Neonatal Convulsions: Aetiology, Late Neonatal Status and Long-Term Outcome

Develop. Med. Child Neurol. 1978, 20, 143-1 58

Neonatal Convulsions: Aetiology, Late Neonatal Status and Long-Term Outcome

Jennifer Dennis

Introduction This is an interim report on a continuing

prospective study of 50 children who convulsed during the first 28 days of life. The study was started in order to evaluate the long-term outcome of such seizures, to see what early factors might be of prognostic significance, and to see how early in life it was possible to predict outcome in individuals. The children are now four to six years old. This is thus the longest contemporary prospective follow-up of this condition. This paper describes the quality of outcome in individuals and considers some criteria by which reason- ably valid predictions of outcome can be made very early in life.

Patients and Methods Choice of Babies

Fifty-six consecutive babies with neonatal convulsions were identified between January 1970 and July 1972. The criteria for inclusion in the study was that babies should present in any one of six Children’s Units within the then ‘United Oxford Hospitals’ before the age of 29 days, having had one or more convulsions. Babies born outside the main teaching units were included, and Table I shows where they were born. Any event thought

to be a convulsion by a person experienced in the care of newborns was considered to be so. These included tonic and clonic seizures and a variety of abnormal behavioural states. Checks were made throughout the 24-year period, which indicated that the report rate was very high. Early discharge from the Maternity Units was prevalent in 1970 and 1971, but enquiry from local family practitioners indicated almost no inclination to treat neonatal seizures at home. The study sample seems then to be a truly rep- resentative, consecutive group.

The study was interrupted for a short time, which prevented the follow-up of six babies born consecutively between September and December 1970. Know- ledge of these six babies therefore is used only to establish over-all and seasonal incidence figures. The remaining 50 babies form the main sample.

TABLE I Place of birth of 56 infants studied

I

Teaching hospital obstetric units Other district general hospitals GP units and cottage hospitals Home

Registrar, Human Development Research Unit, Park Hospital for Children, Old Road, Headington, Oxford.

143

DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1978, 20

Thirty-two of the babies weighed between 2500 and 4000g at birth, five weighed more than 4000g and 13 less than 2500g. Of the low-birthweight babies (< 2500g), two weighed less than 1500g. There were 10 preterm babies (< 37 weeks gestation). Only one of these was less than 30 weeks and this is the only child in the study who was subsequently lost to follow-up. Gesta- tion for one baby was more than 42 weeks. Two were large for dates (+ ~ S D from mean), four were small for dates (- 2SD from mean) and two had other evidence of intra-uterine growth retardation.

Neonatal Observation and Fo/low-up Each baby was seen personally by the

author soon after the first neonatal seizure and then regularly throughout the initial hospital admission. Thereafter follow-up assessments were made personally in the child’s own home at age six weeks, three months, six months, one year, two years and four years. Follow-up was maintained on all children remaining within the United Kingdom and one child in the United States was assessed at age four years by a colleague.

Neurological examination in the neonatal period mas based on the scheme described by Prechtl and Beintema (1964). In early follow-up examinations, the Denver Developmental Screening Test (Frankenburg et a/. 1970) was followed as a basic protocol but with many additions. At age four and older, in addition to formal neurological examination, Sleigh’s (unpublished) neurodevelopmental screening scheme was followed, and significant items described by Peters et a/. (1975) for the special neurological examination of children with learning disabilities were also sought. Attention was always paid to the quality of a child’s interaction, both with fiiinily members and hith the examiner, and to the way in which he applied himself to the tasks in hand. EEGS were recorded on

most babies at age six weeks, six months, one year and two years. Psychological testing will be carried out on each child at the age of six years.

Antenatal and Perinatal Information Comprehensive antenatal records were

obtained for each mother from both family practitioner’s and hospital records. Perinatal information was usually sought direct from those attending the labour and delivery and those warding the baby, as an adjunct to the information contained in the written records.

Perinatal Practice At the time of this survey there was

close co-operation between obstetricians and baediatricians. Sick and other selected newporns were cared for in a special care baby unit, with its own staff of neonatal paediatricians and nurses. This unit was nevertheless different from the highly tech- nologically-based intensive care unit for newborns which now exists in Oxford.

Data Analysis No detailed analysis of data was

allowed until the youngest child was four years old.

Results Incidence

The incidence of neonatal convulsions among babies born in Oxford hospitals was 4 .2 per lo00 live births. There were 29 boys and 21 girls in the sample of 50.

Outcome Eleven patients died and contact was

lost with one, leaving 38 known survivors in follow-up. These have all been assessed at age four or older. The outcome for the whole group is shown in Table 11.

Neonatal death ( N = 9). Three of these babies were abnormal conceptuses with very limited life expectancy. Three were

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JENNIFER DENNIS

Outcome

Neonatal death Late death Adverse Questionable Normal Lost to follow-up

Case and (sex)

No. of infants

9 2

14 2

22 1

J.R.(M)

F.C.(F)

D.W.(M)

P.M.(F)

D.H.(M)

C.S.(M)

P.G.(M)

E.K.(M)

P.B.(F)

S.C.(F) M.E.(M)

R.J.(M)

S.R.(F)

J.S.(M)

18.0 4 .0

28.0 4 .0

44.0 2 . 0

TABLE I1 Outcome at age four years or older

I

- 5.0

35.0 5.0

55.0 -

I * Surviving the neonatal period.

TABLE 111 Adverse outcome in survivors: range of abnormality

Age when last seen 1yrs:mths)

6 :O

5 :4

4:lO

4:8

4 :6

4:3

4:2

4:2

4:2

4 :O 4 :(?

4 :O

4 :O

4:O

Degree of

handicap

Min.

Mod.

Mod.

Sev.

Min.

Mod.

Mod.

Min.

Min.

Sev. Min.

Min.

Min.

Mod.

Problem

Non-febrile seizures in normal, intelligent boy with no abnormal neurological signs. Maternal history of seizures in childhood.

Pudenz valve, frequent blockage. Infrequent seizures. Mild diplegia. Growth retardation. Normal intelligence.

Seizures. Complicated ophthalmoplegia. Poor laterality for handedness. Mild motor dyspraxia. Highly distractable. Retarded language development. Non-verbal skills appro- priate.*

Moderately severe mixed cerebral palsy. Severe growth retardation. Mute. May be near-normal intelligence.

Fine motor and articulatory dyspraxia. Poor laterality for handedness.

Ophthalmoplegia. Mild ataxia. Growth retardation. Distractable. Verv disorganised and immature. Normal language development. Uneven development of visuo-motor skilk.*-

speech. Verbal IQ 60. Performance IQ 70.* Minimal diplegia. Poor concentration. Disorganised. Slow

Spontaneous-arrest hydrocephalus. Ophthalmoplegia. Poor balance. Bright.

AIternating sursumduction. Poor baIance. Steady disproportion- ate slowing in head Prowth. Probably low-normal intelligence.

Severely subkormal. Spastic quadriplegia. Seizures. Paretic !eft hand. Clumsy right hand. Some gross motor difficulty.

Relative microcephaly. Language delay. Immature. Probably

Gross motor difficulties. Marked fine motor dyspraxia. Over-

Seizures. Mild ataxia of gait. Probably mild global retardation.

-

Poor speech. Immature child.

mild global retardation.

excitable and exhausting. Probably normal intelligence.

No obvious deficit on psychological testing at age 3*.

* Psychological testing before set age of six years.

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preterm babies with intraventricular haemorrhage, two showed gross neurological damage following severe perinatal asphyxia, and one had haemorrhagic adrenal necrosis.

Late death ( N = 2) . A child with the Aicardi syndrome (Dennis and Bower 1972) and a child with a presumed inborn metabolic error died in their second year of life.

Adverse outcoine ( N = 14). This group includes all children with mild, moderate or severe neurological or intellectual deficit. It does not include those with apparently isolated psychiatric or behavioural problems. Table I11 shows the range of abnormality found in these children.

Questionable ( N = 2) . At age four there are two boys who do not appear to function intellectually at a four-year-old level but for whom it seems prudent to reserve judgement, as their nurture has been unusually deviant. One appears to be immature and fails on tasks involving

visuo-spatial and verbal skills, and the second has little speech. Neither shows abnormal neurological signs. The status of these two children should become clear in time.

Lost to follow-up ( N = 1). One child went to the United States immediately on discharge from the neonatal unit and was last to follow-up at that time.

Seizures After the Neonatal Period Of the 40 babies in follow-up who

survived the neonatal period, eight (20 per cent) have so far had seizures after the first month of life. Table IV gives details of these seizures, which are listed in order of age of onset. Two of these children (SS and CF) had severe anomalies and are now dead.

Aetiology The individual biographies and labora-

tory findings for these babies were very diverse. Nevertheless, the data showed that all but five of the group could be

TABLE IV Further seizures occurring after neonatal period

I Mime and

(sex)

S.S.(F)

C.F.(Fj

J.S.(M)

S.C.(F)

I.M.(M)

D.W.(M)

J .R.(M)

F.C.(Fj

Aetiologicu/ category*

F

F

P

P

U

P

P

1

Age at onset Seizrrre type ~~

Continuous from neonatal period 43 wks

8 wks

3 mths

14 mths

18 mths

4 yrs 5 mths

4 yrs 6 mths

Variable, included infantile spasms; persisted until death

Variable, included infantile spasms; ultimately devastating and uncontrollable. Minor motor seizures in bouts; frequent absences; severe prolonged grand ma1 at 9 months. Variable; frequent; included infantile spasms. Single 2-hour grand ma1 with mumps. Very infrequent, very severe prolonged nocturnal grand mal. Left parietal spike focus. Convulsions with fever, now converting at age 6 into cold epilepsy. Infrequent left-sided seizures with no loss of consciousness.

Clinical state

Aicardi syndrome; died aged 15 months. Presumed inborn metabolic error; died aged 2 years. See Table 111.

See Table 111.

Normal child.

See Table 111.

See Table 111.

See Table 111.

~

5; F ..= fetus with a problem; P = fundamentally perinatal; I = postnatal insult; U = unclassified.

146

JENNIFER DENNIS

assigned to one of four wide aetiological categories. These were :

THE FETUS WITH A PROBLEM This is an abnormal conceptus with an

insoluble problem. 10 (20 per cent) of the sample of 50 were assigned to this category and the problems encountered are shown in Table V. There are two distinct subgroups: (a, b) babies with major cerebral or non-cerebral structural anomalies whose fundamental problems were further compounded by seizures ; and (c, d ) babies with metabolic errors or multiple minor aberrations who first signalled their fundamental problem by neonatal seizures. All these babies present irreversible or only partially reversible problems, regardless of the quality of perinatal care.

TABLE V ‘The fetus with a problem’

Problem

(a) Recognised CNS anomaly:

(b) Hypoxia as result of major non-

Aicardi syndrome M yelomeningocele

cerebral malformation TOFt + imperf. anus (P.M.) TOF + Fallot’s TOF + renal dysgenesis

(c) Inborn metabolic error* Multiple minor aberrations: cranio-lacunae + relative

microcephaly (R.J.) Large cavum vergae, odd

dermatoglyphs, visual imperception until 4 months (P.B.)

(d) Bizarre facies, VSDt + other minor stigmata (S.R.)

- No.

2

3

2 3

-_

I lo Total

* An enzyme deficiency was not demonstrate in either case. One child showed inconsistent abnormalities of plasma aminoacids and the possibility of an organic acid disturbance is now being investigated using stored tissue. The other, with intractable hypoglycaemia, bleeding and renal failure was found at autopsy to have massive hepatic fibrosis, as was a subsequent sibling (Scurlock et al., unpublished). tTOF + tracheo-oesophageal fistula; VSD + ven- tricular septa1 defect.

Babies with evidence of intra-uterine growth retardation or with blood-group incompatibilities are not included in this category because, although they present initially as an abnormal conceptus, they do not necessarily present insoluble problems and the quality of perinatal care seems for them to be of paramount importance. They are therefore assigned to the ‘perinatal’ category.

The experience of this study concerning babies in groups (c) and (d) was that the seizures with which they signalled their problem were not necessarily frequent or severe. Clues which raised suspicion that a baby without an obvious major anomaly might nevertheless be a fetus with a problem were: (1) seizures, however mild, for no apparent reason (three babies) (2) babies who seemed much more ill than than expected on the basis of information immediately available (two babies) (3) babies whose seizures were difficult to control (two babies) (4) babies whose seizures quickly relapsed (two babies) Fig. 1 shows that eight of the 10 babies in this category began to convulse in the first week of life. The two with later age of onset had major anomalies and their convulsions, caused by hypoxia, were iatrogenic.

FUNDAMENTAL PERINATAL FACTORS Twenty-two (44 per cent) of the sample

were assigned to this category, in which seizures were caused by problems associated with preterm birth (< 37 weeks gestation), with intra-uterine growth retardation and with perinatal trauma and asphyxia.

Fig. 1 shows that 14 of these 22 babies began their seizures in the first 24 hours and all but two had convulsed before 72 hours. These last two were both severely ill

147


n

~. { 4 - I 6 B ii) i z i i 16 i a 20 22 2 1 26 28

tl > DL\S

Fig. 1. Age at onset of seizures, aetiology and outcome .

preterm babies with multiple problems of survival.

SIMPLE HYPOCALCAEMIC TETANY Twenty-one babies were hypocalcaemic.

These included 10 with early hypocalcaemia associated with other perinatal problems, and 11 who began their seizures after the fourth day. Seven of these 11 (14 per cent of the whole sample) were considered to have simple hypocalcaemic tetany and thus had not caused anxiety during the perinatal period. All were normal birthweight, full-term babies.

The criteria for the definition of hypocalcaemia and hyperphosphataemia in the first seven days were 5 2 SD from the mean levels found by Snodgrass et al. (1973) for babies fed four different feeds, including breast-milk. Definition after the seventh day was by means of a sliding scale, based on the assumption that normal child levels are attained by day 15.

Seizures in this category began between the fifth and 10th days (Fig. 1).

POSTNATAL INFECTION OR INSULT Six (12 per cent) of the sample were in

this category, five of whom began their seizures after the 10th day (Fig. 1). Of these five, three had meningitis, one had overwhelming bronchiolitis, and one had severe gastro-enteritis with hyponatraemia. The sixth baby convulsed on day 1 when he inhaled vomit.

UNCLASSIFIED Five (10 per cent) of the sample whose

seizures began between the second and ninth days (Fig. 1) could not be assigned to one of the above four categories. Among these were three babies for whom no cause could be found for the seizures and two for whom there was a possibility of double coding.

Prediction of Outcome Outcome, as already defined, was con-

sidered in relation to the aetiological categories described, the age of onset of seizures and the neurological status of the baby on discharge from the neonatal unit.

Outcome by aetiology. Fig. 2 shows the different patterns of outcome for the aetiological categories described. The numbers in the 'fetus with a problem' and 'simple hypocalcaemic tetany' groups are too small to allow the rigorous statistical .

148

JENNIFER DENNIS

Group

1 2 3 4

analysis shown in Table VI (expected numbers are shown in brackets). However, the clearly significant result strongly suggests that the pattern of outcome in these two groups is distinctively different from that found in the group of babies whose seizures were due to perinatal factors or postnatal insults.

Outcome by age at onset. The first 28 days were divided into three epochs which showed a different pattern of outcome (Table VII). The differences between the three epochs are not significant when babies with simple hypocalcaemic tetany are excluded.

Predictive value of neonatal discharge assessment. Twenty-eight of the 41 children who survived the neonatal period were given a subjective developmental grading on discharge from the neonatal unit and at

26 61 * O (25.0) 44.0 71 *O

Age at onset of seizures (days)

1-4 (5-10 including SHT*) 5-10 (excluding SHT*) 1 1-28 7

every follow-up examination. This was based on (but sometimes given in spite of) the formal results set down. The grades were (1) definitely normal; (2) questionable but probably normal; (3) questionable, probably damaged; and (4) definitely damaged. Thus, grades 1 and 4 were considered to be certainties, grades 2 and 3 were uncertain. Every baby thought to be definitely normal (11) or definitely damaged ( 5 ) on discharge from the neonatal unit proved to be so at age four or older, by which time the total number of normal children was 14 and the total damaged was also 14. Thus, normality was much more frequently positively identified in the neonatal period than was abnormality. In both cases the neonatal discharge assessment was as accurate or more accurate in predicting status at age four

TABLE VI Medical outcome by aetiology, excluding UnclassiEed group (N = 44)

Fetus Simple Perinatal*

problem tetany postnatal Outcome with hypocalcaemic and Total

Dead or damaged 1 lO(5.7)t I O(4.0) 15 (15.3) 25 I Normal 0 (4.3) 7 (3.0) I 12(11*7) I 19

x2 = 16.83, p < 0.001 * For the uuruose of analvsis. of the two children with auestionable outcome in the ueri- natal group; one has been assigned to the damaged and one to the normal category. t Expected numbers in brackets.

1


than was any other assessment until age two years. Grades 2 and 3 did not correlate with outcome.

Discussion Incidence

The incidence of neonatal convulsions in this series was 4 . 2 per 1000 live births. Edinburgh figures have been given as 14.0 per 1000 live births (Brown et al. 1972), and Keen’s two Manchester series had an incidence of 12.2 per 1000 (Keen and Lee 1973) and 7.1 per lo00 (Keen 1969). The report rate in this present series was high, so it seems that in Oxford between 1970 and 1972 the incidence of neonatal seizures was lower than has been reported in other contemporary UK series.

The incidence of simple hypocalcaemic tetany (14 per cent) among babies with neonatal seizures is particularly low when compared with the two UK series-Edin- burgh 53 per cent (seizures due to primary disturbance of calcium, phosphorus or magnesium metabolism) and Manchester (1973) 40 per cent-but not when considered in relation to figures from North America-Boston 13 per cent (Rose and Lombroso 1970), Toronto 16 per cent (Langevin 1974) and mainland Europe- Gottingen 0 per cent (Schulte 1966), Nice and Marseille 2 per cent (Combes et al. 1975). Seizures caused by simple hypocalcaemia may not be generated at a cortical level (Schulte and Lohrnann 1962), and this could account for the absence of such babies in Schulte’s series in which EEG correlates were sought.

However, the low over-all incidence of neonatal seizures in Oxford as compared with Edinburgh and Manchester is not entirely due to the lower incidence of simple hypocalcaemic tetany in Oxford. The incidence of seizures from other causes is also relatively low in Oxford. The incidences in these two distinct groups will be considered separately.

SEIZURES NOT CAUSED BY SIMPLE HYPOCAL- CAEMIA

This group includes babies whose seizures are due to fundamental anomalies (‘fetus with a probIem’), perinatal problems, postnatal infections and insults, and those in whom the cause is unknown or cannot be classified. In Oxford, among hospital-born babies the incidence of seizures in these categories was 3 . 6 per 1000 live births. The Edinburgh and Manchester figures were 6 . 1 and 7.3 respectively. All three are non-metropolitan urban areas served by teaching hospitals. Significant regional variation in the over-all incidence of the ‘fetus with a problem’ is unlikely, except when an area has a high incidence of some particular congenital anomaly.

The prevalence of perinatal and postnatal problems is related to the quality and availability of perinatal care. In 1970 and 1971, the stillbirth rates of babies delivered by the Oxford division of obstetrics and gynaecology was 8 . 8 and 11.3 per 1000 live births, compared with national figures of 13.0 and 12.4 for the same years, and the neonatal death rates were 8 - 8 and 7 . 4 per lo00 live births, compared with national figures of 12.0 and 11-6. These rates indicate high quality obstetric and perinatal care during the two years, which must certainly have contributed to the low incidence of neonatal convulsions. It is also likely that the lower incidence in Oxford reflects the high biological quality of our local population (Baird 1969).

SIMPLE HYPOCALCAEMIC TETANY There are at least two factors associated

with simple hypocalcaemic tetany : (a) excess phosphate load in the first week of life, and (b) maternal vitamin D deficiency during pregnancy. These factors can operate alone or in combination.

Excess phosphate load. The 1968 ‘epi- demic’ (Baum et al. 1968) of simple hypo-

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JENNIFER DENNIS

calcaemic tetany mainly involved normal- birthweight babies who took large amounts of cows’ milk from birth. This drew attention to the r6le played by high phosphate load in this condition. When the feeding practice of normal-birthweight babies was adjusted, the very high incidence of hypocalcaemic tetany was reduced.

Maternal vitamin D deficiency. It is clear that simple hypocalcaemic tetany occurs in a wider range of babies than those obviously overfed with cows’ milk. Some are breast-fed (Fanconi and Prader 1968) and some show neither excessive oral intake nor excessive weight gain after birth. Watney et al. (1971) studied Asian, European and West Indian mothers in Birmingham and found significant racial differences in the serum calcium levels of their infants on the sixth day. Among their conclusions, they suggested that maternal factors might be important in the genesis of neonatal convulsions secondary to transient hypocalcaemia. Purvis et al. (1973) supported this conclusion when they looked at the deciduous teeth of the children in Brown and colleagues’ 1972 series. They reported changes which they believed to indicate a prolonged disturbance of enamel formation in the three months prior to birth in over half the children who had suffered simple hypocalcaemic tetany. However, this dating of the dental lesions is strongly challenged by Levine and Keen (1974), who conclude that the disturbance of enamel formation found in the teeth of such children is entirely postnatal in origin. Purvis et al. (1973) also found an inverse relationship between the hours of bright sunshine and the incidence of both neonatal tetany and severe enamel hypoplasia three months later. In a further study (Roberts et al. 1973), the mothers of infants with simple hypocalcaemic tetany were found to be significantly older, of higher parity and of lower social-class than the mothers of

B 151

other babies born in the same hospital. More recently, Purvis (personal communication) has shown that simple hypocalcaemic tetany did not occur in the infants of a large group of mothers given vitamin D during pregnancy, while the incidence of the condition in a control group remained unchanged.

The seven babies with simple hypocalcaemic tetany in the present study follow the trends observed in the Edin- burgh group. No babies with this condition were born in the months August to November; mothers over 30 are over- represented; and all are social class 111, IV or V. In Edinburgh and Oxford the adverse effect of overfeeding normal birthweight babies was certainly well recognised at the time of both surveys. The Edinburgh babies were fed an evaporated-milk formula, the Oxford babies a variety of powdered-milk formulae, reflecting their varied source of referral.

Stringent biochemical criteria were set for inclusion in this category in the Oxford study, yet only one baby-thought clinically to have simple hypocalcaemic tetany-was excluded from the category through failing to fulfil them.

A possible explanation of the lower Oxford incidence is that in the third trimester the mothers in this region may be in a state of calcium metabolism which tends to minimise the vulnerability of their infants to situations which enhance the period of unstable calcium homeostasis inherent in the first week of life, so we have few babies at risk for this condition. Our local population is biologically well- endowed. We do have more sunshine than Edinburgh and Manchester-3 per cent more in winter, 22 per cent more in summer-and while the difference is small, it could be significant if mothers tend to be on the brink of vitamin D deficiency in pregnancy. Regional variation in a single dietary factor could be important. What-


ever the detail, the striking regional variations in the incidence of this condition in the United Kingdom now seems more likely to derive primarily from differences in maternal status rather than differences in infant feeding practice.

Outcoine Studies of neonatal seizures span 22

years, during which there have been radical changes in perinatal practice. These studies include those of Burke (1954), Ounsted (personal communication), Minkowski et al. (1955), Craig(1960), Harris and Tizard (1960), Prichard (l964), Schulte (l966), Degen and Koschtial (1968), Mclnery and Schubert (1969), Rose and Lombroso (1970), Brown et al. (1972), Keen and Lee (19731, Langevin (1974) and Combes el al. (1975). The global outcome and quality of handicap reported i n each series is peculiar to the population and medical practice from which the study sample was drawn, and to the methodology used (Dennis 19781, and these variables must be considered in reviewing the results.

Mortality in the early studies is high (Burke 40 per cent, Ounsted 60 per cent), and these were self-selected in favour of sick babies because of the then-limited access of paediatricians to newborn infants. The Leipzig study (Degen and Kocchtial 1968) is similarly constrained. Morbidity among survivors was low in Burke’s study, but higher in those of Ounsted and of Degen and Koschtial, in each of which the combined mortality and morbidity is around 80 per cent. Rose and Lombroso’s series, ascertained in the Boston Children‘s Hospital, may also have been selected in favour of very sick babies. Twenty of their 137 babies sustained intracranial birth trauma, including five casec of intraventricular haemorrhage in full-term babies and two skull fractures. It is interesting that although the incidence

of morbidity in their study is relatively low (39 per cent), 90 per cent of their handicapped survivors are severely affected. This incidence of severe handicap is much greater than that found in other contemporary studies.

In contrast, the UK studies of Keen and Lee (1973) and Brown et al. (1972) are self-selected in favour of benign global outcome by virtue of the very large numbers of babies with simple hypocalcaemic tetany. Mortality in both studies is around 10 per cent, less than half that reported in the 10 other studies and in this present Oxford series. Keen and Lee found a low incidence of morbidity (1 3 per cent) among their survivors, but of these 70 per cent are severely affected. The morbidity among survivors in the Brown et al. series (32 per cent) is only slightly less than found elsewhere (35-50 per cent).

In the present study, 50 per cent of the handicapped survivors are moderately or severely affected (see Table Ill), which is similar to the percentages observed by Harris and Tizard (1960), Schulte (1966), Brown et al. (1972), and Combes et al. (1 975).

Seizures After the Neonatal Period Seizures recurred after the neonatal

period in 20 per cent of the babies in this study, and in 26 per cent of those babies whose seizures were not due to simple hypocalcaemic tetany. Among recent studies, five show a recurrence rate between 21 and 25 per cent while that in the Marseille series is 15 per cent (Combes et a/., personal communication).

Aetiology It is generally agreed that aetiology

should correlate with outcome. However, multiple problems are usually encountered in the early biographies of babies with neonatal seizures and the problem of double coding frequently arises. This does

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JENNIFER DENNIS

not only occur when the defined categories are restrictive.

Combes et al. (1975) re-analysed many published reports of neonatal seizures and assigned cases to one of three wide aetiological categories : ‘congenital’ (proven anatomical cerebral anomalies) ; ‘perinatal’ (complicated labours, perinatal trauma and anoxia, intracranial haemorrhage) ; and ‘postnatal’ (i. infections, ii. metabolic). They assigned cases to these categories on the basis of the immediate cause of seizures. Theoretically then, hypoglycaemia in a small-for-dates baby with perinatal asphyxia could be placed in a postnatal ‘metabolic’ group, along with pyridoxine dependency and simple hypocalcaemic tetany. However, the fundamental causes of these disorders are widely disparate and emphasise the need for establishing an over-riding diagnosis before assigning babies to such categories.

Brown et al. (1972) defined only two groups, ‘brain damaged’ and ‘metabolic by exclusion’, which introduced a different problem. One of their basic criteria for brain damage was neurological or intellectual abnormality on follow-up, so that in some cases they defined aetiology by outcome, thus invalidating statements about outcome based on aetiology.

The aetiological categories described in the present study are clearly distinctive and seem clinically useful, provided the prin- ciple of establishing an over-riding diagnosis is followed. With this approach, the possibility of double coding arose in only two of the 50 babies.

The wholly adverse outcome associated with the ‘fetus with a problem’ is statis- tically as significant as the wholly benign outcome associated with simple hypocalcaemic tetany. Therefore, it seems as important to recognise the abnormal conceptus among the group of babies whose seizures are not due to simple hypocalcaemic tetany as it is to define the category

of simple hypocalcaemic tetany itself. If this is done, the extent to which possibly preventable causes of neonatal seizures (perinatal factors and postnatal insults) contribute to long-term handicap is clearly defined (see closing comments on ‘prevention of handicap’).

The category ‘fetus with a problem’ is much wider than Combes’ ‘congenital’ group and than Rose and Lombroso’s similar category confined to proven anatomical cerebral anomalies. However, the proper definition of the category requires some care and is only achieved by constant reappraisal of the situation surrounding each baby. This is because babies with neonatal seizures who do not have a major anomaly tend to be wrongly assigned to other aetiological categories in the early neonatal period. In this study this hap- pened to four such babies, who were initially assigned to the ‘perinatal’ category. Of these four, three were correctly diagnosed within three months, but one who had died was not recognised as having had an inborn metabolic error until a sibling born 21 months later was similarly affected (Scurlock et al., unpublished). Thus, the category ‘fetus with a problem’ tends to be undersubscribed. This failure to recognise the abnormal conceptus, and to wrongly assume that its fundamental problem is of perinatal origin, probably also occurs in other areas of paediatric neurology and mental handicap.

In contrast, when the research notes were compared with the routine clinical notes of the same babies, the category of simple hypocalcaemic tetany was seen to be slightly oversubscribed in routine practice.

Early Prediction of Outcome Parents express grave anxiety about

long-term sequelae when their newborn baby convulses. To date there is little information which helps the clinician to

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154

give a prognosis. Prognosis is based either on a prediction of outcome for the individual or on a group prediction.

PREDICTION OF OUTCOME IN THE INDIVI-

DUAL Prediction of long-term outcome in a

particular infant, based on its neonatal status, has been considered hazardous (Donovan et a/. 1962, Dargassies 1965, Amiel-Tison 1969), partly because attention has focused on the prediction of abnormality. Normality has been defined as the absence of abnormal neurological signs, but this ignores the positive im- pressionistic signal of the intact central nervous system which is transmitted to the experienced examiner. Definition of this signal might require an ethological approach, but that is no reason to ignore it. The subjective gradings recorded in this study indicate that when this signal was acknowledged during observation and examination of newborns it was wholly accurate in predicting normality at age four to six years. Amiel-Tison (1969) followed up 37 babies who had had severe neurological signs in the newborn period, and the seven who appeared normal on discharge from the neonatal unit proved to be 50 at ages two to five years. Donovan et (11. (1962) and Dargassies (1965) also predicted normality with near certainty using standardised techniques of neurological examination, but seemed mainly concerned with the difficulties of predicting abnormality. In the present study, 11 of the 14 children who appear normal at age four here defined as such on discharge from the neonatal unit, and no false prediction of normality was ever made in the neonatal period.

It seems, then, that the neonatologist might allow himself the benefit of his experience and predict normality with confidence in individual babies who preaent to him the positive signal of

normality during careful examination prior to discharge from the neonatal unit. In this study, of the 28 babies given subjective gradings at every examination, 57 per cent on discharge from the neonatal unit were thought and later proved to be definitely normal or abnormal, leaving 43 per cent with doubtful status at that time.

GROUP PREDICTIONS OF OUTCOME

Where outcome in the individual seems uncertain on discharge from the neonatal unit, group predictions must be used and the aetiological categories described in this study provide one useful basis for doing this (see Fig. 2).

Brown et al. (1972) showed that certain neurological signs in association with neonatal convulsions carried different risks for long-term handicap, and state that summation of signs can be used in a quantitative way to determine adversity of prognosis. Age of onset criteria have also been suggested as a basis for the prediction of outcome, but it seems (see Table VII) that this depends mainly on the age specificity of simple hypocalcaemic tetany. This condition is readily diagnosed on clinical and biochemical grounds and does not present a prognostic problem. Age of onset criteria do not seem to be of value in the prognosis of neonatal seizures from other causes.

Combes et al. (1975) and Prichard (1964) found a normal neonatal EEG of more limited group-prognostic value than did Rose and Lombroso (1970), but all agree that ‘flat’, ‘multifocal’ and ‘periodic’ neonatal EEGS are nearly always associated with severe long-term handicap.

Prevention of Handicap Some children have life-long handicap

because of the lesion or insult which precipitated their neonatal convulsions. Prevention of handicap is only possible in those children whose insult is perinatal or

JENNIFER DENNIS

postnatal. Definition of the ‘fetus with a problem’ shows that prenatal anomalies account for 41 per cent of the total morbidity and mortality in this study. This concurs with Amiel-Tison’s conclusion (1969) that these anomalies are responsible for many of the severe definitive encephalopathies. Adverse perinatal events accounted for a further 41 per cent and postnatal insults for 13.5 per cent combined mortality and morbidity-a total of 15 children. The early biographies indicate that prevention was theoretically possible in eight of these children. Thus, preventive

possibilities are considerable even in a population which is biologically well- endowed and where the over-all standards of obstetric and perinatal care are high.

Acknowledgements: I thank Professor Peter Tizard, Dr. Hugh Ellis, Dr. Brian Bower, Dr. Douglas Pickering and Dr. Martin Moncrieff, who have for so long allowed me unrestricted access to their patients; Dr. Christopher Ounsted and Dr. David Taylor for continued advice and support; Patricia Yudkin for statistical analysis; and Dr. Margaret Lynch, who carried out one of the neurodevelopmental assessments at Detroit Metro Airport Holiday Inn. This investigation was funded initially by a Mary Goodger Scholarship and more recently in part by a grant from the Oxford Regional Health Authority Locally Organised Clinical Research Scheme.

SUMMARY A prospective study of 50 consecutive children who convulsed in the first 28 days of life

is in progress. The surviving children are now aged from four to six years. The incidence of simple hypocalcaemic tetany in these children was low (14 per cent) and its benign outcome has been confirmed. In considering neonatal seizures from other causes, the outcome at age four years is as follows: 26 per cent are dead; 33 per cent show adverse sequelae; 5 per cent are of questionable status; and 36 per cent appear to be normal. A wide range of handicap is present among the sample. Seizures have recurred in 20 per cent of all children surviving the neonatal period.

If definite normality or abnormality was predicted in an individual child at the neonatal discharge assessment, the prediction was found to be correct at age four years. Subsequent assessments in the first year of life were of less predictive value for the individual child. Four aetiological categories are defined which are associated with distinctive patterns of outcome and which seem clinically useful in providing group prognoses for those babies whose status is uncertain on discharge from the neonatal unit.

The aetiological category ‘fetus with a problem’ is always associated with morbidity and mortality and accounts for 41 per cent of the total morbidity and mortality in the present study. Definition of this category reveals the extent to which possibly preventable neonatal seizures-i.e. those due to perinatal and postnatal events4ontribute to long-term handicap.

a S U M E Convulsions nkonatales: Etiologie, &tat nkonatal ultkrieur et tvolution 6 long terme

Une Ctude prospective de 50 cas consicutifs d’enfants ayant prCsentC des convulsions dans les 28 premiers jours de la vie est en cours. Les enfants sont actuellement 2gCs de quatre A six ans. La friquence de la simple titanie hypocalcimique chez ces enfants fut faible (14 pour cent) et le pronostic btnin a Cti confirm&. ConsidCrant les crises neonatales d’autres causes, l’tvolution A I’iige de quatre ans est la suivante: 26 pour cent de dices; 33 pour cent de siquelles siveres; cinq pour cent de cas douteux et 36 pour cent apparem- ment normale. Une large variCtC de handicaps est prCsente dans 1’Cchantillon. Des crises sont riapparues chez 20 pour cent de tous les enfants ayant survCcu B la piriode &onatale.

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Lorsque la normalitt ou l’anormalitd fut predite mattriellement dans le bilan de ddcharge d’un nouveau-ne individuel, la prediction s’est trouvee correcte quatre ans. Les apprecia- tions ultkrieures durant la premikre annee de la vie furent d’une valeur predictive moindre pour le cas individuel. Quatre catkgories ktiologiques sont dkfinies, assocites a des manifesta- tions Cvolutives particuliltres et paraissent cliniquement utiles en fournissant un pronostic de groupe pour les enfants dont l’etat est incertain lors du dkpart de I’unitC de soin neonatal.

La categorie Ctiologique ‘fetus avec problkmes’ est toujours associee a une forte morbidit6 et mortalite et est responsable de 41 pour cent de la morbidit6 et mortalitt totale de 1’Ctude prksente. La definition de cette categorie revkle dans quelle mesure les crises neonatales, a priori tvitables-c’est dire likes B des evknements pirinataux et postnataux-contribuent au handicap a long terme.

ZUSAMMENFASSUNG Neugeborenenkriimpfe: Aetiologie, Befund im Sauglingsalter und Langzeitergebnis

50 Kinder, die in den ersten 28 Tagen Krampfe hatten, werden im Rahmen einer Verlaufsstudie nachkontrolliert. Die Kinder sind jetzt vier und sechs Jahre alt. Einfache hypocalcaemische Tetanien traten bei diesen Kindern selten auf (14 Prozent) und ihre gute Prognose bestatigte sich. Betrachtet man die Neugeborenenkrampfe anderer Ursache, so stellt sich das Ergebnis wie folgt dar: 26 Prozent der Kinder sind verstorben, 33 Prozent nahmen eine ungunstige Entwicklung, 5 Prozent waren in einem Grenzbereich und 36 Prozent erschienen normal. Die Kinder sind in verschiedener Weise behindert. Bei 20 Prozent der Kinder, die die Neugeborenenperiode uberlebt hatten, sind erneut Krampfe aufgetreten.

Wenn ein Kind bei der Entlassungsuntersuchung auf der Neugeborenenstation als definitiv normal oder abnorm beurteilt wurde, so konnte dieser Befund im Alter von vier Jahren bestatigt werden. Spatere Beurteilungen im Verlauf des ersten Lebensjahres waren fur das einzelne Kind prognostisch weniger zuverlassig. Es werden vier aetiologische Kategorien definiert, die mit bestimmten klinischen Ergebnissen verbunden sind. Man kann anhand dieser Kategorien Gruppenprognosen fur solche Kinder erstellen, deren Status bei der Entlassung von der Neugeborenenstation als zweifelhaft beurteilt wurde.

Die aetiologische Kategorie ‘Fetus mit Problem’ ist immer mit Morbiditat und Mortalitat verbunden und ist verantwortlich fur 41 Prozent der Gesamtmorbiditat und -mortalitat in dieser Studie. Die Definition dieser Kategorie zeigt, in welchem Ausmass eventuell vermeid- bare Neugeborenenkrampfe4.h. Krampfe, die durch peri- und postnatale Ereignisse verursacht wurden-zu einer Langzeitbehinderung beitragen.

RESUMEN Convulsiones neonatales: etiologia, estado neonatal tardio y curso a largo tkrmino

Esth en curso un estudio prospectivo de 50 niiios consecutivos que padecieron convulsiones en 10s primeros 28 dias de vida. Los niiios tienen ahora de cuatro a seis aiios de edad. La incidencia de una tetania simple hipocalcemica en estos niiios fue baja (14 por ciento) y su curso homogeneo ha sido confirmado. A1 considerar las convulsiones neonatales debidas a otras causas, la situaci6n a la edad de cuatro aiios es la siguiente: 26 por ciento han muerto; 33 por ciento muestran secuelas adversas; 5 por ciento esthn en un status cuestionable y un 36 por ciento aparecen normales. En la muestra se observa un amplio margen de minusvalencia. Las convulsiones han tenido lugar en un 20 por ciento de todos 10s nifios supervivientes a1 periodo neonatal.

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JENNIFER DENNIS

Si en la valoraci6n realizada en el momento de ser dado de alta a1 final del periodo neonatal se hizo una prediccih definida de normalidad o anormalidadd en un niiio determinado, se vi6 que la predicci6n era correcta a la edad de cuatro aiios. Las valoraciones subsiguientes en el primer aiio de vida tienen un valor predictivo menor en un determinado niiio, se definen cuatro categorias etiol6gicas como asociadas a distintos esquemas de evoluci6n y se presentan como clinicamente titiles en conseguir grupos de pron6stico para aquellos niiios cuyo status es incierto a1 ser dados de alta de la unidad de neonatologia.

La categoria etiol6gica de ‘feto con problema’ va siempre asociada con morbilidad y mortalidad y es el responsable del 41 por ciento de la morbilidad y mortalidad totales del presente estudio. La definici6n de esta categoria revela hasta que punto las convulsiones neonatales posiblemente prevenibles, por ejemplo las debidas a acontecimientos peri y postnatales, contribuyen a una minusvalencia a largo plazo.

REFERENCES Amiel-Tison, C. (1969) ‘Cerebral damage in full-term newborn, aetiological factors, neonatal status and

Baird, D. (1969) In Butler, N. R., Alberman, E. (Eds.) PerinatalProblems. Edinburgh: E. & S. Livingstone.

Baum, D., Cooper, L., Davies, P. A. (1968) ‘Hypocalcaemic fits in neonates.’Lancet, 1,598-599. Brown, J. K., Cockburn, F., Forfar, J. 0. (1972) ‘Clinical and chemical correlates in convulsions of the

Burke, J. B. (1954) ‘The prognostic significance of neonatal convulsions.’ Archives of Disease in Childhood,

Combes, J.-G., Rufo, M., Vallade, M.-J., Pinsard, N., Bernard, R. (1975) ‘Les convulsions nCo-natales.

Craig, W. S. (1960) ‘Convulsive movements occurring in the first ten days of life.’ Archives of Disease in

Dargassies, S . S. (1965) ‘Neurological examination of the neonate.’ Proceedings of the Royal Society of

Degen, R., Koschtial, I. (1968) ‘Die Spatprognose von Krampfen in der Neugeborenen-periode.’ Monatss-

Dennis, J. (1978) ‘The implications of neonatal seizures.’ In Guilleminault, C., Korobkin, R. (Eds.) Advances

Donovan, D. E., Coues, P., Paine, R. S. (1962) ‘The prognostic implications of neurologic abnormalities in

- Bower, B. D. (1972) ‘The Aicardi syndrome.’ Developmental Medicine and Child Neurology, 14,382-39C. Fanconi, A., Prader, A. (1968) ‘Hypocalcaemic fits in neonates.’ Lancet, 1,864-865. Frankenburg, W. K., Dodds, J. B., Fandal, A. W. (1970) Denver Devefopmental Screening Test. Denver:

Harris, R., Tizard, J. P. M. (1960) ‘The electroencephalogram in neonatal convulsions.’ Journal of’Pediatrics,

Keen, J. H. (1969) ‘Significance of hypocalcaemia in neonatal convulsions.’ Archives of Disease in Childhood, 44, 356-361. - Lee, D. (1973) ‘Sequelae of neonatal convulsions.’ Archives of Disease in Childhood, 48,542-548. Langevin, P. (1974) ‘Les convulsions en pCriode nCo-natale, evaluation de 21 cas.’ L‘Union Mtdicale du

Canada, 103,465-469. Levine, R. S., Keen, J. H. (1974) ‘Neonatal enamel hypoplasia in association with symptomatic neonatal

hypocalcaemia.’ British Dental Journal, 137,429433. McInery, T. K., Schubert, W. K. (1969) ‘Prognosis of neonatal seizures.’ American fournu1 of Diseases of

Children, 117, 261-264. Minkowski, A., Dargassies, S. S., Dreyfus-Brisac, C., Samson, D. (1955) ‘L’Ctat de ma1 convulsif du

nouveau-nC.’ Archives Francaises de Pgdiatrie, 12, 271-284. Peters, J. E., Romine, J. S., Dykman. R. A. (1975) ‘A special neurological examination for children with

learning disabilities.’ Developmental Medicine and Child Neurology, 17, 63-78. Prechtl, H., Beintema, D. (1 964) The Neurological Examination of the Full-term Newborn Infant. Little Club

Clinics in Developmental Medicine, No. 12. London: Spastics Society with Heinemann Medical. Prichard, J. S. (1964) ‘The character and significance of epileptic seizures in infancy.’ In Kellaway, P..

Peterson, P. (Eds.) Neurological and Electroencephalographic Correlztive Studies in Infancy. New York : Grune & Stratton. p. 273.

Purvis, R. J., Barre, W. J., Mackay, G. S., Wilkinson, E. M., Cockburn, F., Belton, N. R., Forfar, J. 0.. (1973) ‘Enamel hypoplasia of the teeth associated with neonatal tetany : a manifestation of maternal vitamin D deficiency.’ Lancet, 2, 811-814.

long-term follow-up.’ Biobgica Neonatorum, 14, 234250.

p.28 1.

newborn.’ Lancet, 1, 135-138.

29, 342-345.

Circonstances d’apparition et crireres de pronostic.’ Pkdiatrie, 30, 477-492.

Childhood, 35, 33G344.

Medicine, 58, 5.

chriji fur Kinderheilkunde, 116, 133-1 35.

in Perinatal Neurology. New York: Spsctrum.

the neonatal period.’ Neurology, 12, 910-914.

University of Colorado Medical Center.

57, 501-520.

157


Roberts, S. A., Cohen, M. D., Forfar, J. 0. (1973) ‘Antenatal factors associated with neonatal hypocalcaemic convulsions.’ Lancet, 2, 809-81 1.

Rose, A. L., Lombroso, C. T. (1970) ‘Neonatal seizure states. A study of clinical, pathological and electroencephalographic features in 137 full-term babies with a long-term follow-up.’ Pediatrics, 45, 404-425.

Schulte, F. J. (1966) ‘Neonatal convulsions and their relation to epilepsy in early childhood.’ Developmental Medicine and Child Neurology, 8, 38 1-392. - Lohmann, A. (1962) ‘The electroencephalogram and electromyogram in experimental hypocalcaemia.’ Electroencephalography and Clinical Neurophysioiogy, 14, 91 5-920.

Snodgrass, G. J. A. I., Stimmler, L., Went, J., Abrams, M. E., Will, E. J. (1973) ‘Interrelations of plasma calcium, inorganic phosphate, magnesium and protein over the first week of life.’ Archives of Disease in Childhood, 48, 219-285.

Stimniler, L., Snodgrass, G. J. A. I . , Jaffe, E. (1973) ‘Dental defects associated with neonatal symptomatic hypocalcaemia.’ Archives of Disease in Childhood, 48, 21 7-220.

Watney, P. J. M., Chance. G. W., Scott, P., Thompson, J . M. (1971) ‘Maternal factors in neonatal hypocalcaemia: a study in three ethnic groups.’ British Medical Joiimal, 2, 432436.

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Neonatal Convulsions: Aetiology, Late Neonatal Status and Long-Term Outcome