Prognostic value of the electroencephalogram in neonatal asphyxia

60

Electroencephalography and Clinical Neurophysiology, 1982, 5 3 : 6 0 - - 7 2 Elsevier/North-Holland Scientific Publishers, Ltd.

PROGNOSTIC VALUE OF THE ELECTROENCEPHALOGRAM IN NEONATAL ASPHYXIA GREGORY HOLMES 1, JONELLE ROWE, JAMES H A F F O R D , RUTH SCHMIDT, MARCIA TESTA and ANDREW ZIMMERMAN

Departments of Neurology, Pediatrics, and Research in Health Education, University of Connecticut Health Center, Farmington, Conn. and Newington Children's Hospital, Newington, Conn. 06111 (U.S.A.) (Accepted for publication: September 16, 1981)

Hypoxic-ischemic encephalopathy is the single most important neurological problem occurring in the perinatal period (Volpe 1976) and accounts for the majority of non-progressive neurological deficits seen in children. The reported incidence of neonatal asphyxia has varied depending on how asphyxia has been defined. Drage et al. (1964) defining asphyxia using a 5 min Apgar score of below 7 found an incidence of neonatal asphyxia of 5.3% while MacDonald et al. (1980) requiring 1 min or more of positive pressure ventilation before spontaneous sustained respirations found an incidence of 1.2%. Experimental animal studies have demonstinted that severe oxygen deprivation can lead to widespread neuronal changes in the neonatal brain (Brierly et al. 1973; Hedner 1978). This damage to the cytoarchitecture and cellular structure of the immature brain may have profound effects on later development. Clinically useful techniques which can evaluate and quantitate integrity of synaptic, dendritic, myelin, glial and neuronal structures of the neonatal brain and identify infants at risk for neurological sequelae are needed. In order to meet this need a variety of techniques have been used to establish reliable criteria for the prediction of neu-

1 Supported in part by a Teacher Investigator Award from the National Institute of Neurological arrd Communicative Disorders and Stroke, NSI-EA 1K07 NS 538-01.

rological sequelae in neonates including the evaluation of Apgar scores (Nelson and Ellenberg 1981), prenatal factors (MacDonald et al., 1980), neurological examinations (Donovan et al. 1962; Graziani and Korberly 1972; Saint-Anne Dargassies 1972; Brown et al. 1974), visual evoked responses (Hrbek et al. 1977) and neonatal EEGs (Engel 1964, 1965, 1975; Rosen and Satran 1966; Monod and Ducas 1968; Tortes and Blaw 1968; Rose and Lombroso 1970; Monod et al. 1972; Sarnat and Sarnat 1976; Plouin et al. 1977; Watanabe et al. 1980). Opinions differ greatly with regard to the reliability of the neurological examination in predicting long-term neurological and intellectual outcome in newborns. Donovan et al. (1962), in a prospective study, could not correlate examinations in newborns with neurological examinations later in childhood. Graziani and Korberly (1972) felt that it was impossible to determine the location, nature and extent of the neuropathic effects of fetal hypoxia by clinical examination of the newborn infant alone. Other authors (Saint-Anne Dargassies 1972; Brown et al. 1974) argue that abnormal neurological findings in the neonatal period are of value in detecting infants at risk for neurological sequelae. Like the neurological examination there is controversy regarding the value of the neonatal electroencephalogram in predicting outcome. Tortes and Blaw (1968), in an unselected sample of 153 infants who had an

0013-4649/82/0000--0000/$02.75 © 1982 Elsevier/North-Holland Scientific Publishers, Ltd.

EEG IN NEONATAL ASPHYXIA EEG within the first days of life and who were followed to age 4 years, f o u n d that the initial EEG had no significant prognostic value in determining subsequent clinical development of these infants. Rose and L o m b r o s o (1970) and Monod et al. (1972) found that certain neonatal EEG patterns are highly correlated with neurological sequelae. Monod et al. (1972) reviewed 691 EEGs of 270 newborn babies recorded during the first months of age and correlated the findings with neurological sequelae. O u t c o m e was classified as either favorable, i.e., children with normal or minor sequelae, or unfavorable, i.e., children with major sequelae or death. Statistical studies of various EEG patterns were then correlated with outcome. The authors found that normal neonatal EEGs were highly correlated with favorable outcomes, while low voltage, inactive or paroxysmal EEGs were highly prognostic of poor outcomes. The authors did n o t correlate EEG findings with specific neonatal insults. In a study of 137 full-term babies with neonatal seizures, Rose and Lombroso (1970) found that neonates with seizures and a normal EEG had an 86% chance of normal development at age 4 years regardless of other clinical data as compared with neonates with 'flat', 'periodic', or 'multifocal' EEGs in which there was only a 7% chance of normal development. Their study also demonstrated that multifocal epileptogenic activity carried a more ominous prognosis for neurological sequelae than unifocal epileptogenic activity. Engel (1975) confirmed the value of the EEG as a prognostic tool in infants with seizures. Severely depressed EEGs were associated with poor outcomes while normal EEG tracings correlated with normal outcomes. The majority of studies. on neonatal EEGs have included infants with various etiological groups into the same study, e.g. neonatal seizures. Watanabe et al. (1980) reviewed EEGs from 132 full-term infants with neonatal asphyxia, defined as an episode of fetal distress or an Apgar score of 5 or less at 1 or 5 min after delivery. Background EEG activity was found to be an

61 excellent indicator of prognosis while paroxysmal EEG abnormalities had far less prognostic significance. In one of the few prognostic studies in neonatal asphyxia, Sarnat and Sarnat (1976) evaluated EEGs of 20 infants with perinatal asphyxia and classified their EEG and clinical examinations into clinical stages. They found the EEG findings paralleled the clinical status of the infants and r e c o m m e n d e d that serial EEGs be obtained in infants with neonatal asphyxia. These authors observed that the time course of both the clinical and EEG changes provided a sounder basis for prognosis than did isolated symptoms and signs, the presence of seizures, or EEG changes alone. Correlation of the initial EEG with eventual o u t c o m e was n o t done. Because of the controversies regarding the relative values of the neonatal neurological examination and EEG, a retrospective study was performed comparing the neurological examination with the initial EEG in 38 patients with asphyxia neonatorum.

Methodology Records of 38 full-term infants with neonatal asphyxia who had EEGs within 2 weeks after birth were reviewed. Asphyxia neonatorum was operationally defined using the following criteria: (1) history of a welldefined episode of fetal distress as determined b y fetal monitoring or thick meconium staining, and (2) Apgar scores of 5 or less at 1 or 5 min after delivery. None of the infants had evidence of congenital heart disease, traumatic cerebral injuries, hydrocephalus, or infection. Infants with meconium aspiration, respiratory distress syndrome, or other illnesses resulting in chronic, continuing hypoxia were excluded. Respiratory assistance was required in m a n y of the cases to assure adequate pO2, pCO2, and pH levels. All infants had determinations of serum glucose, calcium, magnesium, and electrolytes as part of their initial evaluation. Infants unable to maintain adequate oral intake were given intravenous

62

fluids. Seizures were treated with phenobarbital, 20 mg/kg loading dose followed by 5 rag/ kg per day. If seizures persisted, phenytoin was given intravenously, 20mg/kg loading dose and then 5 mg]kg per day. Phenytoin was discontinued after the infant was seizurefree for 48--72 h. Phenobarbital was continued until the patient was seen in follow-up. If the patient remained seizure-free the phenobarbital was tapered and discontinued at approximately 6 months of age. Serum anticonvulsant levels were monitored and maintained in the therapeutic range (phenobarbital 15--25 ~g/ml, phenytoin 10--20/~g/ml). Serial general and neurological examinations were performed in the neonatal intensive care unit every 24 h by a pediatric neurologist and/or neonatologist. Neurological examination included evaluation of the level of consciousness, spontaneous movements, cranial nerves, muscle tone, strength, deep tendon reflexes, and primitive reflexes, such as the grasp, suck, and Moro. Results of the examination were coded as follows: (I) normal; (II) mild-to-moderate abnormalities; and (III) severe abnormalities. Category II abnormalities included infants with mild hypotonia, overactive stretch reflexes, weak suck, grasp, or Moro, lethargy, and decreased spontaneous movements. Category III infants were either flaccid with diminished muscle stretch reflexes and decreased spontaneous movement, or hypertonic with hyperreflexia and spontaneous clonus. Primitive reflexes were absent. The infants were lethargic, stuporous or comatose. The neurological examination on the day of the EEG was used for this study. EEGs were performed within 2 weeks of birth (mean 4.8 days, S.E. +0.42). EEGs were recorded in the newborn intensive care unit using a 10~channel electroencephalograph with a modified International 10-20 system of electrode placement with electrodes in the F1-2, C3-4, P3-4, T3-4, T5-6, O1-2 positions (Werner et al. 1977). In the majority of cases 7 channels were utilized for EEG using both monopolar and bipolar montages. Additional

G. HOLMES ET AL.

EEG channels were used for electrocardiographic monitoring, lateral eye movements and respirations. All infants were recorded during both the awake and sleep states. Sleep was recorded until the child cycled through both quiet and active (REM) sleep or was asleep for 60 min. A paper speed of 15 mm/ sec was used at times to assess degree of interhemispheric synchrony. Sensitivity was 50 p V / 7 . 5 m m during the majority of the recording. All EEGs were reviewed blindly by one author (G.H.) who had no knowledge of the patient's neurologicar examination. The EEG background was classified using criteria similar to Monod et al. {1972) as normal, slow, maturationally delayed, low voltage, isoelectric or burst suppression. The criteria used were as follows: Slow EEGs. Continuous and diffuse delta waves in both the awake and sleep states with little activity in the theta range. The EEG did not change with state of the infant (Fig. 1). Maturationally delayed. Immature EEG pattern for gestational age. This was evaluated using criteria described by Werner et al. (1977) and Lombroso (1979), including calculation of degree of interhemispheric synchrony of trac~ alternant bursts and number of spindle
EEG IN NEONATAL ASPHYXIA

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G. HOLMES ET AL.

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EEG IN N E O N A T A L ASPHYXIA

epileptiform activity was classified independently from background activity. Unifocal EEGs were characterized by high voltage sharp waves or spikes that originated locally (Fig. 5). In some cases there was slow spread to contiguous areas. The discharges occurred randomly but at times developed into well-sustained, rhythmic discharge often accompanied by clinical seizure activity (Fig. 6). MuItifocal EEG patterns consisted of two or more independent discharges arising in one or both hemispheres (Fig. 7). At times the discharges would become rhythmic and were accompanied by clinical seizures (Fig. 8). Generalized discharges consisted of generalized spikes, sharp waves, or slow waves often, but not always, accompanied by clinical seizures (usually myoclonic) (Fig. 9). Patients were re-evaluated at varying lengths of time following discharge. All patients in

65

this study were seen at least once in follow-up and had complete developmental and neurological evaluations. Average length of follow-up was 24 months. Neurological and developmental examinations were coded as (I) normal; (II) mild-to-moderate deficits; and (III) severe deficits or death. Mild-to-moderate deficits included mild developmental delay, motor abnormalities, including spasticity, hypertonia, hypotonia, dystonia, weakness or mild cerebeUar findings such as ataxia. Severe abnormalities included both severe mental and motor retardation or severe developmental delay alone, i.e., no speech, walking, etc. Children in category III who survived generally required total nursing care. The results were analyzed statistically using the z test for proportions (Mendenhall and Ott 1980} and the t test for ordered classification (Snedecor and Cochran 1967).

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Fig. 5. Example of unifocal EEG with sharp wave focus at T5.

66 G. HOLMES ET AL.

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Fig. 6. Example of unifocal, rhythmic seizure discharge.

Fig 7. Example of multifocal EEG pattern with sharp waves at F1 and T4.

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G. HOLMES ET AL.

TABLE I Comparison of initial neurological examination with follow-up neurological and developmental examination. Initial neurological examination

Follow-up neurological and developmental examination I. Normal

Normal Mild/moderate abnormalities Severe abnormalities Total

II. Mild/moderate abnormalities

III. Severe abnormalities

9 5 2

0 1 2

0 2 17

16

3

19

Results

The mean gestational age of the infants was 39.27 weeks (S.E. +0.31). Table I compares the initial neurological examination and follow-up neurological and developmental examinations. All infants with initial normal neurological examinations were normal on follow-up. Although the majority of infants, 17 of 21 (81.0%), with severely abnormal exams were severely abnormal in follow-up, 2 of 21 (9.5%) had normal outcomes. Overall the percentage of exact agreement (efficiency) between the two examinations was 71% (27/ 38). Table II compares initial electroencephalo-

graphic results with subsequent neurological and developmental outcome. Normal and maturationally delayed EEGs were associated with normal outcomes in all of the patients while low voltage and burst suppression/electrocerebral inactivity EEGs were always associated with severe or mild to moderate abnormalities. For statistical purposes normal and maturationally delayed EEGs were classified as normal, slow EEGs as moderate abnormalities, and low voltage, electrocerebral inactivity and burst suppression EEGs as severe abnormalities. The efficiency using the EEG as apredictive test was significantly higher, 89.5% (34/38)

TABLE II Comparison of initial electroencephalogram with follow-up neurological and developmental examination. Initial EEG

Follow-up neurological and developmental examination I. Normal

II. Mild/moderate abnormalities

Normal Normal Maturationally delayed

12 3

0 0

0 0

Moderate abnormalities Slow

1

1

1

Severe abnormalities Low voltage Burst suppression/electroeerebral inactivity

0 0

1 1

8 10

16

3

19

Total

III. Severe abnormalities

EEG IN NEONATAL ASPHYXIA

69

was compared (Table III). In brief, the EEG increased the overall efficiency of the initial diagnostic assessment primarily by increasing its specificity. Table IV is a summary table comparing initial neurological examination, follow-up neurological and developmental examination and initial EEG. Table V compares follow-up neurological and developmental examination with the presence of epileptiform activity on the EEG. Of the 27 patients without a burst suppression pattern on the EEG 14 had epileptiform activity. A severity score was assigned to each diagnostic level and a mean severity score was computed for each group. Those patients with epileptiform activity showed slightly more abnormalities than those without epileptiform activity (t = 2.0, df = 25, two-tailed P < 0.10). Table VI compares background EEG activity and epileptiform activity with follow-up neurological and developmental examinations. Patients with epileptiform activity on normal or maturationally delayed background activity were normal in follow-up in 100% (6/6), while epileptiform activity on low voltage backgrounds did poorly with 87.5% (7/8) having severe abnormalities in follow-up. Twenty-three patients had clinical seizures. Table VII compares outcome with presence or absence of clinical seizures. No significant dif-

TABLE III Comparison of efficacy, specificity, sensitivity and efficiency of initial neurological examination and initial EEG. Efficacy measure (%) Initial diagnostic criterion

Specificity Sensitivity Moderate and severe Moderate only Severe only Efficiency Error reduction a

Clinical examination

EEG

56.3

93.75 (15/16)

(9/16)

81.2 (18122) 33.3 (113) 89.5 (17/19) 71.1 (27/38) 63.2

87.4 33.3 94.7 89.5 78.9

(19/22) (1/3) {18/19) (34/38)

Note: Using the follow-up neurological and developmental examination as the standard: sensitivity = no. of correctly diagnosed positives/all positives; specificity = no. of correctly diagnosed negatives/all negatives. a In prediction of follow-up neurological and developmental examination using results of initial neurological examination and initial EEG.

than the initial neurological examination, 71.1% (27/38) (z = 2.0, P < 0.05). Using the follow-up neurological and developmental examination as the standard, the efficacy of the initial EEG and neurological examination TABLE IV

Comparison of initial neurological examination, follow-up neurological and developmental examination and initial EEG.

Initial neurological examination

Follow-up neurological and developmental examination

Initial E E G

Normal (9) Mild/moderate (8)

Normal (9) Normal (5) Mild/moderate (1) Severe (2)

9 3 --

Severe ( 21 )

Normal (2)

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Mild/moderate (2) Severe (17)

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Normal (12)

Maturational delay (3)

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Low voltage (9)

Burst suppression/ electrocerebral inactivity ( 11 )

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70

G. HOLMES ET AL.

TABLE V Comparison of initial electroencephalogram and outcome: epileptiform versus no epileptiform activity (severity score in parentheses). Initial EEG

Follow-up neurological and developmental examination Total N

I. Normal (1)

II. Mild/moderate abnormalities (2)

III. Severe abnormalities (3)

Mean severity score

13 14

10 6

1 1

2 7

1.38 2.07

Without epileptiform activity With epileptiform activity

TABLE VI Comparison of epileptiform activity and background activity with outcome (epileptiform activity/non-epileptiform activity). Initial EEG

Normal (12) Maturational delay (3) Slow (3) Low voltage (9)

Follow-up neurological and developmental examination I. Normal

II. Mild/moderate abnormalities

III. Severe abnormalities

9/3 0/3 1/0 0/0

0/0 0/0 1/0 0/1

0/0 0/0 1/0 1/7

TABLE VII Comparison of clinical seizures and follow-up neurological and developmental examinations Follow-up neurological and developmental examination

With clinical seizures Without clinical seizures

Total N

I. Normal

II. Mild/moderate abnormalities

III. Severe abnormalities

23 15

8 8

2 1

13 6

ference was found between those with and without seizures (t = 1.11534, df = 36, N.S.).

Discussion This study demonstrates that a single EEG done within the first 2 weeks of life is valuable in predicting clinical outcome. When compared to the initial neurological examination

the EEG is a better indicator of outcome. The background activity on the EEG was the important determining factor in the correlation with follow-up. Our results generally agree with prior studies by Rose and Lombroso (1970), Monod et al. (1972), Lombroso (1974, 1979) and Watanabe et al. (1980) that EEGs that show low voltage, burst suppression or electrocerebral inactivity patterns are highly correlated with neurological sequelae

EEG IN NEONATAL ASPHYXIA or death, while a normal EEG is associated with a good prognosis. Similar to the findings of the Watanabe et al. (1980) study we did not find epileptiform abnormalities to be extremely useful in determining prognosis. Although infants with epileptiform activity showed a tendency to have worse outcomes than those without epileptiform activity the difference did n o t achieve a significance of P<~ 0.05. Because the majority of our patients with epileptiform activity had multifocal activity we were n o t able to c o m p a r e prognoses of unifocal versus multifocal activity. However, patients with epileptiform activity on a low voltage background uniformly had poor prognoses while patients with epileptiform activity on a normal or maturationaUy delayed background had more favorable outcomes. Based on our data it appears that a single EEG, if done early in the newborn period, is highly predictive of neurological and developmental o u t c o m e .

Summary In order to determine whether an EEG early in the course of asphyxia n e o n a t o r u m is of any more value than the neurological examination in predicting o u t c o m e we reviewed case histories of 38 infants with asphyxia neonatorum. The EEG background activity was valuable in predicting outcome. Normal and maturationally delayed EEGs were associated with normal outcomes while low voltage, electrocerebral inactivity and burst suppression EEGs were highly correlated with severe neurological sequelae. Epileptiform activity was n o t as predictive of o u t c o m e as background activity. Although initial normal neurological examinations were associated with normal developmental and neurological outcomes, moderately and severely abnormal infants had more variable courses. A single EEG done early in the course of asphyxia neonatorum is a more sensitive predictor of o u t c o m e than the neurological examination.

71 R~sum~

Valeur pronostique de l'EEG dans l'asphyxie ndonatale Afin de d~terminer si un EEG pratiqud tr~s tSt au cours d'une asphyxie n~onatale a plus de valeur que l'examen neurologique pour en pr~dire l'dvolution, l'auteur a dtudi~ le cas de 38 nourrissons avec asphyxie ndonatale. L'activit~ de fond EEG permet de pr~dire l'~volution. Des EEG normaux ou avec retard maturatif s'associent ~ des ~volutions normales tandis que les EEG de bas-voltage, l'inactivitd ~lectroc~r~brale et les p~riodes de bouff~es de suppression d'activitd sont fortement corr~l~es ~ des s~quelles neurologiques graves. L'activit~ paroxystique n'est pas aussi predictive de l'~volution que ne l'est l'activitd de fond. Bien que des examens neurologiques initiaux normaux puissent s'associer aussi bien un d~veloppement normal qu'~ des suites neurologiques, les enfants avec examen mod~r~ment ou gravement anormal ont des ~volutions plus variables. Un EEG isol~, fait pr~coc~ment apr~s l'asphyxie ndonatale est un pr~dicteur plus sensible de l'~volution que ne l'est l'examen neurologique.

References Briefly, J.B., Meldrum, B.S. and Brown, A.W. The threshold and neuropathology of cerebral 'anoxicischemic' cell change. Arch. Neurol. (Chic.), 1973, 29 : 367--374. Brown, J.K., Purvis, R.J., Forfar, J.O. and Cockburn, F. Neurological aspects of perinatal asphyxia. Develop. Med. Child Neurol., 1974, 16: 567--580. Donovan, E.E., Coues, P. and Paine, R.S. The prognostic implications of neurologic abnormalities in the neonatal period. Neurology (Minneap.), 1962, 12:

910---914. Drage, J.S., Kennedy, C. and Schwartz, B.K. The Apgar score as an index of neonatal mortality. A report from the collaborative study of cerebral palsy. Obstet. Gynec., 1964, 24: 222--230. Engel, R. Abnormal electroencephalograms in the newborn period and their significance. Amer. J. ment. Defic., 1964, 69: 341--346. Engel, R. Maturational changes and abnormalities

72 in the newborn electroencephalogram. Develop. Med. Child Neurol., 1965, 7: 498--506. Engel, R. Abnormal Electroencephalogram in the Neonatal Period. Thomas, Springfield, Ill., 1975: 65--72. Graziani, L.J. and Korberly, B. Limitations of neurologic and behavior assessments in the newborn infant. In: L. Gluck (Ed.), Intrauterine Asphyxia and the Developing Brain. Year Book Medical Publishers, Chicago, Ill., 1972: 431--442. Hedner, T. Central monoamine metabolism and neonatal oxygen deprivation. Acta physiol, scand., 1978, 460 (Suppl.): 1--34. Holmes, G.L., Logan, W., Kirkpatrick, B. and Myer, E. Central nervous system maturation in the stressed premature. Ann. Neurol., 1979, 6: 518-522. Hrbek, A., Karlberg, P., Kjellmer, I., Olsson, T. and Riha, M. Clinical application of evoked electroencephalographic responses in newborn infants. I. Perinatal asphyxia. Develop. Med. Child Neurol., 1977, 19: 34--44. Lombroso, C.T. Seizures in the newborn period. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 15. North-Holland Publ., Amsterdam, 1974: 189--218. Lombroso, C.T. Quantified electrographic scales on 10 pre-term healthy newborns followed up to 40-43 weeks of conceptual age by serial polygraphic recordings. Electroeneeph. clin. Neurophysiol., 1979, 46: 460--474. MacDonald, H.M., Mulligan, J.C., Allen, A.C. and Taylor, P.M. Neonatal asphyxia. I. Relationship of obstetric and neonatal complications to neonatal mortality in 38,405 consecutive deliveries. J. Pediat., 1980, 96: 898--902. Mendenhall, W. and Ott, L., Understanding Statistics. Duxbury Press, North Scituate, Mass., 1980: 200-205. Monod, N. and Ducas, P. The prognostic value of the electroencephalogram in the first two years of life. In: P. Kellaway and I. Peters~n (Eds.), Clinical Electroencephalographs of Children. Grune and Stratton, New York, 1968: 61--76. Monod, N., Pajot, N. and Guidasci, S. The neonatal EEG: statistical studies and prognostic value in full-term and pre-term babies. Electroenceph. clin. Neurophysiol., 1972, 32: 529--544. Mulligan, J.C., Painter, M.J., O'Donoghue, P.A., MacDonald, H.M., Allen, A.C. and Taylor, P.M. Neonatal asphyxia. II. Neonatal mortality and

G. HOLMES ET AL. long-term sequelae. J. Pediat., 1980, 96: 903-907. Nelson, K.B. and Ellenberg, J.H. Apgar scores as predictors of chronic neurological disability. Pediatrics, 1981, 68: 36--44. Parmelee, A.H., Wenner, W.H., Akiyama, Y., Schultz, M. and Stern, E. Sleep states in premature infants. Develop. Med. Child. Neurol., 1967, 9: 70--77. Parmelee, A.H., Schulte, F.J., Akiyama, Y., Wenner, W.H., Schultz, M.A. and Stern, E. Maturation of EEG activity during sleep in premature infants. Electroenceph. clin. Neurophysiol., 1968, 24: 319--329. Plouin, P., Moussalli, F., L~rique, A., Mises, J., Lavoisy, P. et Navelet, Y. Evolution clinique apr~s un trac~ n~onatal consid~r~ comme grave. Rev. EEG Neurophysiol., 1977, 7 : 410--415. Rose, A.L. and Lombroso, C.T. A study of clinical pathological and electroencephalographic features in 137 full-term babies with a long term follow-up. Pediatrics, 1970, 45: 404--425. Rosen, M.G. and Satran, R. The neonatal electroencephalogram. Clinical applications. Amer. J. Dis. Child., 1966, 111: 133--141. Saint-Anne Dargassies, S. Neurodevelopmental symptoms during the first year of life. I. Essential landmarks for each key age. II. Practical examples and the application of this assessment method to the abnormal infant. Develop. Med. Child Neurol., 1972, 14: 235--264. Sarnat, H.B. and Sarnat, M.S. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch. Neurol. (Chic.), 1976, 33: 696--705. Snedecor, G.W. and Cochran, W.G. Statistical Methods. Iowa State University Press, Iowa City, 1967: 243--246. Tortes, F. and Blaw, M.E. Longitudinal EEG-clinical correlations in children from birth to 4 years of age. Pediatrics, 1968, 41: 945--954. Volpe, J.J. Perinatal hypoxic ischemic brain injury. Pediat. Clin. N. Amer., 1976, 23: 383--397. Watanabe, K., Miyazaki, S., Hara, K. and Hakamada, S. Behavioral state cycles, background EEGs and prognosis of newborns with perinatal hypoxia. Electroenceph. clin. Neurophysiol., 1980, 49: 618--625. Werner, S.S., Stockard, J.E. and Bickford, R.G. Atlas of Neonatal Electroencephalography. Raven Press, New York, 1977.