Eur J Pediatr (1992) 151 : 608-612
European Journal of
Pediatrics
9 Springer-Verlag1992
Benign infantile familial convulsions F. Vigevano 1, L. Fusco 1, M. Di Capua 1, S. Ricci 1, R. Sebastianelli 1, and P. Lucchini 2 ~Section of Neurophysiology, "Bambino Ges~" Children's Hospital, National Medical Research Institute, Piazza S. Onofrio 4, 1-00165 Rome, Italy 2General Hospital, Treviso, Italy Received July 2, 1991 / Accepted after revision October 29, 1991
Abstract. Five infants, three girls and two boys, first had convulsions between the ages of 4 and 6 months. Although the aetiology of the attacks was unknown, all the infants had a family history of similar convulsions occurring at the same age and having a benign outcome. The attacks, which always occurred in a cluster, were promptly controlled, in four cases with phenobarbital and in one case with valproate. Seizures were partial with secondary generalization and were characterized by head and eye deviation (not always the same side in each attack) diffuse hypertonia and then bilateral limb jerks. The interictal E E G was normal. The ictal E E G showed diffuse discharge with onset in the central-occipital region. Laboratory, radiological and neurological findings were normal. A history in at least one paternal relative (the father in four cases) of similar seizures, occurring at the same age suggested a genetic predisposition. No seizures or E E G anomalies were observed during the follow up.
Key words: Epilepsy - Infantile seizures - Familial convulsions - Benign epilepsy - Epileptic syndromes
In this study we present the extensive data of five patients with benign partial epilepsy [9], whose seizures first appeared between 4 and 7 months. The disorder was familial and the outcome of the epilepsy was favourable.
Clinical features The Table and Fig. 1 summarize clinical and familial data of our patients. Our series consisted of five infants, three girls and two boys. All of them had one or more paternal relatives with a history of benign seizures at the same age. In four families the affected member was the child's father. Analogous seizures were identified in 13 relatives. Two of these also had febrile convulsions (III 6 and II 4 in family 2). One other relative (III 2 in family 3), who had febrile convulsions alone, was excluded from the study. In the probands, the age at onset ranged from 4 to 7 months; in the relatives it ranged from 4 to 8 months and peaked around the 6th month (Fig. 2). None of them had seizure onset either in the neonatal age or after the 8th month of life. The prenatal and perinatal history of our patients was normal. The infants' psychomotor development before seizure onset was normal: the attacks always appeared when the infant was in good health. The results of all diagnostic investigations, including cerebral computed tomography, were normal. The epilepsy appeared to have no connection with diet.
Introduction The recent International Classification of Epilepsies and Epileptic Syndromes [2] lists among the idiopathic forms with onset in the 1st year of life three entities: benign neonatal familial convulsions, benign neonatal convulsions and benign myoclonic epilepsy in infancy. The first two appear in the neonatal period, the third at the age of about 1 year. All three are classified as generalized forms. The current classification recognizes no other forms of benign idiopathic epilepsy - either partial or generalized - with onset in the 1st year of life. Indeed, the consensus is that epilepsies arising in the 1st year of life have an unfavourable outlook. Offprint requests to: F. Vigevano
Seizure manifestations All the probands were observed in the acute phase and seizures were E E G recorded. The patients' attacks occurred mainly in clusters, lasting over a 2 - 4 - d a y period, in n u m b e r of four to ten episodes a day, both in wakefulness and sleep. The duration of each cluster correlated strictly with the start of therapy. In two patients (3 and 5) the cluster was the only seizure manifestation, and occurred respectively at 6 and 4 months. In the other three patients the cluster was preceded by isolated seizures: patient 1 had two seizures at 7 months, one at 8 months, and the cluster at 10 months; patient 2 had three isolated seizures at 5 months, within
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and then involving the entire brain, and increasing in amplitude. The discharges ended in both hemispheres synchronously or asynchronously; asynchronous activity lasted longer in the hemisphere that was secondarily involved (Fig. 3). After only a few hours E E G recording, the alternating clinical pattern was confirmed by the demonstration of seizures originating sometimes from the right, sometimes from the left hemisphere (Fig. 4).
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Fig. 1A-E. Family trees of the five patients. (A) Family i - III 3: patient 1; II 5: seizures between 6 and 12 months; III 4: only one generalized afebrile seizure at 8 months. (B) Family 2 - IV 1: patient 2; III 3: seizures between 6 and 8 months; III 6 and II 4: febrile and afebrile seizures between 8 and 11 months. (C) Family 3 - I I I 3: patient 3; III 5: isolated seizures at 8 and 18 months; III 2: febrile seizures at 2 years (excluded). (D) Family 4 III 2: patient 4; II 2: seizures at 6 months. (E) Family 5 - IV 1: patient 5; III 1, 2, 4 and II 2, 3: seizures between 4 and 5 months; I 1: seizures between 4 and 6 months
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6 MONTHS
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Treatment and follow up
9
Fig. 2. Age at onset of seizures in probands and relatives. • Probands (5 cases); ~ relatives (13 cases)
20 days, then the cluster; patient 4 had four isolated seizures at 6 months, in the 11 days preceding the cluster. In the relatives, the attacks reportedly occurred singly or in clusters. In the probands, the seizures lasted from i to several minutes: the initial seiures were usually longer, even as long as 10-15 minutes, becoming shorter as the treatment took effect. Clinically the seizures were characterized by psychomotor arrest, slow deviation of the head and eyes to one side, diffuse hypertonia, cyanosis, and unilateral limb jerks, which became bilateral and were synchronous or asynchronous. Although the seizures were highly stereotyped, the direction of the head and eye deviation sometimes changed from seizure to seizure in the same patient. No clear automatism could be identified. The interictal E E G in sleep and wakefulness was always normal. The ictal E E G was characterized by a recruiting rhythm, beginning in the left or right central occipital areas, spreading over the hemisphere
The patients underwent treatment only when their seizures were in clusters. Four infants were treated with intramuscular phenobarbital (5 mg/kg per day), and one with sodium valproate (25 mg/kg per day) per os. Therapy brought the seizures under control within 24-48 h. The same drugs were then administered orally. Follow up now reached 24-32 months. None of the children had further seizures; their E E G s and the psychomotor develo p m e n t were normal. Patients 1, 4 and 5 stopped therapy after 1 year of treatment; the other two are now in the withdrawal phase. Detailed data about the treatment of the relatives were not available; most of t h e m were never treated. Nevertheless only one relative had a seizure after the age of 1 year, at 18 months. All the relatives had normal psychomotor development and no E E G anomalies were reported.
Discussion The salient distinguishing feature in this group of children with benign partial seizures with an onset in the 1st year of life is the good prognosis. There was a family
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B Fig. 3A, B. Patient 2 - Ictal E E G of one seizure recorded on the 1st day of the cluster, during sleep: an ictal recruiting rhythm began in the right occipital regions, later involved the central and temporal area and finally the left hemisphere (A). The end of the
discharge was asynchronous between the two sides (B). Clinically the seizure was characterized by slow left head and eyes deviation, diffuse hypertonia, cyanosis, asynchronous limb jerks, initially left and then bilateral
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B Fig. 4A, B. Patient 4: on the 4th day from the onset of the cluster, two seizures were recorded in 1 h during sleep: the first one (A) started from the right occipital region, and the second one (B) from the same region of the contralateral hemisphere. The
semeiology of both seizures was the same as that in patient 2; the side of the head and eye deviation was contralateral to the side of seizure onset
612 history for similar seizures at the same age, with no other aetiology. Some features of our patients' seizures coincide with the category of benign neonatal familial convulsions: a normal neurological state; absence of known causative factors; normal psychomotor development after the attacks; and family history of seizures at a similar age. Plouin [8] and Miles and H o l m e s [7] reported that the onset of seizures m a y occur even in the early months of life. Onset of seizures later than 3 months and 15 days has never b e e n reported, either in probands or relatives, yet in none of our subjects did seizures start before the age of 4 months. Furthermore, the absence of a clear E E G pattern in benign neonatal familial convulsions makes a comparison with our cases impossible. Leppert et al. [6] have identified a genetic m a r k e r for the benign neonatal familial convulsion syndrome, located on the long arm of c h r o m o s o m e 20. We are now studying the genetic status of our patients to see whether a m a r k e r exists for the syndrome described here. Familial convulsions may also be caused in the 1st year of life by a pyridoxine dependency or deficiency. In the typical f o r m [1] the convulsions always a p p e a r in the first days of life; only in the atypical form [5], does the onset occur in the first months. Both forms are resistant to treatment with c o m m o n antiepileptic drugs. The clinical picture is always severe and contrasts with the evolving character of benign seizure disorders. In our opinion, the absence of aetiological factors and the familial nature of our patients' convulsions class them as idiopathic. The current Classification of Epilepsies and Epileptic syndromes [2] recognizes no idiopathic forms - partial or generalized - with an onset between 4 and 8 months. R e p o r t e d data are contrasting. In a review of 17 cases of benign partial epilepsy with an onset ranging from 8 days to 3 years, Dulac et al. [3], mention no case with an onset between 3 and 15 months. Benign infantile epilepsy with partial seizures has however been mentioned by F u k u y a m a [4] and W a t a n a b e et al. [9]. W a t a n a b e et al. have recently described benign partial epilepsy that a p p e a r e d . b e t w e e n 3 and 20 months of age in nine patients, four of w h o m had a family history of benign infantile convulsions. Some of these cases might therefore overlap ours. On the other hand, their patients' seizures clearly had a temporal lobe onset whereas ours had an extratemporal onset.
The E E G and clinical features in our patients are typical of partial seizures. The location of the ictal discharge sometimes in one hemisphere, sometimes in the other, in the same patient, is a typical feature of an immature brain. It is also a distinguishing feature differentiating these seizures from the stereotyped attacks usually seen in lesional epilepsies. To summarize, we describe five infants with partial seizures with onset between 4 and 8 months; there was no known causative factors; the psychomotor developm e n t before the seizures was normal; the course was benign; the interictal E E G s were normal; and there was a family history of seizures with a benign course and similar age of onset. Since the onset of the recorded seizures occurred in later infancy, we propose to call t h e m "Benign Infantile Familial Convulsions".
References 1. Bankier A, Turner M, Hopkins J (1983) Pyridoxine dependent seizures: a wider clinical spectrum. Arch Dis Child 58: 415-418 2. Commission on Classification and Terminology of the International League Against Epilepsy (1989) Proposal for revised classifications of epilepsies and epileptic syndromes. Epilepsia 30 : 389-399 3. Dulac O, Cusmai R, Oliveira K de (1989) Is there a partial benign epilepsy in infancy? Epilepsia 30 : 798-801 4. Fukuyama Y (1963) Borderland of epilepsy with special reference to febrile convulsions and so called infantile convulsions. Clin Psychiatry 5:211-223 5. Gouti6res F, Aicardi J (1985) Atypical presentations of pyridoxine-dependent seizures: a treatable cause of intractable epilepsy in infants. Ann Neurol 17:117-120 6. Leppert M, Anderson VE, Quattlebaum T, Stauffer D, O'Connel P, Nakamura Y, Lalouel JM, White R (1989) Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 337 : 647-648 7. Miles KD, Holmes GL (1990) Benign neonatal seizures. J Clin Neurophysiol 7: 369-379 8. Plouin P (1985) Benign neonatal convulsions (familial and non-familial). In: Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P (eds) Epileptic syndromes in infancy, childhood and adolescence. John Libbey Eurotext, London, pp 2-11 9. Vigevano F, Di Capua M, Fusco L, Ricci S, Sebastianelli R, Lucchini P (1990) "Sixth-month benign familial convulsions". Epilepsia 31 : 613 10. Watanabe K, Yamamoto N, Negoro T, Takahashi I, Aso K, Machara M (1990) Benign infantile epilepsy with complex partial seizures. J Clin Neurophysiol 7 : 409-416
European Journal of
Pediatrics
9 Springer-Verlag1992
Benign infantile familial convulsions F. Vigevano 1, L. Fusco 1, M. Di Capua 1, S. Ricci 1, R. Sebastianelli 1, and P. Lucchini 2 ~Section of Neurophysiology, "Bambino Ges~" Children's Hospital, National Medical Research Institute, Piazza S. Onofrio 4, 1-00165 Rome, Italy 2General Hospital, Treviso, Italy Received July 2, 1991 / Accepted after revision October 29, 1991
Abstract. Five infants, three girls and two boys, first had convulsions between the ages of 4 and 6 months. Although the aetiology of the attacks was unknown, all the infants had a family history of similar convulsions occurring at the same age and having a benign outcome. The attacks, which always occurred in a cluster, were promptly controlled, in four cases with phenobarbital and in one case with valproate. Seizures were partial with secondary generalization and were characterized by head and eye deviation (not always the same side in each attack) diffuse hypertonia and then bilateral limb jerks. The interictal E E G was normal. The ictal E E G showed diffuse discharge with onset in the central-occipital region. Laboratory, radiological and neurological findings were normal. A history in at least one paternal relative (the father in four cases) of similar seizures, occurring at the same age suggested a genetic predisposition. No seizures or E E G anomalies were observed during the follow up.
Key words: Epilepsy - Infantile seizures - Familial convulsions - Benign epilepsy - Epileptic syndromes
In this study we present the extensive data of five patients with benign partial epilepsy [9], whose seizures first appeared between 4 and 7 months. The disorder was familial and the outcome of the epilepsy was favourable.
Clinical features The Table and Fig. 1 summarize clinical and familial data of our patients. Our series consisted of five infants, three girls and two boys. All of them had one or more paternal relatives with a history of benign seizures at the same age. In four families the affected member was the child's father. Analogous seizures were identified in 13 relatives. Two of these also had febrile convulsions (III 6 and II 4 in family 2). One other relative (III 2 in family 3), who had febrile convulsions alone, was excluded from the study. In the probands, the age at onset ranged from 4 to 7 months; in the relatives it ranged from 4 to 8 months and peaked around the 6th month (Fig. 2). None of them had seizure onset either in the neonatal age or after the 8th month of life. The prenatal and perinatal history of our patients was normal. The infants' psychomotor development before seizure onset was normal: the attacks always appeared when the infant was in good health. The results of all diagnostic investigations, including cerebral computed tomography, were normal. The epilepsy appeared to have no connection with diet.
Introduction The recent International Classification of Epilepsies and Epileptic Syndromes [2] lists among the idiopathic forms with onset in the 1st year of life three entities: benign neonatal familial convulsions, benign neonatal convulsions and benign myoclonic epilepsy in infancy. The first two appear in the neonatal period, the third at the age of about 1 year. All three are classified as generalized forms. The current classification recognizes no other forms of benign idiopathic epilepsy - either partial or generalized - with onset in the 1st year of life. Indeed, the consensus is that epilepsies arising in the 1st year of life have an unfavourable outlook. Offprint requests to: F. Vigevano
Seizure manifestations All the probands were observed in the acute phase and seizures were E E G recorded. The patients' attacks occurred mainly in clusters, lasting over a 2 - 4 - d a y period, in n u m b e r of four to ten episodes a day, both in wakefulness and sleep. The duration of each cluster correlated strictly with the start of therapy. In two patients (3 and 5) the cluster was the only seizure manifestation, and occurred respectively at 6 and 4 months. In the other three patients the cluster was preceded by isolated seizures: patient 1 had two seizures at 7 months, one at 8 months, and the cluster at 10 months; patient 2 had three isolated seizures at 5 months, within
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and then involving the entire brain, and increasing in amplitude. The discharges ended in both hemispheres synchronously or asynchronously; asynchronous activity lasted longer in the hemisphere that was secondarily involved (Fig. 3). After only a few hours E E G recording, the alternating clinical pattern was confirmed by the demonstration of seizures originating sometimes from the right, sometimes from the left hemisphere (Fig. 4).
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Fig. 1A-E. Family trees of the five patients. (A) Family i - III 3: patient 1; II 5: seizures between 6 and 12 months; III 4: only one generalized afebrile seizure at 8 months. (B) Family 2 - IV 1: patient 2; III 3: seizures between 6 and 8 months; III 6 and II 4: febrile and afebrile seizures between 8 and 11 months. (C) Family 3 - I I I 3: patient 3; III 5: isolated seizures at 8 and 18 months; III 2: febrile seizures at 2 years (excluded). (D) Family 4 III 2: patient 4; II 2: seizures at 6 months. (E) Family 5 - IV 1: patient 5; III 1, 2, 4 and II 2, 3: seizures between 4 and 5 months; I 1: seizures between 4 and 6 months
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Treatment and follow up
9
Fig. 2. Age at onset of seizures in probands and relatives. • Probands (5 cases); ~ relatives (13 cases)
20 days, then the cluster; patient 4 had four isolated seizures at 6 months, in the 11 days preceding the cluster. In the relatives, the attacks reportedly occurred singly or in clusters. In the probands, the seizures lasted from i to several minutes: the initial seiures were usually longer, even as long as 10-15 minutes, becoming shorter as the treatment took effect. Clinically the seizures were characterized by psychomotor arrest, slow deviation of the head and eyes to one side, diffuse hypertonia, cyanosis, and unilateral limb jerks, which became bilateral and were synchronous or asynchronous. Although the seizures were highly stereotyped, the direction of the head and eye deviation sometimes changed from seizure to seizure in the same patient. No clear automatism could be identified. The interictal E E G in sleep and wakefulness was always normal. The ictal E E G was characterized by a recruiting rhythm, beginning in the left or right central occipital areas, spreading over the hemisphere
The patients underwent treatment only when their seizures were in clusters. Four infants were treated with intramuscular phenobarbital (5 mg/kg per day), and one with sodium valproate (25 mg/kg per day) per os. Therapy brought the seizures under control within 24-48 h. The same drugs were then administered orally. Follow up now reached 24-32 months. None of the children had further seizures; their E E G s and the psychomotor develo p m e n t were normal. Patients 1, 4 and 5 stopped therapy after 1 year of treatment; the other two are now in the withdrawal phase. Detailed data about the treatment of the relatives were not available; most of t h e m were never treated. Nevertheless only one relative had a seizure after the age of 1 year, at 18 months. All the relatives had normal psychomotor development and no E E G anomalies were reported.
Discussion The salient distinguishing feature in this group of children with benign partial seizures with an onset in the 1st year of life is the good prognosis. There was a family
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B Fig. 3A, B. Patient 2 - Ictal E E G of one seizure recorded on the 1st day of the cluster, during sleep: an ictal recruiting rhythm began in the right occipital regions, later involved the central and temporal area and finally the left hemisphere (A). The end of the
discharge was asynchronous between the two sides (B). Clinically the seizure was characterized by slow left head and eyes deviation, diffuse hypertonia, cyanosis, asynchronous limb jerks, initially left and then bilateral
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B Fig. 4A, B. Patient 4: on the 4th day from the onset of the cluster, two seizures were recorded in 1 h during sleep: the first one (A) started from the right occipital region, and the second one (B) from the same region of the contralateral hemisphere. The
semeiology of both seizures was the same as that in patient 2; the side of the head and eye deviation was contralateral to the side of seizure onset
612 history for similar seizures at the same age, with no other aetiology. Some features of our patients' seizures coincide with the category of benign neonatal familial convulsions: a normal neurological state; absence of known causative factors; normal psychomotor development after the attacks; and family history of seizures at a similar age. Plouin [8] and Miles and H o l m e s [7] reported that the onset of seizures m a y occur even in the early months of life. Onset of seizures later than 3 months and 15 days has never b e e n reported, either in probands or relatives, yet in none of our subjects did seizures start before the age of 4 months. Furthermore, the absence of a clear E E G pattern in benign neonatal familial convulsions makes a comparison with our cases impossible. Leppert et al. [6] have identified a genetic m a r k e r for the benign neonatal familial convulsion syndrome, located on the long arm of c h r o m o s o m e 20. We are now studying the genetic status of our patients to see whether a m a r k e r exists for the syndrome described here. Familial convulsions may also be caused in the 1st year of life by a pyridoxine dependency or deficiency. In the typical f o r m [1] the convulsions always a p p e a r in the first days of life; only in the atypical form [5], does the onset occur in the first months. Both forms are resistant to treatment with c o m m o n antiepileptic drugs. The clinical picture is always severe and contrasts with the evolving character of benign seizure disorders. In our opinion, the absence of aetiological factors and the familial nature of our patients' convulsions class them as idiopathic. The current Classification of Epilepsies and Epileptic syndromes [2] recognizes no idiopathic forms - partial or generalized - with an onset between 4 and 8 months. R e p o r t e d data are contrasting. In a review of 17 cases of benign partial epilepsy with an onset ranging from 8 days to 3 years, Dulac et al. [3], mention no case with an onset between 3 and 15 months. Benign infantile epilepsy with partial seizures has however been mentioned by F u k u y a m a [4] and W a t a n a b e et al. [9]. W a t a n a b e et al. have recently described benign partial epilepsy that a p p e a r e d . b e t w e e n 3 and 20 months of age in nine patients, four of w h o m had a family history of benign infantile convulsions. Some of these cases might therefore overlap ours. On the other hand, their patients' seizures clearly had a temporal lobe onset whereas ours had an extratemporal onset.
The E E G and clinical features in our patients are typical of partial seizures. The location of the ictal discharge sometimes in one hemisphere, sometimes in the other, in the same patient, is a typical feature of an immature brain. It is also a distinguishing feature differentiating these seizures from the stereotyped attacks usually seen in lesional epilepsies. To summarize, we describe five infants with partial seizures with onset between 4 and 8 months; there was no known causative factors; the psychomotor developm e n t before the seizures was normal; the course was benign; the interictal E E G s were normal; and there was a family history of seizures with a benign course and similar age of onset. Since the onset of the recorded seizures occurred in later infancy, we propose to call t h e m "Benign Infantile Familial Convulsions".
References 1. Bankier A, Turner M, Hopkins J (1983) Pyridoxine dependent seizures: a wider clinical spectrum. Arch Dis Child 58: 415-418 2. Commission on Classification and Terminology of the International League Against Epilepsy (1989) Proposal for revised classifications of epilepsies and epileptic syndromes. Epilepsia 30 : 389-399 3. Dulac O, Cusmai R, Oliveira K de (1989) Is there a partial benign epilepsy in infancy? Epilepsia 30 : 798-801 4. Fukuyama Y (1963) Borderland of epilepsy with special reference to febrile convulsions and so called infantile convulsions. Clin Psychiatry 5:211-223 5. Gouti6res F, Aicardi J (1985) Atypical presentations of pyridoxine-dependent seizures: a treatable cause of intractable epilepsy in infants. Ann Neurol 17:117-120 6. Leppert M, Anderson VE, Quattlebaum T, Stauffer D, O'Connel P, Nakamura Y, Lalouel JM, White R (1989) Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 337 : 647-648 7. Miles KD, Holmes GL (1990) Benign neonatal seizures. J Clin Neurophysiol 7: 369-379 8. Plouin P (1985) Benign neonatal convulsions (familial and non-familial). In: Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P (eds) Epileptic syndromes in infancy, childhood and adolescence. John Libbey Eurotext, London, pp 2-11 9. Vigevano F, Di Capua M, Fusco L, Ricci S, Sebastianelli R, Lucchini P (1990) "Sixth-month benign familial convulsions". Epilepsia 31 : 613 10. Watanabe K, Yamamoto N, Negoro T, Takahashi I, Aso K, Machara M (1990) Benign infantile epilepsy with complex partial seizures. J Clin Neurophysiol 7 : 409-416
