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Keywords:

  • epileptic syndrome;
  • etiologic factors;
  • severe myoclonic epilepsy in infancy;
  • symptomatic epilepsy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STUDY ON THE ETIOLOGIC FACTORS OF SYMPTOMATIC EPILEPSY
  5. CLINICAL CHARACTERISTICS AND RECENT ADVANCES OF GENETIC RESEARCH OF SMEI
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Abstract  We discuss the presumptive etiologic factors of symptomatic epilepsy from the clinical standpoint, based on our experience of 383 inpatients with epilepsy, with a focus on children. The main (top three) presumptive etiologic factors in partial epilepsy are intracranial infection, cerebral malformation and perinatal brain damage. In generalized epilepsy, the main presumptive etiologic factors are perinatal brain damage, intracranial infection, and cerebral malformation. As regards presumptive etiologic factors in partial epilepsy, cerebral malformation was most common in frontal lobe epilepsy, initial convulsive status in temporal lobe epilepsy and perinatal brain damage in occipital lobe epilepsy. Electroclinical characteristics of severe myoclonic epilepsy in infancy, the most intractable epilepsy syndrome in infancy, is the focus and recent advances of genetic research are introduced.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STUDY ON THE ETIOLOGIC FACTORS OF SYMPTOMATIC EPILEPSY
  5. CLINICAL CHARACTERISTICS AND RECENT ADVANCES OF GENETIC RESEARCH OF SMEI
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Recent advances in neuroimaging and molecular genetics have resulted in an accumulation of new findings on the etiology of symptomatic epilepsy. The international classification of epilepsy and epileptic syndromes is based on not only the seizure type but also on the etiology, clinical course and prognosis.1 Therefore, it is important to categorize subjects based on the classification of epileptic syndromes with consideration of the etiology. We consider the presumptive etiologic factors of symptomatic epilepsy from the clinical standpoint, based on our results. In particular, we focus on severe myoclonic epilepsy in infancy (SMEI), the  most  intractable  epilepsy  syndrome  of  infancy, and the recent advances of genetic research will be introduced.

STUDY ON THE ETIOLOGIC FACTORS OF SYMPTOMATIC EPILEPSY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STUDY ON THE ETIOLOGIC FACTORS OF SYMPTOMATIC EPILEPSY
  5. CLINICAL CHARACTERISTICS AND RECENT ADVANCES OF GENETIC RESEARCH OF SMEI
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Subjects and methods

A total of 383 inpatients (199 males and 184 females) admitted to the pediatric epilepsy ward of our hospital during 1993 and 1994 were recruited in the study. Based on the findings of past history, EEG, clinical seizures and neurological imaging, the relationship of the epilepsy type and epileptic syndrome with etiology or lesion was investigated. Almost all patients were intractable cases with weekly or monthly epileptic seizures. The age at the time of study ranged from 3 months to 35 years (mean, 10 years). The majority (296 cases, 77%) were pediatric cases aged under 15 years.

Results

The epilepsy diagnoses of the subjects were as follows: three cases of idiopathic generalized epilepsy, 135 cases of symptomatic generalized epilepsy, four cases of idiopathic partial epilepsy, 195 cases of symptomatic partial epilepsy (70 cases of frontal lobe epilepsy, 22 cases of temporal lobe epilepsy, 25 cases of occipital lobe epilepsy, two cases of parietal lobe epilepsy, 76 cases of multilobe or difficult-to-locate cases), and 46 cases of undetermined epilepsy (including 12 cases of SMEI) (Table 1). There were only seven cases (1.8%) of idiopathic epilepsy because almost all patients were admitted for treatment purposes.

Table 1. Patients
EpilepsyNo. (%)
Idiopathic generalized 3 (0.8)
Symptomatic generalized135 (35.2)
 Lennox syndrome  19
 West syndrome  15
Idiopathic partial 4 (1.1)
Symptomatic partial195 (50.9)
 Frontal 70
 Temporal 22
 Parietal 2
 Occipital 25
 Multi/Unknown 76
Undetermined 46 (12.0)
 Severe myoclonic epilepsy in infancy 12
Total383 (100.0)

The main (top three) presumptive etiologic factors of each epilepsy type are shown in Table 2. In partial epilepsy, the order was intracranial infection seen in 30 cases (15%), followed by cerebral malformation in 26 cases (13%), and perinatal brain damage in 25 cases (13%). In generalized epilepsy, the order was perinatal brain damage in 26 cases (19%), intracranial infection in 10 cases (7.4%), and cerebral malformation in nine cases (6.7%).

Table 2. Etiologic factors
 Partial epilepsy n = 199 No. (%)Generalized epilepsy n = 135 No. (%)
CNS infection30 (15.1)10 (7.4)
Cerebral malformation26 (13.1) 9 (6.7)
Perinatal brain damage25 (12.6)26 (19.3)
Head trauma10 (5.0) 1 (0.7)
Initial convulsive status14 (7.0) 3 (2.2)
Neurocutaneous syndrome7 (3.5) 7 (5.2)
Cerebrovascular accident5 (2.5) 2 (1.5)
Tumor5 (2.5) 1 (0.7)
Hereditary progressive disease1 (0.5) 6 (4.4)
Others3 (1.5) 5 (3.7)
Unknown73 (36.7)65 (48.2)

The relation between the presumptive etiologies and the subclassification of partial epilepsy was examined (Table 3). In frontal lobe epilepsy, the most common cause was cerebral malformation such as focal cortical dysplasia seen in 15 cases (21%), followed by intracranial infection in nine cases (13%), and perinatal brain damage in six cases (9%). In comparison, in temporal epilepsy, the most common etiologic factors were a history of febrile initial convulsive status epilepitcus in seven cases (32%), followed by intracranial infection in four cases (18%). In occipital lobe epilepsy, the order was perinatal brain damage in eight cases (32%), cerebral malformation in five cases (20%), and head trauma in three cases (12%).

Table 3. Etiologic factors in 119 patients with intractable partial epilepsy
 Frontal n = 70 No. (%)Temoral n = 22 No. (%)Occipital n = 25 No. (%)Parietal n = 2 No. (%)
Cerebral malformation15 (21) 5 (20) 
Neurocutaneous syndrome4 (6)   
Chromosomal abnormality1 (1)   
perinatal brain damage6 (9) 8 (32) 
CNS infection 9 (13)4 (18) 1 (4) 
Head trauma3 (4)1 (4.5)3 (12) 
Tumor3 (4)1 (4.5)  
Initial convulsive status 7 (32) 1 (50)
Cerebrovascular accident2 (3)  1 (4) 
Others2 (3)   
Unknown25 (36)9 (41)7 (28)1 (50)

These results demonstrated that the ranking of presumptive etiologies varies when partial epilepsies are subclassified. In particular, cerebral malformation, chiefly cortical dysplasia, was the primary factor in frontal lobe epilepsy, while initial convulsive status epilepticus was the primary factor in temporal lobe epilepsy. An indication of surgery treatment was obtained in some cases.

CLINICAL CHARACTERISTICS AND RECENT ADVANCES OF GENETIC RESEARCH OF SMEI

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STUDY ON THE ETIOLOGIC FACTORS OF SYMPTOMATIC EPILEPSY
  5. CLINICAL CHARACTERISTICS AND RECENT ADVANCES OF GENETIC RESEARCH OF SMEI
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

SMEI is the most intractable epileptic syndrome among the epilepsies with infancy onset. This syndrome lacks a history of brain damage. The patient is usually normal until the onset of epilepsy. Convulsive seizures start before 1 years of age. Although the seizures are closely associated with fever, they also occur in a non-febrile state and are extremely pharmaco-resistant. Cognitive prognosis is poor.1,2 Among the subjects recruited in the present study, there were 12 SMEI cases, occupying 3.1% of all cases. This high frequency is biased by the fact that our hospital is a national epilepsy center and most patients that are admitted are intractable cases. The actual incidence of this syndrome is rare. The diagnosis of SMEI is confirmed from the appearance of myoclonic seizures. Although myoclonic seizures commonly appear between 1 and 3 years of age, the seizure frequency, time of manifestation, and period of manifestation, range widely depending on cases. The same can be said for complex partial seizures. The spectrum ranges from transient manifestation to long-term continuous manifestation.

Although SMEI is an established epilepsy syndrome, detailed observation of individual cases reveals a considerable diversity in phenotype. This syndrome is recognized as being associated with a family history of epilepsy or febrile convulsion.2–4 We have observed identical manifestation in two pairs of concordant monozygotic twins, strongly suggesting the involvement of predisposing genetic factors in its pathogenesis.5,6 Recently, mutation of the gene that codes the neuronal voltage gated sodium channel alpha subunit type 1 gene (SCN1A), has been reported to be closely related to the etiology of SMEI.7 This genetic change is a de novo mutation producing an abnormal pattern of the sodium channel protein. Our colleagues detected a high frequency of this mutation in Japanese SMEI patients, and confirmed that this mutation is closely related to the etiology of SMEI.8 From these studies, SMEI was established as the ion channelopathy.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STUDY ON THE ETIOLOGIC FACTORS OF SYMPTOMATIC EPILEPSY
  5. CLINICAL CHARACTERISTICS AND RECENT ADVANCES OF GENETIC RESEARCH OF SMEI
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

The presumptive etiologic factors of symptomatic epilepsy are in the order of antenatal disorder, prenatal disorder, and perinatal disorder. When the presumptive etiologic factors are examined according to a subclassification of partial epilepsy, the differences are conspicuous. While cerebral malformation, notably cortical dysplasia was the primary factor in frontal lobe epilepsy, initial convulsive status epilepticus was the primary factor in temporal lobe epilepsy.

The importance of febrile status epilepticus in infancy and early childhood as an etiologic factors of temporal lobe epilepsy, especially medial temporal lobe epilepsy, was well known.9,10 In addition, the present results also support our past report.11 Since medial temporal lobe epilepsy has a good surgical outcome, it is vital to distinguish this type early from among the epilepsies showing an intractable course. In this differentiation, a history of febrile status epilepticus is an important reference. The present study group differed from adult cases and a low proportion of temporal lobe epilepsy among partial epilepsies is remarkable. Whether this finding is due to a lower prevalence of temporal lobe epilepsy than frontal lobe epilepsy among pediatric cases, or difficulties in diagnosing temporal lobe epilepsy in children, will be a topic of future study.

The identification of mutation of SCN1A as the etiology of SMEI has been a great advance. However, it remains unclear as to how the mutation is associated with the process of acquiring epileptogenecity in SMEI. Further basic physiological research is required. On the other hand, the de novo mutation currently reported does not explain the occurrence of SMEI among siblings and familial aggregation in families with a history of epilepsy and febrile convulsion.2–4 Future development of research in this area is anticipated. Furthermore, the relationship between genotype and phenotype in SMEI patients is an important research topic in the future.

ACKNOWLEDGMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STUDY ON THE ETIOLOGIC FACTORS OF SYMPTOMATIC EPILEPSY
  5. CLINICAL CHARACTERISTICS AND RECENT ADVANCES OF GENETIC RESEARCH OF SMEI
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

This study was partly supported by a grant (7 A-1) from Nervous and Mental Disorders from the Ministry of Health and Welfare.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STUDY ON THE ETIOLOGIC FACTORS OF SYMPTOMATIC EPILEPSY
  5. CLINICAL CHARACTERISTICS AND RECENT ADVANCES OF GENETIC RESEARCH OF SMEI
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES
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  • 2
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    Benlounis A, Nabbout R, Feingold J et al. Genetic predisposition to severe myoclonic epilepsy in infancy. Epilepsia 2001; 42: 204209.
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    Fujiwara T, Nakamura H, Watanabe M et al. Cinicoelectrographic concodance between monozygotic twins with severe myoclonic epilepsy in infancy. Epilepsia 1990; 31: 281286.
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    Fujiwara T, Watanabe M, Takahasi Y et al. Long-term course of childhood epilepsy with intractable grand mal seizures. Jpn J. Psychiatr. Neurol. 1992; 46: 297302.
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    Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1 A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 2001; 68: 13271332.
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    Sugawara T, Mazaki-Miyazaki E, Fukushima K et al. Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy. Neurology (in press).
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    Falconer MA, Serafetinides EA, Corsellis JA. Etiology and pathogenesis of temporal lobe epilepsy. Arch. Neurol. 1964; 10: 233248.
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    Bassel AK, Andermann E, Andermann F et al. Temporal lobe epilepsy after prolonged febrile convulsions: Excellent outcome after surgical treatment. Epilepsia 1993; 34: 878883.
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    Fujiwara T, Ishida S, Miyakoshi M et al. Status epilepticus in childhood: a retrospective study of initial convulsive status and subsequent epilepsies. Folia Psychiatr. Neurol. Jpn 1979; 33: 125128.