- Email: [email protected]
Neonatal Seizures
135
seizures could cause brain damage as a result of neuronal necrosis secondary to increased neuronal energy requirement. In some studies neonatal seizures have been associated with increased mortality and morbidity. Eriksson and Zetterstrom3 followed 77 infants with seizures; only 53% had no signs of neurological sequelae, 13% died, 30% had severe psychomotor retardation, and 19% had epilepsy or cerebral palsy. The American National Collaborative Perinatal4 project similarly documented that although 70% of 181 babies with neonatal seizures were normal at 7 years, 13% had cerebral palsy, 19% had an IQ of less than 70, and 20% had epilepsy. In that survey, only 0-5% of all infants had had seizures in the neonatal period, but this group accounted for 21 % of those with moderate or severe cerebral palsy. By contrast, only 0-3% of neurologically intact infants had had seizures. Infants with neonatal seizures were 55-70 times more likely to have severe cerebral palsy and 18 times more likely to have epilepsy than those without seizures. Early-onset seizures were associated with the highest mortality, but the number of days of seizure activity was an important predictor of neurological impairment (cerebral palsy and mental retardation). The nature and severity of the underlying cerebral lesion appear to be the main determinants of the frequency and duration of associated seizure activity and subsequent neurological outcome of the infant. Neonatal seizures may be due to metabolic disturbances, intracerebral birth injuries, ischaemic hypoxic encephalopathy, central nervous system infection or malformation, or withdrawal of maternal drugs.5 In preterm infants, intraventricular haemorrhage and periventricular leucomalacia are also common causes. Eriksson and Zetterstrom3 showed that in full-term infants the most common cause was perinatal hypoxia (48% of 77 cases); infection, hypoglycaemia, and hypocalcaemia each accounted for 12% of seizures. Seizures caused by asphyxia had the worst prognosis, with neurological complications and seizures at follow-up in 85% of patients, whereas those due to hypocalcaemia and hypoglycaemia had a good prognosis if treated promptly. Several varieties of neonatal seizures can be distinguished by their clinical characteristics, but classification according to clinical manifestations is of little importance because it does not relate to cause, prognosis, or therapy. Moreover, detection of neonatal seizures by clinical observation is difficult, because newborn babies seldom have wellorganised symmetrical generalised tonic clonic convulsions. Seizure manifestation in the newborn period may include abnormal movements or alteration in tone in the trunk or extremities; facial, oral, lingual, or ocular movements, and respiratory manifestations. The relative maturity in newborn babies of the temporal lobe compared with the cortex explains the high frequency of temporal manifestations.
Repeated
Neonatal Seizures THE frequency of neonatal seizures-previously said to be between 0-5 and 1.4%-is uncertain because many such episodes are difficult to recognise in newborn babies and non-epileptic events may be confused with seizures. Statistics also vary with the population studied: 3 % of babies admitted to neonatal intensive care facilities have seizuresl and, if only high-risk admissions are considered, the frequency may be even higher.2 25% of infants with congenital malformations of the central nervous system, birth asphyxia, respiratory distress, sepsis, metabolic disturbance, or evidence of intracranial haemorrhage, or leucomalacia detected by cranial ultrasonography were shown to have seizures.2 These data were collected by continuous monitoring. In view of this very high frequency and the large proportion of seizures without clinical manifestations (42%), continuous monitoring of all high-risk patients in neonatal units might seem sensible. To justify such an approach it would be necessary to show that neonatal seizures lead to serious neurological morbidity, that continuous monitoring yields the most accurate data, and that safe, effective anticonvulsant therapy is available. Seizure activity in the immediate postnatal period, a time of active myelination and continuing cell division, may lead to a reduction in DNA content and number of brain cells.
1. Ment
LR, Freedman RM, Ehrenkranz RA.Neonates with seizures attributable to perinatal complications. Am J Dis Child 1982; 136: 548-50. 2. Connell J, Oozeer R, de Vries L, Dubowitz LMS, Dubowitz V.Continuous EEG monitoring for neonatal seizures: diagnostic and prognostic considerations.Arch Du Child 1989; 64: 452-58.
The abnormal summations of neuronal electrical discharges characteristic of seizures are readily detectable by a standard electroencephalogram (EEG), which enables correlation of clinical manifestations with paroxysmal electrical discharge.
3. Eriksson M, Zetterstrom R. Neonatal convulsions. Acta Paed Scand 1979; 68: 807-11. 4. Holden KR, Mellits ED, Freeman JM. Neonatal seizures I. Correlation of prenatal and perinatal events with outcome. Pediatrics 1982; 70: 165-76. 5. Rose AL, Lombroso CT. A study of clinical, pathological and electroencephalographic features in 137 full-term babies with long-term follow-up.Pediatrics 1970; 45: 404-25.
136
EEG abnormalities are aetiologically non-specific, except in pyridoxine deficiency, and are related to the severity of the lesion. The conventional multichannel EEG has clinical value in acute assessment6 and is a well established and sensitive guide to outcome.3 Holmes et al6 claimed that a single EEG recorded in the first 2 weeks has a higher predictive efficiency for outcome than does a neurological examination by a paediatric neurologist or neonatologist. Rose and Lombroso5 showed that 86% of newborn babies with seizures and a normal EEG had normal development at 4 years vs only 7% with a flat or periodic multifocal EEG. Infants with one very abnormal EEG (isoelectric, paroxysmal, or excessively slow background) had some type of neurological complication or had died/ The EEG is also useful in preterm infants: deterioration in the EEG may anticipate the ultrasound diagnosis of intraventricular haemorrhage8,9 and be an early indication of periventricular leucomalacia.10 The severity of the EEG abnormality is proportional to the severity of the ultrasound abnormality, subcortical leucomalacia is associated with maximum background depression and periventricular cysts with lesser degrees of
abnormality." Standard EEGs are often subject to electrical interference in neonatal intensive care units because of surrounding electronic equipment, and may be affected by spontaneous movements and by nursing and medical procedures. The recorders are large and may obscure access to the infant, and the recordings require application of multiple electrodes, which may be impractical in a small sick preterm infant intolerant of handling. Yet for prognostic purposes the initial EEG should be recorded within 10 days, because many EEG abnormalities will have resolved after that time.12 In some babies frequent or even continuous monitoring for ictal activity may be desirable, because they may have persistent or recurrent seizures and clinical manifestations may be masked by paralysing drugs given to facilitate mechanical ventilation. To meet such needs, monitors have been devised that provide continuous EEG recording within the neonatal intensive care unit. One such system is the ’Medilog’(Oxford Medical Systems), which allocates
6. Holmes G, Rowe J, Hafford J, Schmidt R, Testa M, Zimmerman A. Prognostic value of the EEG in neonatal asphyxia. Electroencephalogr Clin Neurophysiol 1982; 53: 60-72. 7. Tharp B, Cukier F, Monod N. The prognostic value of the electroencephalogram in premature infants. Electroencephalogr Clin Neurophysiol 1981; 51: 219-36. 8. Clancy RR, Tharp BR, Enzman D. EEG in premature infants with intraventricular haemorrhage. Neurology 1984; 34: 583-90. 9. Lacey DJ, Topper WH, Buckwald S, Zom WA, Berger D Preterm and very low birthweight neonates: relationship of EEG to intracranial haemorrhage, perinatal complications and developmental outcome. Neurology 1986; 34: 1084-87. 10. Marret S, Paraain D, Samson-Dollfus D, Jeannot E, Fessard C Positive rolandic sharp waves and periventricular leukomalacia in the newborn. Neuropediatrics 1986; 17: 199-202. 11. Connell JA, Oozeer RC, Dubowitz V Continuous 4-channel EEG monitoring a guide to interpretation, with normal values, in preterm infants Neuropediatrics 1987; 18: 138-45. 12. Monod N, Dreyfus-Brisac C, Sfaelleo Z Despitage et prognostic de l’état de mal neno-natal d’après l’étude de 150 cas. Arch Francais Pediatr 1969; 26: 1085-102.
channels to EEG and one to electrocardiographic recording, while the fourth is used for monitoring respiration or as an event marker. This system is light, compact, and battery driven, and the short distance between the electrodes and preamplifiers minimises electrical interference. Cerebral function monitoring (CFM) has also been used for a similar purpose in neonatal intensive care units, its signal is derived from a single pair of parietal electrodes and, unlike the medilog, a processed EEG signal is produced continuously. Both monitors can distinguish intermittent periods of low amplitude discontinuous activity (a common feature of neonatal EEGs) and detect frequency changes. In addition, the medilog, with two EEG channels, can assess interhemispheric symmetry, whereas the CFM, with only one channel cannot lateralise and is also less reliable in detecting short, less organised seizures or those with a slow frequency because it incorporates a low-frequency filter. Data provided by both the medilog and the CFM systems are usually sufficient to fulfil the prognostic role already shown by the standard EEG recordings, being prognostically significant in 79% of 43 infants who either died or had serious neurological impairment.2 Bjerre et al13 compared CFM with conventional EEGs and found agreement in background and ictal paroxysmal activity in 35 of 39 infants. A persistent discontinuous CFM was associated with abnormal outcome, 15 of 18 dying and 3 having abnormal neurological findings.13 Archbald and colleagues14 confirmed the accuracy of CFM: 18 of 20 infants with normal traces in their series had no deficit at follow-up compared with 8 infants with a low voltage pattern who died. Continuous monitoring has also shown a high frequency of seizures without clinical manifestations among high-risk infants2,15,16 and those ventilated and paralysed.17 Connell et a!/ who evaluated continuous EEG recording in 275 full-term and preterm infants, prospectively observed that by comparison with EEG seizures with clinical manifestations, EEG seizures without such manifestations were equally associated with cerebral lesions and were equally resistant to treatment. 18 Standard EEGs also provide data about localisation of seizure activity and detailed information about sleep states and so cannot totally be replaced. It has been two
Bjerre I, Hellstrom-Westas L, Rosen I, Swenningsen N. Monitoring of cerebral function after severe asphyxia m infancy. Arch Dis Child 1983; 58: 997-1002. 14. Archbald F, Verma UL, Tejam NA, Handweiker SM. Cerebral function monitor in the neonate: birth asphyxia. Dev Med Child Neurol 1984; 26: 162-68. 15. Eyre JA, Oozeer R, Wilkinson AR. Diagnosis of neonatal seizure by continuous recording and rapid analysis of the electroencephalogram. Arch Dis Child 1983; 58: 13.
785-90. 16.
Bridges SL, Ebersole JS, Ment LR, Ehrenkranz RA, Silva CG. Cassette electroencephalography in the evaluation of neonatal seizures. Arch Neurol 1986,
17.
Eyre JA, Oozeer R, Wilkinson AR. Continuous electroencephalographic recordings to detect seizures in paralysed newboms. Br Med J 1983; 286: 1017-18. Connell J, Oozeer RC, de Vnes L, Dubowitz LMS, Dubowitz V. Clinical and EEG response to anticonvulsants in neonatal seizures. Arch Dis Child 1989; 64: 459-64.
43: 49-51.
18
137
that both types of monitoring should be used. Prospective continuous monitoring might be restricted to the highest risk period for seizures; a positive finding with such monitoring could be used as an indication for a standard EEG.2 Postnatal age could be used as a guide since most neonatal seizures occur in the first 3 days of life; 23% begin in the first 12 hours, 19% in the second 12 hours, 65% within the first 2 days, and only 13% after the second week.s High-risk groups would include infants who had had an acute collapse, babies less than 32 weeks’ gestational age, and those being mechanically ventilated.l’ The most important function of EEG recordings is to detect seizures to indicate the need for therapy, so before even limited continuous monitoring can be recommended safe effective therapy must be available. Sadly, this cannot be guaranteed. There are several anticonvulsants for treatment of neonatal seizures, but they may be of only limited benefit18,19 and all have side-effects.2O-24 The efficacy of four anticonvulsants was compared in 55 infants, 31 of whom received treatment with anticonvulsants.18 The results were disappointing: only 2 of 31 had a complete (clinical and EEG) response and a further 8 showed a clinical but not an EEG response to phenobarbitone. Preterm infants with severe haemorrhage or ischaemic lesions and full-term infants with hypoxic encephalopathy responded poorly. The 27 infants (7 untreated) with pronounced EEG abnormalities had a poor outcome-death, or survival with severe neurological impairment-irrespective of treatment. The two aims of anticonvulsant treatment-to arrest seizure activity and to prevent recurrenceinfluence the choice of drugs, because some agents are only useful acutely. Thus intravenous diazepam terminates seizures but cannot be used for long-term therapy since levels are not maintained for more than 30 min. By contrast, phenobarbitone will prevent seizures in infants with severe asphyxia; when given within 60 min of a delivery complicated by asphyxia, 57% of phenobarbitone-treated infants had convulsions vs 87% of controls.25 Phenobarbitone has been recommended as the drug of choice for neonatal seizures,26 but this proposal is not supported by new evidence from Rochefort and Wilkinson.19 These
suggested
19 Rochefort
MJ, Wilkinson AR. The safety and efficacy of alternative anticonvulsant regimes to control newborn seizures. Early Hum Dev (in press) 20 Diaz J, Schain RJ, Bailey BG. Phenobarbital-induced brain growth retardation in artificially reared rat pups. Biol Neonate 1977; 32: 77-82. 21 Diaz J, Schain RJ. Phenobarbital: effects of long-term administration on behaviour and brain of artificially reared rats Science 1978; 199: 90-91. 22 Selhorst JB, Kaupman B, Horwitz JJ. Diphenylhydantoin-induced cerebellar degeneration. Arch Neurol 1972; 27: 453-55. 23. Swaimann KF, Neale EA, Schner BK, et al. Toxic effect of phenytoin on developing cortical neurones in culture. Ann Neurol 1983; 13: 48-52. 24. Schiff D, Chan G, Stem L. Drug combinations and displacement of bilirubin from albumin Pediatrics 1971; 48: 139-41. 25. Svenningsen NW, Blennow G, Lindroth M, Gaddlin PO, Ahlstrom H. Brain orientated intensive care treatment in severe neonatal asphyxia. Arch Dis Child
1982, 57: 176-83. 26. Dekharghani F, Sarnat HB. Neonatal seizures. Topics in neonatal York. Grune and Stratton, 1984: 209-32.
neurology. New
anticonvulsants four compared (phenobarbitone, phenytoin, clonazepam, and sodium valproate) in a randomised controlled trial and found phenytoin to be the most effective. All the drugs had side-effects such as deleterious changes in heart rate, blood pressure, respiratory rate, and
workers
transcutaneous
oxygen levels.
The dose regimen also influences the efficacy and safety of the anticonvulsant. To improve the efficacy, a therapeutic concentration of the drug should be attained as soon as possible. Only if seizure control is not achieved should additional forms of therapy be considered. The loading dose must be sufficient to achieve a prompt therapeutic level; small repeated doses, resulting in only a gradual approach to the steady state, should be avoided.2’ Loading doses of 30 mg/kg of phenobarbitone have been given without any adverse short-term effects,28 but monitoring of drug levels subsequently becomes very important. Maintenance therapy, even with a dose of 5 mg/kg of phenobarbitone, leads to very high levels in some infants;29 this response may be related to the very long half-life of the drug (up to 148 h) in severely
asphyxiated babies.28 There have been no large controlled clinical studies to determine the most appropriate duration of therapy. Gillam et al30 suggested that long-term anticonvulsants beyond the neonatal period are unnecessary if the infant has ceased convulsing and is neurologically intact, whereas others adopt the more cautious approach of 3-6 months’ maintenance therapy. The duration of anticonvulsant therapy partly depends on the aetiology of the seizures and therefore the risk of recurrence. Newborn babies with cerebral malformations have the highest risk of recurrence-up to 80%-followed by those with meningitis and hypoxic cerebral insults. 31 Subsequent neurological development, the persistence of neurological defects, and the evolution of the EEG also aid decisions about duration of treatment. Infants with neurological or EEG abnormalities at 3 to 6 months of age are at high risk of recurrent seizures. Randomised controlled trials to determine the safest and most effective anticonvulsant and duration of therapy are urgently needed. Only after such studies have been completed can the place of continuous monitoring be determined accurately. Meanwhile, severely asphyxiated infants who require paralysis to facilitate mechanical ventilation seem obvious candidates.
27. Jailing B. Plasma concentrations of phenobarbital in the treatment of seizures m newborns. Acta Paediatr Scand 1975; 64: 514-24. 28. Staudt F, Scholl ML, Coen RW, Bickford RB. Phenobarbital therapy in neonatal seizures and the prognostic value of the EEG. Neuropediatrics 1982; 13: 24-33. 29. Donn SM, Grasela TH, Pharm D, Goldstein GW. Safety of a higher loading dose of phenobarbital m the term newborn. Pediatrics 1985; 75: 1061-65. 30. Gillam GL. Convulsions following birth asphyxia/birth trauma: are long term anticonvulsants necessary? Aust Pediatr J 1982; 18: 90-91. 31. Wantanabe K, Kuroyanagi M, Hara K Neonatal seizures and subsequent epilepsy. Brain Dev 1982; 4: 341-46.
seizures could cause brain damage as a result of neuronal necrosis secondary to increased neuronal energy requirement. In some studies neonatal seizures have been associated with increased mortality and morbidity. Eriksson and Zetterstrom3 followed 77 infants with seizures; only 53% had no signs of neurological sequelae, 13% died, 30% had severe psychomotor retardation, and 19% had epilepsy or cerebral palsy. The American National Collaborative Perinatal4 project similarly documented that although 70% of 181 babies with neonatal seizures were normal at 7 years, 13% had cerebral palsy, 19% had an IQ of less than 70, and 20% had epilepsy. In that survey, only 0-5% of all infants had had seizures in the neonatal period, but this group accounted for 21 % of those with moderate or severe cerebral palsy. By contrast, only 0-3% of neurologically intact infants had had seizures. Infants with neonatal seizures were 55-70 times more likely to have severe cerebral palsy and 18 times more likely to have epilepsy than those without seizures. Early-onset seizures were associated with the highest mortality, but the number of days of seizure activity was an important predictor of neurological impairment (cerebral palsy and mental retardation). The nature and severity of the underlying cerebral lesion appear to be the main determinants of the frequency and duration of associated seizure activity and subsequent neurological outcome of the infant. Neonatal seizures may be due to metabolic disturbances, intracerebral birth injuries, ischaemic hypoxic encephalopathy, central nervous system infection or malformation, or withdrawal of maternal drugs.5 In preterm infants, intraventricular haemorrhage and periventricular leucomalacia are also common causes. Eriksson and Zetterstrom3 showed that in full-term infants the most common cause was perinatal hypoxia (48% of 77 cases); infection, hypoglycaemia, and hypocalcaemia each accounted for 12% of seizures. Seizures caused by asphyxia had the worst prognosis, with neurological complications and seizures at follow-up in 85% of patients, whereas those due to hypocalcaemia and hypoglycaemia had a good prognosis if treated promptly. Several varieties of neonatal seizures can be distinguished by their clinical characteristics, but classification according to clinical manifestations is of little importance because it does not relate to cause, prognosis, or therapy. Moreover, detection of neonatal seizures by clinical observation is difficult, because newborn babies seldom have wellorganised symmetrical generalised tonic clonic convulsions. Seizure manifestation in the newborn period may include abnormal movements or alteration in tone in the trunk or extremities; facial, oral, lingual, or ocular movements, and respiratory manifestations. The relative maturity in newborn babies of the temporal lobe compared with the cortex explains the high frequency of temporal manifestations.
Repeated
Neonatal Seizures THE frequency of neonatal seizures-previously said to be between 0-5 and 1.4%-is uncertain because many such episodes are difficult to recognise in newborn babies and non-epileptic events may be confused with seizures. Statistics also vary with the population studied: 3 % of babies admitted to neonatal intensive care facilities have seizuresl and, if only high-risk admissions are considered, the frequency may be even higher.2 25% of infants with congenital malformations of the central nervous system, birth asphyxia, respiratory distress, sepsis, metabolic disturbance, or evidence of intracranial haemorrhage, or leucomalacia detected by cranial ultrasonography were shown to have seizures.2 These data were collected by continuous monitoring. In view of this very high frequency and the large proportion of seizures without clinical manifestations (42%), continuous monitoring of all high-risk patients in neonatal units might seem sensible. To justify such an approach it would be necessary to show that neonatal seizures lead to serious neurological morbidity, that continuous monitoring yields the most accurate data, and that safe, effective anticonvulsant therapy is available. Seizure activity in the immediate postnatal period, a time of active myelination and continuing cell division, may lead to a reduction in DNA content and number of brain cells.
1. Ment
LR, Freedman RM, Ehrenkranz RA.Neonates with seizures attributable to perinatal complications. Am J Dis Child 1982; 136: 548-50. 2. Connell J, Oozeer R, de Vries L, Dubowitz LMS, Dubowitz V.Continuous EEG monitoring for neonatal seizures: diagnostic and prognostic considerations.Arch Du Child 1989; 64: 452-58.
The abnormal summations of neuronal electrical discharges characteristic of seizures are readily detectable by a standard electroencephalogram (EEG), which enables correlation of clinical manifestations with paroxysmal electrical discharge.
3. Eriksson M, Zetterstrom R. Neonatal convulsions. Acta Paed Scand 1979; 68: 807-11. 4. Holden KR, Mellits ED, Freeman JM. Neonatal seizures I. Correlation of prenatal and perinatal events with outcome. Pediatrics 1982; 70: 165-76. 5. Rose AL, Lombroso CT. A study of clinical, pathological and electroencephalographic features in 137 full-term babies with long-term follow-up.Pediatrics 1970; 45: 404-25.
136
EEG abnormalities are aetiologically non-specific, except in pyridoxine deficiency, and are related to the severity of the lesion. The conventional multichannel EEG has clinical value in acute assessment6 and is a well established and sensitive guide to outcome.3 Holmes et al6 claimed that a single EEG recorded in the first 2 weeks has a higher predictive efficiency for outcome than does a neurological examination by a paediatric neurologist or neonatologist. Rose and Lombroso5 showed that 86% of newborn babies with seizures and a normal EEG had normal development at 4 years vs only 7% with a flat or periodic multifocal EEG. Infants with one very abnormal EEG (isoelectric, paroxysmal, or excessively slow background) had some type of neurological complication or had died/ The EEG is also useful in preterm infants: deterioration in the EEG may anticipate the ultrasound diagnosis of intraventricular haemorrhage8,9 and be an early indication of periventricular leucomalacia.10 The severity of the EEG abnormality is proportional to the severity of the ultrasound abnormality, subcortical leucomalacia is associated with maximum background depression and periventricular cysts with lesser degrees of
abnormality." Standard EEGs are often subject to electrical interference in neonatal intensive care units because of surrounding electronic equipment, and may be affected by spontaneous movements and by nursing and medical procedures. The recorders are large and may obscure access to the infant, and the recordings require application of multiple electrodes, which may be impractical in a small sick preterm infant intolerant of handling. Yet for prognostic purposes the initial EEG should be recorded within 10 days, because many EEG abnormalities will have resolved after that time.12 In some babies frequent or even continuous monitoring for ictal activity may be desirable, because they may have persistent or recurrent seizures and clinical manifestations may be masked by paralysing drugs given to facilitate mechanical ventilation. To meet such needs, monitors have been devised that provide continuous EEG recording within the neonatal intensive care unit. One such system is the ’Medilog’(Oxford Medical Systems), which allocates
6. Holmes G, Rowe J, Hafford J, Schmidt R, Testa M, Zimmerman A. Prognostic value of the EEG in neonatal asphyxia. Electroencephalogr Clin Neurophysiol 1982; 53: 60-72. 7. Tharp B, Cukier F, Monod N. The prognostic value of the electroencephalogram in premature infants. Electroencephalogr Clin Neurophysiol 1981; 51: 219-36. 8. Clancy RR, Tharp BR, Enzman D. EEG in premature infants with intraventricular haemorrhage. Neurology 1984; 34: 583-90. 9. Lacey DJ, Topper WH, Buckwald S, Zom WA, Berger D Preterm and very low birthweight neonates: relationship of EEG to intracranial haemorrhage, perinatal complications and developmental outcome. Neurology 1986; 34: 1084-87. 10. Marret S, Paraain D, Samson-Dollfus D, Jeannot E, Fessard C Positive rolandic sharp waves and periventricular leukomalacia in the newborn. Neuropediatrics 1986; 17: 199-202. 11. Connell JA, Oozeer RC, Dubowitz V Continuous 4-channel EEG monitoring a guide to interpretation, with normal values, in preterm infants Neuropediatrics 1987; 18: 138-45. 12. Monod N, Dreyfus-Brisac C, Sfaelleo Z Despitage et prognostic de l’état de mal neno-natal d’après l’étude de 150 cas. Arch Francais Pediatr 1969; 26: 1085-102.
channels to EEG and one to electrocardiographic recording, while the fourth is used for monitoring respiration or as an event marker. This system is light, compact, and battery driven, and the short distance between the electrodes and preamplifiers minimises electrical interference. Cerebral function monitoring (CFM) has also been used for a similar purpose in neonatal intensive care units, its signal is derived from a single pair of parietal electrodes and, unlike the medilog, a processed EEG signal is produced continuously. Both monitors can distinguish intermittent periods of low amplitude discontinuous activity (a common feature of neonatal EEGs) and detect frequency changes. In addition, the medilog, with two EEG channels, can assess interhemispheric symmetry, whereas the CFM, with only one channel cannot lateralise and is also less reliable in detecting short, less organised seizures or those with a slow frequency because it incorporates a low-frequency filter. Data provided by both the medilog and the CFM systems are usually sufficient to fulfil the prognostic role already shown by the standard EEG recordings, being prognostically significant in 79% of 43 infants who either died or had serious neurological impairment.2 Bjerre et al13 compared CFM with conventional EEGs and found agreement in background and ictal paroxysmal activity in 35 of 39 infants. A persistent discontinuous CFM was associated with abnormal outcome, 15 of 18 dying and 3 having abnormal neurological findings.13 Archbald and colleagues14 confirmed the accuracy of CFM: 18 of 20 infants with normal traces in their series had no deficit at follow-up compared with 8 infants with a low voltage pattern who died. Continuous monitoring has also shown a high frequency of seizures without clinical manifestations among high-risk infants2,15,16 and those ventilated and paralysed.17 Connell et a!/ who evaluated continuous EEG recording in 275 full-term and preterm infants, prospectively observed that by comparison with EEG seizures with clinical manifestations, EEG seizures without such manifestations were equally associated with cerebral lesions and were equally resistant to treatment. 18 Standard EEGs also provide data about localisation of seizure activity and detailed information about sleep states and so cannot totally be replaced. It has been two
Bjerre I, Hellstrom-Westas L, Rosen I, Swenningsen N. Monitoring of cerebral function after severe asphyxia m infancy. Arch Dis Child 1983; 58: 997-1002. 14. Archbald F, Verma UL, Tejam NA, Handweiker SM. Cerebral function monitor in the neonate: birth asphyxia. Dev Med Child Neurol 1984; 26: 162-68. 15. Eyre JA, Oozeer R, Wilkinson AR. Diagnosis of neonatal seizure by continuous recording and rapid analysis of the electroencephalogram. Arch Dis Child 1983; 58: 13.
785-90. 16.
Bridges SL, Ebersole JS, Ment LR, Ehrenkranz RA, Silva CG. Cassette electroencephalography in the evaluation of neonatal seizures. Arch Neurol 1986,
17.
Eyre JA, Oozeer R, Wilkinson AR. Continuous electroencephalographic recordings to detect seizures in paralysed newboms. Br Med J 1983; 286: 1017-18. Connell J, Oozeer RC, de Vnes L, Dubowitz LMS, Dubowitz V. Clinical and EEG response to anticonvulsants in neonatal seizures. Arch Dis Child 1989; 64: 459-64.
43: 49-51.
18
137
that both types of monitoring should be used. Prospective continuous monitoring might be restricted to the highest risk period for seizures; a positive finding with such monitoring could be used as an indication for a standard EEG.2 Postnatal age could be used as a guide since most neonatal seizures occur in the first 3 days of life; 23% begin in the first 12 hours, 19% in the second 12 hours, 65% within the first 2 days, and only 13% after the second week.s High-risk groups would include infants who had had an acute collapse, babies less than 32 weeks’ gestational age, and those being mechanically ventilated.l’ The most important function of EEG recordings is to detect seizures to indicate the need for therapy, so before even limited continuous monitoring can be recommended safe effective therapy must be available. Sadly, this cannot be guaranteed. There are several anticonvulsants for treatment of neonatal seizures, but they may be of only limited benefit18,19 and all have side-effects.2O-24 The efficacy of four anticonvulsants was compared in 55 infants, 31 of whom received treatment with anticonvulsants.18 The results were disappointing: only 2 of 31 had a complete (clinical and EEG) response and a further 8 showed a clinical but not an EEG response to phenobarbitone. Preterm infants with severe haemorrhage or ischaemic lesions and full-term infants with hypoxic encephalopathy responded poorly. The 27 infants (7 untreated) with pronounced EEG abnormalities had a poor outcome-death, or survival with severe neurological impairment-irrespective of treatment. The two aims of anticonvulsant treatment-to arrest seizure activity and to prevent recurrenceinfluence the choice of drugs, because some agents are only useful acutely. Thus intravenous diazepam terminates seizures but cannot be used for long-term therapy since levels are not maintained for more than 30 min. By contrast, phenobarbitone will prevent seizures in infants with severe asphyxia; when given within 60 min of a delivery complicated by asphyxia, 57% of phenobarbitone-treated infants had convulsions vs 87% of controls.25 Phenobarbitone has been recommended as the drug of choice for neonatal seizures,26 but this proposal is not supported by new evidence from Rochefort and Wilkinson.19 These
suggested
19 Rochefort
MJ, Wilkinson AR. The safety and efficacy of alternative anticonvulsant regimes to control newborn seizures. Early Hum Dev (in press) 20 Diaz J, Schain RJ, Bailey BG. Phenobarbital-induced brain growth retardation in artificially reared rat pups. Biol Neonate 1977; 32: 77-82. 21 Diaz J, Schain RJ. Phenobarbital: effects of long-term administration on behaviour and brain of artificially reared rats Science 1978; 199: 90-91. 22 Selhorst JB, Kaupman B, Horwitz JJ. Diphenylhydantoin-induced cerebellar degeneration. Arch Neurol 1972; 27: 453-55. 23. Swaimann KF, Neale EA, Schner BK, et al. Toxic effect of phenytoin on developing cortical neurones in culture. Ann Neurol 1983; 13: 48-52. 24. Schiff D, Chan G, Stem L. Drug combinations and displacement of bilirubin from albumin Pediatrics 1971; 48: 139-41. 25. Svenningsen NW, Blennow G, Lindroth M, Gaddlin PO, Ahlstrom H. Brain orientated intensive care treatment in severe neonatal asphyxia. Arch Dis Child
1982, 57: 176-83. 26. Dekharghani F, Sarnat HB. Neonatal seizures. Topics in neonatal York. Grune and Stratton, 1984: 209-32.
neurology. New
anticonvulsants four compared (phenobarbitone, phenytoin, clonazepam, and sodium valproate) in a randomised controlled trial and found phenytoin to be the most effective. All the drugs had side-effects such as deleterious changes in heart rate, blood pressure, respiratory rate, and
workers
transcutaneous
oxygen levels.
The dose regimen also influences the efficacy and safety of the anticonvulsant. To improve the efficacy, a therapeutic concentration of the drug should be attained as soon as possible. Only if seizure control is not achieved should additional forms of therapy be considered. The loading dose must be sufficient to achieve a prompt therapeutic level; small repeated doses, resulting in only a gradual approach to the steady state, should be avoided.2’ Loading doses of 30 mg/kg of phenobarbitone have been given without any adverse short-term effects,28 but monitoring of drug levels subsequently becomes very important. Maintenance therapy, even with a dose of 5 mg/kg of phenobarbitone, leads to very high levels in some infants;29 this response may be related to the very long half-life of the drug (up to 148 h) in severely
asphyxiated babies.28 There have been no large controlled clinical studies to determine the most appropriate duration of therapy. Gillam et al30 suggested that long-term anticonvulsants beyond the neonatal period are unnecessary if the infant has ceased convulsing and is neurologically intact, whereas others adopt the more cautious approach of 3-6 months’ maintenance therapy. The duration of anticonvulsant therapy partly depends on the aetiology of the seizures and therefore the risk of recurrence. Newborn babies with cerebral malformations have the highest risk of recurrence-up to 80%-followed by those with meningitis and hypoxic cerebral insults. 31 Subsequent neurological development, the persistence of neurological defects, and the evolution of the EEG also aid decisions about duration of treatment. Infants with neurological or EEG abnormalities at 3 to 6 months of age are at high risk of recurrent seizures. Randomised controlled trials to determine the safest and most effective anticonvulsant and duration of therapy are urgently needed. Only after such studies have been completed can the place of continuous monitoring be determined accurately. Meanwhile, severely asphyxiated infants who require paralysis to facilitate mechanical ventilation seem obvious candidates.
27. Jailing B. Plasma concentrations of phenobarbital in the treatment of seizures m newborns. Acta Paediatr Scand 1975; 64: 514-24. 28. Staudt F, Scholl ML, Coen RW, Bickford RB. Phenobarbital therapy in neonatal seizures and the prognostic value of the EEG. Neuropediatrics 1982; 13: 24-33. 29. Donn SM, Grasela TH, Pharm D, Goldstein GW. Safety of a higher loading dose of phenobarbital m the term newborn. Pediatrics 1985; 75: 1061-65. 30. Gillam GL. Convulsions following birth asphyxia/birth trauma: are long term anticonvulsants necessary? Aust Pediatr J 1982; 18: 90-91. 31. Wantanabe K, Kuroyanagi M, Hara K Neonatal seizures and subsequent epilepsy. Brain Dev 1982; 4: 341-46.