were able to subclassify 15 infants with catastrophic infantile epilepsy with focal seizures into three subgroups based on clinico-electrical and etiopathogenic features, as well as clinical evolution. However, the short-term and long-term seizure and intellectual outcomes were generally poor in all patients. The clinical and EEG seizure manifestations were also similar, exhibiting frequent focal motor seizures appearing singly and consecutively involving alternating sides of the body, and arising from multifocal regions in both hemispheres in the P and NPD groups regardless of etiology. At the peak of the clinical course the seizures frequently appeared in
clusters and evolved to status epilepticus, at times requiring generalized pentobarbital anesthesia. Although we performed all available laboratory examinations, including urinary amino acid and organic acid screenings and muscle biopsy to exclude such rare metabolic disorders, we could not identify the etiology in approximately one half of the infants. Regarding known metabolic encephalopathies capable of causing intractable infantile focal epilepsies, there have been an increasing number of case reports attributed to newly identified causes, including mitochondrial disorders [16], peroxisomal disease [17], selenium deficiency [12], glutathione synthetase deficiency [18], glucose transporter deficiency syndrome [19], and sulfite oxidase deficiency [20]. In two of the three patients in the P group, Alpers syndrome was pathologically confirmed. One patient demonstrated cytochrome C oxidase deficiency, whereas the etiology of the other patient remained biochemically undetermined. Although the underlying metabolic abnormality is difficult to confirm in this group, progressive brain atrophy and deterioration of EEG background activity within a several-month interval in addition to rapidly progressive neurologic deterioration strongly suggested the degenerative nature of the etiology. Although the remaining 12 patients in the NP group did not demonstrate such rapidly progressive neurologic deterioration, most of the NPD patients had already exhibited arrested development at an early infant period. The underlying cerebral abnormality was so severe that it would significantly disturb early development in addition to producing catastrophic focal seizures. Thus observation by
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periodic neuroradiologic, EEG, and clinical examinations at intervals of several months would help to distinguish the P group from the NPD group. Coppola et al. [5] described the epileptic condition characterized by seizure onset at less than 6 months of age, nearly continuous electrographic seizures involving multiple independent areas whose onset migrated across both hemispheres, absence of identifiable cause, and poor seizure and intellectual outcomes. They designate this condition as migrating partial seizure in infancy based on the clinical and EEG characteristics in addition to the inability to identify the specific pathology in two patients who underwent postmortem examination. Although there was no further pathologic proof, subsequent reports of this syndrome have been sporadically published worldwide [6-8]. However, it is not easy to establish a diagnosis of this syndrome without pathologic examinations because there are so many possible underlying causes that could induce similar focal seizures in this age range. In addition, we are not always able to identify the cause by currently available laboratory examinations because of clinical and technical limitations. Although a number of our patients in the NPD group clinically and electroencephalographically resemble this syndrome, we cannot exclude diffuse microscopic cortical dysplasia. As evident in our series, medical treatment, including all available antiepileptic drugs, was not effective in every infant, with pentobarbital anesthesia being required in seven infants. However, high-dose phenytoin, valproic acid, and potassium bromide appeared to be partially effective in a few patients with a nonprogressive clinical course. There have recently been several sporadic reports from Japan regarding the successful treatment using potassium bromide in infants with intractable focal seizures [7,21,22]. The clinical details of these infants did not reveal any metabolic or structural abnormality, although there were intractable multifocal and shifting foci with numerous focal or secondarily generalized seizures, consistent with the diagnosis of migrating partial seizures in infancy. Thus potassium bromide should be tried for these patients as early as possible after confirming the inefficacy of conventional antiepileptic drugs, including high-dose valproic acid and phenytoin treatment. Wyllie and other investigators in the United States appear to take a more practical approach for analyzing catastrophic infantile epilepsies, searching for a therapeutic strategy in individual cases [14,15,23-25]. She recommends extensive neuroradiologic examinations to identify surgically remediable catastrophic focal epilepsy because early surgical intervention may alter the long-term prognosis. Increasing numbers of infants with catastrophic epilepsy have recently been considered for surgical treatment because of the recent progress in neuroimaging devices. Our three patients in the NPU group should be included as representative of surgically remediable catastrophic infantile focal epilepsy. In catastrophic infantile epilepsy with focal seizures, we must carefully evaluate all
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the seizures electrographically and clinically to establish that they arise from one hemisphere or both hemispheres independently even if magnetic resonance imaging does not identify the abnormality. We should repeat magnetic resonance imaging examinations on patients with lateralized EEG epileptogenic foci because the poor myelination of this age may obscure subtle magnetic resonance imaging abnormalities. However, as we have reported in this study, a significant number of infants appear to have diffuse cortical pathology without any identifiable cause, as well as resectable lesions and these cases run a pessimistic clinical course even in nonprogressive patients. Although the shifting or migrating nature of the seizures has received attention since the reports by Coppla, this phenomenon itself appears to be nonspecific, as demonstrated in this study, and may be attributed to nonspecific electrophysiologic responses in the immature brain to multifocal severe brain abnormality caused by any pathologic process. Accumulating rare metabolic cases, as well as pathologically proven cases of catastrophic infantile focal epilepsy or migrating partial seizures in infancy, should be encouraged to build up the classification of intractable infantile epilepsy.
We thank Dr. Shibata, Department of Pathology, Tokyo Women’s Medical University, for valuable comments on the pathologic findings of Alpers syndrome.
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