Develop. Med. Child Nmrol. 1976, 18, 381-391
Annotations PREVENTION OF EPILEPSY IN CHILDREN EPILEPSYis but a symptom of a vast number of brain disorders, consequently the problems posed by its prevention are diverse and no single approach can be expected to solve them satisfactorily. Prevention of chronic epilepsy is obviously the important matter, but isolated fits are so closely related aetiologically with chronic convulsive disorders that they cannot be neglected when considering the possibilities of preventing epilepsy in general. The prevention of epilepsy can be approached at three levels: (1) by attack on the aetiological roots of convulsive disorders; ( 2 ) by limitation of the complications of fits; and (3) by prevention of the psycho-social consequences of seizure disorders. Only the first two approaches are preventive in terms of the number of people affected. Prevention of such complications as status epilepticus and repeated fits by proper management can reduce the prevalence of epilepsy by avoiding the accidental occurrence of epileptic brain-damage, which is able to transforni a relatively benign epilepsy into a severe lesional one. Attack on the causes of convulsive disorders is, however, the main target of any preventive policy. Seizures i n children fall into two broad aetiological categories : those resulting from organic brain anomalies, whether due to abnormal development or to insults incurred during prenatal life, birth or postnatally ; and those resulting from functional disturbances, the nature of wliich is largely unknown but which are, at least in part, genetically determined. These two categories partially overlap, since several genetic disorders induce fits through organic brain abnormalities. The convulsive disorders in which genetic factors play an important r61e include the primary generalised epilepsies (primary grand mnl, petit mal, benign epilepsy with rolandic spikes, and some myoclonic epilepsies), the common febrile seizures, as well as uncommon specific diseases such as tuberous sclerosis, phenylketonuria and other rare conditions. Except in the last group, where precise Mendelian laws are known to operate, our knowledge of the nature of the inherited factors and of the precise rules of transmission is limited. Present evidence indicates that patients with specific heritable conditions, such as tuberous sclerosis, should be advised against procreation. In the more common generalised epilepsies, there is no compelling reason to advise against marriage, but patients should be informed of the empirical risks of having affected children'.2, Counsellirig should be cautious, however, because the present models are of uncertain validity and the conditions to be prevented are largely benign and treatable. Relatively little can be expected from the genetic approach to prevention at population levels. On the other hand, i t may be of value in particular cases. In addition, knowledge of the genetic background may be of importance in certain circumstances: for example a strong genetic tendency to febrile convulsions would make one reluctant to perform some immunisations (pertussis, smallpox) and would indicate vigorous prophylactic treatment during febrile episodes. Epilepsies resulting from acquired brain-damage offer greater opportunities for prevention. Postnatally acquired epileptogenic brain-damage is probably the area where pre381
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
1976, 18
vention can be most effective. Infections, especially purulent meningitides3, trauma4 and long-lasting seizures-particularly febrile onesj-’-rank among the main causes of chronic epilepsy. Prompt recognition and early antibiotic treatment are essential in cases of meningitis. Prophylactic anticonvulsant therapy should be systematically added in the treatment of such children, as the incidence of convulsions is very high is this age-groups and as seizures and the consequent brain hypoxia are likely to play a r81e in the genesis of postmeningitic encephalopathy9. Long-lasting febrile convulsions are a significant cause of late lesional epilepsy. Clinical’O and experimental” evidence indicates that the duration of the convulsions, irrespective of their cause, is the main factor of brain damage. In consequence, every effort should be made to quichly stop any lasting seizure. In my experience, intravenous diazepam has been the most effective drug. Intramuscular phenobarbitone is too slowly absorbed to be recommended in such an emergencyl2. l3 and the same seems to apply to intramuscular diazepam. Our preliminary results suggest that 30 to 45 minutes are necessary for the peak blood-level to be obtained. Rectal instillation may hold promise, since it has been shown to produce rapidly high plasma concentration^'^. Paraldehyde and rapidly-acting barbiturates’j have also been found suitable, on a clinical basis. Since febrile seizures are apt to recur, and because brain damage can follow upon any fit, the question arises of prophylactic treatment to prevent recurrences. At present no conclusive evidence has been adduced, but several studies have shown that continuous phenobarbital may diminish the incidence of recurrences16-18. Theoretically, traumatic brain-damage is preventible. The r81e of physicians is important in the diagnosis of battering, since so many cases still go unrecognised and because the recurrence rate is so high19. 20. Improvement in the treatment of head trauma and subdural haematomata is desirable, but social and legal adjustments are of greater import than improvement in purely medical treatment. Prevention of epilepsy resulting from perinatal injuries is also within our reach. Physical trauma has already been largely eliminated by the improvement of obstetric practice, and anoxic injury is being successfully combatted by both obstetricians and neonatologists. It is not unreasonable to expect that the same reduction which has taken place in the incidence of some types of cerebral palsy during the past few yearsz1*22 could be duplicated in the incidence of epileptogenic brain damage. Prenatal insults, which probably constitute the largest group and give rise to the severest handicaps, largely escape preventive measures. Among the infectious fetopathies, rubella can be suppressed by inimunisation of prepubertal girls, and syphilis can be detected and treated during pregnancy. Efforts are being made towards diagnosis and treatment of toxoplasmosis in pregnant womenz3, and the possibilities of a vaccine against cytomegalovirus are being actively explored24. Possibly, monitoring of ‘high-risk’ pregnancies by hormonal and electronic means, combined with the use of labour induction or section, will reduce the incidence of late fetal distress resulting in epileptogenic injuries. The large group of brain malformations, fetopathies of obscure origin, fetal growth retardation, etc., offers no preventive possibility at present. It is difficult to assess the magnitude of the effects that can be expected to result from the use of the medical means now at our disposal. Our knowledge of the epidemiology of epilepsy is limitedz5, and comparisons between various periods or different populations are hazardous. Moreover, any possible decline in frequency would be difficult to evaluate, as many non-medical factors can be expected to act in the same direction as medical preventive steps. Such factors as frequency and severity of infections in general, age of occurrence of common infantile exanthemata, incidence of physical trauma, family size and birth382
ANNOI’ATIQNS
spacing among others, are likely to influence the incidence of epilepsy. These in turn are more dependent on socio-economic level and public-health regulations than upon medical knowledge per se. Therefore the fight against epilepsy clearly should not be limited to the medical field; sociaI, economic and political action also needs to be included in a broad preventive approach. However, the rB1e of physicians is crucial, and great efforts should be made to improve teaching and knowledge in the field of convulsive disorders if we really want the present possibilities of prevention to be used fully. JFAN AICARDI HBpital Saint-Vincent de Paul, 74 Aveuue Denfert-Rochereau, 75674 Paris, France. REFERENCES I. Metrakos, J. D.. Metrakos. K. (1961 ) ‘Genetics of convulsive disorders. 11. Genefic and electroencephalographic studies in centrencephalic epilepsy.’ Neurology, 11,474.
2. Doose, H.. Gerken, H. (1973) ‘Possibilities and limitations of epilepsy prevention in siblings of epilep!ic children.’ In Parsonage, M. J. ( E d . ) Prevention of Epilepsy and Its Conseqneirces. London: Intrrnational Bureau for Epilepsy. 3. Aicardi, J. (1973) ’Epileptic attacks accompanying or following infantile infections acquired during the first three years of life.’ I n Parsonage, M. J . (Ed.) Prevenrion of Epilepsy und Its Corrsecpencc~.~. London: International Bureau for Epilepsy. Jennett, R. (1973) ‘Trauma as a cause of epilepsy in childhood.’ Developmental Medicine and Child Neurology, 15. 56. cmd Clinical Lennox-Buchthal, M. (1973) ‘Febrile convulsions. A reappraisal.’ Elecrroencepha/cJ~~ap/Iy Neurophysiology, Su ppl. 3 2. Otinsted, C . , Lindsay, J., Norman, R. M. (1966) Biological Factors in Temporal Lobe Epi1ep.i.v. Clinics in Developmental Medicine No. 22. London: S.I.M.P. with Heinemann Medical. Falconer, M . A . (1974) ‘Mesial temporal (Amnion’s horn) sclerosis as a common cause of epilepsy.’ Lancet, 2,767 8. Ounsted, C. (1951) ‘Significance of convulsions in children with purulent meningitis.’ Lancer. 1, 1245. 9. Swarz, M . N., Dodge, P. R. (1965) ‘Bacterial meningitis. A review of selected aspects. 11. Special neurologic problems, post-meningitic complications and clinico-pathological correlations. New England Jorirnul of Medicine, 272, 954. 10. Aicardi, J., Chevrie. J. J. (1976) ‘Febrile convulsions: neurological sequelae and mental retardation.’ In International Brain Research Organisation Monograph Series No. 2. New York: Raven (in the press.) I I . Meldrum, B. S., Brierley, J. B. (1973) ‘Prolonged epileptic seizures in primates. Ischemic cell change and its relation to ictal physiological events.’ Archives ofNeurology, 28, 10. 12. Jalling, B. (1974) ‘Plasma and cerebrospinal fluid concentrations of phenobarbital in infants given single doses.’ Deidopmcwtal Medicine and Child Neurology, 16,78 I . 13. Brachet-Liermain. A.. Goutieres, F., Aicardi. J . (1975) ‘Absorption of phenobarbital after the intraniuscular administration of single doses in infants.’Joirrnal qfPedfatrics,87,624. 14. Agurell, S.. Berlin, A,, Ferngran, H., HellstrGni, B. (1975) ‘Plasma levels of diazepam after parenteral and rectal administration in children.’ Epilepsia, 16,277. 15. Taylor, D. C., Bower, B. D. (1971) ‘Prevention in epileptic disorders.’ Lancet, 2, 1136. 16. Faerar, O., Kastrup, K . W., Nielsen, E. L., Melchior, J. C.. Thorn, I. (1972) ‘Successful prophylaxis of febrile convulsions with phenobarbital.’ Epilvpsia, 13, 279. 17. Thorn, I. (1975) ‘A controlled study of prophylactic long-term treatment of febrile convulsions with phenoharbital.’ 4 c f a Nerirologica Scandinuvica, 52, Suppl. 60.67. 18. Wallace. S. J. ( 1975) ‘Continuous prophylactic anticonvulsants in selected children with febrile convulsions.’ Acta Neurologica Scandinmica, 52, Suppl. 60, 62. 19. Kempe. C . H., Helfer, R. E. (Eds.) (1972) Helping the Battered Child and Hi.r Fam i I ~ ~Philadelphia: . J. B. Lippincott. 20. Mac Keith, R. (1974) ‘Speculations on non-accidental injury as a cause of chronic brain disorder.’ Developmental Medicine and Child Neurology, 16, 421. 21. Hagberg, B., Olow, I, Hagberg, G . (1973) ‘Decreasing incidence of low-birthweight diplegia. An achievement of modern neonatal care.’ Act0 Paediatrica Scandinmica, 62,199. 77 --. Davies, P. A.. Tizard, J. P. M., Bleck, E. E. (1975) ‘Very low birthweight and subsequent neurological defect (with special reference to spastic diplegia).’ DevelopmentalMedicine and Child Nerirolog.y, 17, 3. 23. Couvreur, .I. ( 1971) ‘Prospective study of acquired toxoplasmosis in pregnant women, with special reference to the outcome of the fetus.’In Hentsch, D. (Ed.) Toxoplasmosis.Bern: H. Huber. 24. Elek, S. D., Stern, H. (1974) ‘Development of a vaccine against mental retardation caused by cytoniegalovirus infections in titero.’ Lancet, 1, 15. 25. Alter, M. Hauser, W. A. (Eds.) (1972) The Epidemiology of Epilepsy. NINDS Monogranh Series No. 14. Washington: U S . Department of Health, Education and Welfare.
383
Annotations PREVENTION OF EPILEPSY IN CHILDREN EPILEPSYis but a symptom of a vast number of brain disorders, consequently the problems posed by its prevention are diverse and no single approach can be expected to solve them satisfactorily. Prevention of chronic epilepsy is obviously the important matter, but isolated fits are so closely related aetiologically with chronic convulsive disorders that they cannot be neglected when considering the possibilities of preventing epilepsy in general. The prevention of epilepsy can be approached at three levels: (1) by attack on the aetiological roots of convulsive disorders; ( 2 ) by limitation of the complications of fits; and (3) by prevention of the psycho-social consequences of seizure disorders. Only the first two approaches are preventive in terms of the number of people affected. Prevention of such complications as status epilepticus and repeated fits by proper management can reduce the prevalence of epilepsy by avoiding the accidental occurrence of epileptic brain-damage, which is able to transforni a relatively benign epilepsy into a severe lesional one. Attack on the causes of convulsive disorders is, however, the main target of any preventive policy. Seizures i n children fall into two broad aetiological categories : those resulting from organic brain anomalies, whether due to abnormal development or to insults incurred during prenatal life, birth or postnatally ; and those resulting from functional disturbances, the nature of wliich is largely unknown but which are, at least in part, genetically determined. These two categories partially overlap, since several genetic disorders induce fits through organic brain abnormalities. The convulsive disorders in which genetic factors play an important r61e include the primary generalised epilepsies (primary grand mnl, petit mal, benign epilepsy with rolandic spikes, and some myoclonic epilepsies), the common febrile seizures, as well as uncommon specific diseases such as tuberous sclerosis, phenylketonuria and other rare conditions. Except in the last group, where precise Mendelian laws are known to operate, our knowledge of the nature of the inherited factors and of the precise rules of transmission is limited. Present evidence indicates that patients with specific heritable conditions, such as tuberous sclerosis, should be advised against procreation. In the more common generalised epilepsies, there is no compelling reason to advise against marriage, but patients should be informed of the empirical risks of having affected children'.2, Counsellirig should be cautious, however, because the present models are of uncertain validity and the conditions to be prevented are largely benign and treatable. Relatively little can be expected from the genetic approach to prevention at population levels. On the other hand, i t may be of value in particular cases. In addition, knowledge of the genetic background may be of importance in certain circumstances: for example a strong genetic tendency to febrile convulsions would make one reluctant to perform some immunisations (pertussis, smallpox) and would indicate vigorous prophylactic treatment during febrile episodes. Epilepsies resulting from acquired brain-damage offer greater opportunities for prevention. Postnatally acquired epileptogenic brain-damage is probably the area where pre381
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
1976, 18
vention can be most effective. Infections, especially purulent meningitides3, trauma4 and long-lasting seizures-particularly febrile onesj-’-rank among the main causes of chronic epilepsy. Prompt recognition and early antibiotic treatment are essential in cases of meningitis. Prophylactic anticonvulsant therapy should be systematically added in the treatment of such children, as the incidence of convulsions is very high is this age-groups and as seizures and the consequent brain hypoxia are likely to play a r81e in the genesis of postmeningitic encephalopathy9. Long-lasting febrile convulsions are a significant cause of late lesional epilepsy. Clinical’O and experimental” evidence indicates that the duration of the convulsions, irrespective of their cause, is the main factor of brain damage. In consequence, every effort should be made to quichly stop any lasting seizure. In my experience, intravenous diazepam has been the most effective drug. Intramuscular phenobarbitone is too slowly absorbed to be recommended in such an emergencyl2. l3 and the same seems to apply to intramuscular diazepam. Our preliminary results suggest that 30 to 45 minutes are necessary for the peak blood-level to be obtained. Rectal instillation may hold promise, since it has been shown to produce rapidly high plasma concentration^'^. Paraldehyde and rapidly-acting barbiturates’j have also been found suitable, on a clinical basis. Since febrile seizures are apt to recur, and because brain damage can follow upon any fit, the question arises of prophylactic treatment to prevent recurrences. At present no conclusive evidence has been adduced, but several studies have shown that continuous phenobarbital may diminish the incidence of recurrences16-18. Theoretically, traumatic brain-damage is preventible. The r81e of physicians is important in the diagnosis of battering, since so many cases still go unrecognised and because the recurrence rate is so high19. 20. Improvement in the treatment of head trauma and subdural haematomata is desirable, but social and legal adjustments are of greater import than improvement in purely medical treatment. Prevention of epilepsy resulting from perinatal injuries is also within our reach. Physical trauma has already been largely eliminated by the improvement of obstetric practice, and anoxic injury is being successfully combatted by both obstetricians and neonatologists. It is not unreasonable to expect that the same reduction which has taken place in the incidence of some types of cerebral palsy during the past few yearsz1*22 could be duplicated in the incidence of epileptogenic brain damage. Prenatal insults, which probably constitute the largest group and give rise to the severest handicaps, largely escape preventive measures. Among the infectious fetopathies, rubella can be suppressed by inimunisation of prepubertal girls, and syphilis can be detected and treated during pregnancy. Efforts are being made towards diagnosis and treatment of toxoplasmosis in pregnant womenz3, and the possibilities of a vaccine against cytomegalovirus are being actively explored24. Possibly, monitoring of ‘high-risk’ pregnancies by hormonal and electronic means, combined with the use of labour induction or section, will reduce the incidence of late fetal distress resulting in epileptogenic injuries. The large group of brain malformations, fetopathies of obscure origin, fetal growth retardation, etc., offers no preventive possibility at present. It is difficult to assess the magnitude of the effects that can be expected to result from the use of the medical means now at our disposal. Our knowledge of the epidemiology of epilepsy is limitedz5, and comparisons between various periods or different populations are hazardous. Moreover, any possible decline in frequency would be difficult to evaluate, as many non-medical factors can be expected to act in the same direction as medical preventive steps. Such factors as frequency and severity of infections in general, age of occurrence of common infantile exanthemata, incidence of physical trauma, family size and birth382
ANNOI’ATIQNS
spacing among others, are likely to influence the incidence of epilepsy. These in turn are more dependent on socio-economic level and public-health regulations than upon medical knowledge per se. Therefore the fight against epilepsy clearly should not be limited to the medical field; sociaI, economic and political action also needs to be included in a broad preventive approach. However, the rB1e of physicians is crucial, and great efforts should be made to improve teaching and knowledge in the field of convulsive disorders if we really want the present possibilities of prevention to be used fully. JFAN AICARDI HBpital Saint-Vincent de Paul, 74 Aveuue Denfert-Rochereau, 75674 Paris, France. REFERENCES I. Metrakos, J. D.. Metrakos. K. (1961 ) ‘Genetics of convulsive disorders. 11. Genefic and electroencephalographic studies in centrencephalic epilepsy.’ Neurology, 11,474.
2. Doose, H.. Gerken, H. (1973) ‘Possibilities and limitations of epilepsy prevention in siblings of epilep!ic children.’ In Parsonage, M. J. ( E d . ) Prevention of Epilepsy and Its Conseqneirces. London: Intrrnational Bureau for Epilepsy. 3. Aicardi, J. (1973) ’Epileptic attacks accompanying or following infantile infections acquired during the first three years of life.’ I n Parsonage, M. J . (Ed.) Prevenrion of Epilepsy und Its Corrsecpencc~.~. London: International Bureau for Epilepsy. Jennett, R. (1973) ‘Trauma as a cause of epilepsy in childhood.’ Developmental Medicine and Child Neurology, 15. 56. cmd Clinical Lennox-Buchthal, M. (1973) ‘Febrile convulsions. A reappraisal.’ Elecrroencepha/cJ~~ap/Iy Neurophysiology, Su ppl. 3 2. Otinsted, C . , Lindsay, J., Norman, R. M. (1966) Biological Factors in Temporal Lobe Epi1ep.i.v. Clinics in Developmental Medicine No. 22. London: S.I.M.P. with Heinemann Medical. Falconer, M . A . (1974) ‘Mesial temporal (Amnion’s horn) sclerosis as a common cause of epilepsy.’ Lancet, 2,767 8. Ounsted, C. (1951) ‘Significance of convulsions in children with purulent meningitis.’ Lancer. 1, 1245. 9. Swarz, M . N., Dodge, P. R. (1965) ‘Bacterial meningitis. A review of selected aspects. 11. Special neurologic problems, post-meningitic complications and clinico-pathological correlations. New England Jorirnul of Medicine, 272, 954. 10. Aicardi, J., Chevrie. J. J. (1976) ‘Febrile convulsions: neurological sequelae and mental retardation.’ In International Brain Research Organisation Monograph Series No. 2. New York: Raven (in the press.) I I . Meldrum, B. S., Brierley, J. B. (1973) ‘Prolonged epileptic seizures in primates. Ischemic cell change and its relation to ictal physiological events.’ Archives ofNeurology, 28, 10. 12. Jalling, B. (1974) ‘Plasma and cerebrospinal fluid concentrations of phenobarbital in infants given single doses.’ Deidopmcwtal Medicine and Child Neurology, 16,78 I . 13. Brachet-Liermain. A.. Goutieres, F., Aicardi. J . (1975) ‘Absorption of phenobarbital after the intraniuscular administration of single doses in infants.’Joirrnal qfPedfatrics,87,624. 14. Agurell, S.. Berlin, A,, Ferngran, H., HellstrGni, B. (1975) ‘Plasma levels of diazepam after parenteral and rectal administration in children.’ Epilepsia, 16,277. 15. Taylor, D. C., Bower, B. D. (1971) ‘Prevention in epileptic disorders.’ Lancet, 2, 1136. 16. Faerar, O., Kastrup, K . W., Nielsen, E. L., Melchior, J. C.. Thorn, I. (1972) ‘Successful prophylaxis of febrile convulsions with phenobarbital.’ Epilvpsia, 13, 279. 17. Thorn, I. (1975) ‘A controlled study of prophylactic long-term treatment of febrile convulsions with phenoharbital.’ 4 c f a Nerirologica Scandinuvica, 52, Suppl. 60.67. 18. Wallace. S. J. ( 1975) ‘Continuous prophylactic anticonvulsants in selected children with febrile convulsions.’ Acta Neurologica Scandinmica, 52, Suppl. 60, 62. 19. Kempe. C . H., Helfer, R. E. (Eds.) (1972) Helping the Battered Child and Hi.r Fam i I ~ ~Philadelphia: . J. B. Lippincott. 20. Mac Keith, R. (1974) ‘Speculations on non-accidental injury as a cause of chronic brain disorder.’ Developmental Medicine and Child Neurology, 16, 421. 21. Hagberg, B., Olow, I, Hagberg, G . (1973) ‘Decreasing incidence of low-birthweight diplegia. An achievement of modern neonatal care.’ Act0 Paediatrica Scandinmica, 62,199. 77 --. Davies, P. A.. Tizard, J. P. M., Bleck, E. E. (1975) ‘Very low birthweight and subsequent neurological defect (with special reference to spastic diplegia).’ DevelopmentalMedicine and Child Nerirolog.y, 17, 3. 23. Couvreur, .I. ( 1971) ‘Prospective study of acquired toxoplasmosis in pregnant women, with special reference to the outcome of the fetus.’In Hentsch, D. (Ed.) Toxoplasmosis.Bern: H. Huber. 24. Elek, S. D., Stern, H. (1974) ‘Development of a vaccine against mental retardation caused by cytoniegalovirus infections in titero.’ Lancet, 1, 15. 25. Alter, M. Hauser, W. A. (Eds.) (1972) The Epidemiology of Epilepsy. NINDS Monogranh Series No. 14. Washington: U S . Department of Health, Education and Welfare.
383
