Bioelectric brain maturation in fullterm infants and in healthy and pathological preterm infants at term post-menstrual age

Early Human Development, 28 (1992) 31-63 Elsevier Scientific

Publishers

Ireland

31

Ltd.

EHD 01207

Bioelectric brain maturation in fullterm infants and in healthy and pathological preterm infants at term post-menstrual age Fabrizio Ferraria, Assunta Torricellia, Annamaria Giustardi”, Angela Benattia, Roberto Bolzani”, Luca Ori” and Giuliana Frigieri” ‘Institute of Pediatrics and Neonatal Medicine and hInstitute of Ophthalmology, Laboratory of Bioengineering, University of Modena (Italy) (Received

28 August

1991; revision

received

18 October

1991; accepted

6 November

1991)

Summary At the same post-menstrual age (39-41 weeks), EEG maturation assessed according to the Nolte and Haas method (Nolte, R. and Haas, H.G. (1978) Dev. Med. Child Neurol., 20, 167- 182) was studied in 16 fullterm infants (FT), 17 healthy preterm infants (HP) and 18 pathological preterm infants (PP) affected by brain lesions (haemorrhage and/or leucomalacia). There were no significant differences in respect to EEG maturational codes, EEG types or bioelectrical age between the FT and HP groups. The preterm infants affected by brain lesions presented higher percentages of younger EEG codes (i.e. 36 weeks) in State 1 and a higher number of fluctuations between one maturation code and another in both State 1 and State 2, with respect to the HP group. Also, although the PP infants with young EEG codes did not present serious background EEG abnormalities, they did reveal minor EEG abnormalities, such as excessive asynchrony of the ‘trace alternant’, lack of frontal sharp transients and monomorphic TA ‘bouffees’ with little activity at 2-6 c/s. However, no relationship between young EEG codes and onset-offset or duration of the states was found: young codes were often randomly distributed in successive State l-State 2 epochs, regardless of groupings. Bioelectric age appropriate to the post-menstrual age precedes a normal development or only minor handicap at 24 months, while EEG immaturity of more than 2 weeks corresponds to later major handicaps. The prognostic value of EEG immaturity of between 1.1 and 2 weeks is uncertain.

Correspondence to: F. Ferrari, sitario, 41100 Modena, Italy.

Istituto

di Clinica

Pediatrica,

Universita’

0378-3782/92/$05.00 0 1992 Elsevier Scientific Printed and Published in Ireland

Publishers

Ireland

Ltd

di Modena,

Policlinico

Univer-

38

Key words: preterm cerebral

infants;

EEG;

bioelectrical

maturation;

peri-

and

neonatal

lesions

Introduction The way in which the central nervous system develops in utero or extrautero, providing that there are no pathologies in either situation, is still open to conjecture. Various studies have emphasized the close correlation between the maturation of the infant’s EEG patterns and its conceptional age while asserting that EEG maturation is independent both of postnatal age [4,5,8,21,28] and of birthweight [33]. More thorough analyses of EEG patterns have basically confirmed the above observations while setting limits to the correlation between EEG maturation and post-menstrual age. However, the findings are in part contradictory: some authors claim that a longer exposure to the extrauterine world may have a moderatelyaccelerating effect on the development of either the basic EEG patterns or specific grapho-elements [7,9,19,37], whereas others assert that premature infants at term have more immature patterns mixed with term patterns than seen in term newborn infants [5,29]. The effects of peri- and neonatal cerebral lesions on the EEG maturation of preterm infants at term have as yet received scant attention. To the best of our knowledge, only one work [24] deals with the EEG maturation of 13 high-risk preterm infants observed longitudinally from birth to 44 weeks of post-menstrual age (PMA); another study [38] that deals with serial EEGs in high-risk preterm infants only occasionally performed EEGs at 38-42 weeks. Accordingly, we carried out a polygraphic study of bioelectrical brain maturation in fullterm infants and in healthy and pathological preterm infants at term post-menstrual age. The aims of this research were: (1) to assess the specific effect of preterm birth on EEG maturation. This part of the study is largely a remake of previous studies carried out when US scans were not yet available and brain lesions could not be excluded with any certainty; (2) to assess the effect of germinal matrix and intraventricular haemorrhage (GMH-IVH) and/or periventricular leucomalacia (PVL); (3) to find out whether age-inappropriate EEG patterns, which are reported by various authors under pathological conditions, are randomly distributed or show a specific sequence and/or state relationship; (4) to assess the prognostic value of EEG maturation at term. Subjects

Fullterm infants Sixteen fullterm (FT) infants (9 male, 7 females) from the nursery of the University Hospital of Modena underwent a polygraphic recording on their third to fifth day of life between January 1984 and December 1985. These infants were chosen because pregnancy and labour had been free of complications, delivery had been spontaneous and vaginal with the foetus in vertex position and no local or general anaesthetic or analgesics were used. Their Apgar scores were 8 or more at 1 min and

1

Case

Sex

Clinical data,

TABLE

signs

signs

No abnormal DQ 108

No abnormal DQ 96

PMA 40 weeks: normal

PMA 38 weeks: normal

day):

day):

Mild RDS. CPAP (lst-2nd max. bil. lev. 256.5 pmolll (6th day) Mild RDS. CPAP (lst-2nd max. bil. lev. 136.8 ~molil (1 Ith day)

1450

1270

30

30

8

signs

No. abnormal DQ 103 PMA 38 weeks: normal

Max. bil. lev. 136.8 pmolil (4th day)

1330

PMA 40 weeks: normal

No abnormal DQ 99

29.4

(4th day)

Mild RDS. CPAP (Ist-2nd max. bil. lev. 102.6 rmolil

day):

8

signs

signs

1300

(7th day)

Mild RDS, CPAP( Ist-2nd max. bil. lev. 188 pmolll

1

29.4

No abnormal DQ 110

PMA 40 weeks: GMH-IVH grade

day):

8

1300

(5th day)

29

signs

No abnormal DQ 105

PMA 39 weeks: normal

Max. bil. lev. 162.4 pmolil

9

1400

signs

No abnormal DQ 97

PMA 39 weeks: normal

Max. bil. lev. 136.8 pmolil (9th day)

IO

at 24 months

signs

Outcome

No abnormal DQ 110

US scan findings

PMA 37 weeks: normal

data

Short apnoeas; max. bil. lev. 239.4 pmolll (8th day)

Pre and post-natal

CA of I7 HP infants.

7

(5’)

APGAR

at 24 months

28.6

0.880

1200

27.5

28

BW

and outcome

GA

US scan findings

CA

1500

1930

34

34

F

M

16

17

= continuous

1450

33.5

M

15

CA = corrected age, CPAP distress syndrome.

1850

32.1

F

14

positive airways

Max. bil. lev. I71 pmol/l

9

pressure,

(3rd day)

Max. bil. lev. 153.9 pmol/l (3rd day)

10

Max. bil. lev. = maximal

bilirubin

level, PMA

=

PMA 39 weeks: normal

PMA 40 weeks: normal

PMA 38 weeks: normal

Mild RDS, CPAP (Ist-4th short apnoeas, max. bil. lev. 222.3 pmol/l (3rd day)

9

day).

PMA 38 weeks: normal

Mild RDS, CPAP (lst-2nd day) short apnoeas; max. bil. lev. 273.6 pmol/l (15th day)

post-menstrual

DQ 90 age,

=

signs

signs

signs

signs

RDS

No abnormal

No abnormal DQ 109

No abnormal DQ 105

signs

No abnormal DQ 108

PMA 37 weeks: GMH-IVH grade

Max. bil. lev. 256.5 rmol/l (5th day)

1480

31.4

M

13

1

signs

No abnormal DQ 98

PMA 40 weeks: normal

Max. bil. lev. 222.3 pmolll (5th day)

1530

31

M

12

No abnormal DQ 104

PMA 40 weeks: normal

(7th day)

Max. bil. lev. 171 pmol/l

signs

1400

signs

31

M

11

No abnormal DQ 94

CA

respiratory

at 24 months

No abnormal DQ 100

I

Outcome

PMA 39 weeks: normal

US scan findings

Max. bil. lev. 153.9 pmolll (4th day)

data

1700

30.3

M

10

8

Pre and post-natal

PMA 36 weeks: GMH-IVH grade

1300

30.1

F

9

APGAR (5’) Mild RDS, CPAP (lst-3rd day); short apnoeas; max. bil. lev. 256.5 pmolll (6th day)

BW

GA

Sex

I (Continued)

Case

TABLE

41

10 at 5 min. Their birthweights were within the norms laid down by the Italian growth chart [31] for their gestational age, which, according to reliable maternal dates, ranged at birth from 38.1 to 41 weeks (average = 39.6 weeks). The physical condition of all 16 babies was excellent throughout the neonatal period. Preterm infants Thirty-live preterm infants (21 males, 14 females) from the Department of Neonatal Medicine of the University of Modena underwent polygraphic recording at the expected date of delivery, e.g. from 38 to 41 weeks post-menstrual age (PMA), between January 1984 and November 1986. Their gestational age at birth, estimated according to reliable maternal dates, ranged from 26.3 to 34.1 weeks (average = 30.6 weeks). The preterm infants were all scanned by the same examiner (G.F.) through the anterior fontanelle in the coronal and parasagittal planes, three times during the first week of life, once a week during the first and second months, twice monthly during the third and fourth months. GMH-IVH and PVL were classified according to Trounce et al. [39] and the PVL sites were also determined. Preterm infants were divided into two groups on the basis of US scan findings: healthy preterm infants (HP) and pathological preterm infants (PP). The HP group consisted of 17 subjects with normal US scan or grade 1 GMH-IVH. They were also judged to be normal on the basis of their birthweights which were appropriate for their gestational age [31], healthy condition at birth and absence of serious complications during the neonatal period. Their clinical data, US scan images and outcome at 24 months are summarized in Table I. The PP group consisted of 18 subjects with grade 2/3/4 GMH-IVH or PVL. All were affected by serious neonatal complications, e.g. respiratory and/or neurological problems, which required intensive care support. Their clinical data, US scan and outcome at 24 months are summarized in Table II.

Methods Polygraphic recordings were performed at 38-41 PMA and were part of a longitudinal research programme of 4-weekly recordings conducted with the same group of preterm infants. The recordings were carried out between feeds under standardized conditions (infants normally dressed; room temperature, 25-26”C)‘with a portable OTE-Biomedica 12-channel machine, and included

-

EEG from 6 bipolar leads (Fp2-C4; C4-02; Fpl-C3; C3-01; T3-01) according to the electrode position defined by the international lo-20 system with time constant 0.3, gain 50 uV/6 mm and low pass filter 35 Hz; EMG from the chin muscles; EOG recorded by mechanogram using a small piezo-electrical crystal attached to one eyelid [26] or by two small cups applied to the outer canthi of the eyes; nasal respiration recorded by a thermistor placed in front of the infant’s nostrils; thorax and abdominal respiration recorded by strain gauge; independent observation of opening or closing of the eyes and of eyes and body movements.

Sex

M

M

F

M

M

F

1

2

3

4

5

6

data,

Clinical

Case

II

TABLE

29.5

29.2

28.3

28

21.4

26.3

GA

US scan findings

Resuscitation bag and mask, severe RDS, IPPV (Ist-7th day); CPAP (Ith-10th day), prolonged apnoeas Resuscitation bag and mask, RDS, CPAP (lst-6th day; 1 Ith14th day) Apathy s. and prolonged apnoeas. Max. bil. lev. 324.9 pmol/l (5th day)

8

6

1300

1520

Resuscitation bag and mask, RDS, CPAP (Ist-7th d), hyperexcitability s. (8th day). max. bil. lev. 376.2 pmolfl (5th day) Resuscitation bag and mask, RDS, CPAP (Ist-4th d), prolonged apnoeas, IPPV (5th21st day), severe hypoxic episode on 7th day, tonic and subtle seizures, apathy s. (2nd week)

6

1050

day),

bag and mask,

RDS, CPAP (1st-4th prolonged apnoeas

Resuscitation

4

5

1020

apnoeas, hypers. (7th day);

data

max. bil. lev. 342 pmolll (4th day)

Prolonged excitability

Pre and post-natal

CA of 18 PP infants.

1200

9

(5’)

APGAR

at 24 months

1200

BW

and outcome

PVL

PMA 37 weeks: PVL (1 > r): central and subcortical atrophy

PMA 38 weeks: bilateral-frontoparietal-occipital

PMA 40 weeks: bilateral frontoparietal PVL

PMA 36 weeks: GMH-IVH grade 4

PMA 35 weeks: GMH-IVH grade 3, bilateral parietal PVL

PMA 35 weeks: GMH-IVH grade 4

US scan findings

at 24 months

Quadriplegia. conv. strab. DQ 54, mental retardation

Quadriplegia, epilepsy, DQ 40, severe mental retardation

Quadriplegia partial deafness: DQ 49, severe mental retardation

Quadriplegia. DQ 53, mental retardation

Mild diplegia DQ 97

DQ 69 mild mental retardation.

Outcome

CA

F

M

M

M

F

M

I

8

9

10

11

12

32

31

30.4

30.1

30

29.5

1

I

6

1350

1620

5

9

8

1870

0.950

1610

1600

day).

1 previous

miscarriage,

clonic seizures (2nd-3rd day). hypoglycaemia, short apnoeas, early anaemia and leucopenia

antepartum haemorrhage, mild RDS, CPAP (lst-3rd

1 previous preterm birth, CS day).

PMA 34 weeks: GMH-IVH grade 3, moderate and symmetrical dilatation

Antepartum haemorrhage, placenta praevia, RDS, CPAP (lst-8th day), severe apnoeas. Max. bil. lev. 319.7 pmolil (11th day) Bilateral ROP grade 3

PMA 35 weeks: left parietal cyst

of the lateral ventricles grade I

PMA 32 weeks: GMH-IVH grade 2. ventricular dilatatation grade 1, increased diffuse periventricular echogenicity

Vaginal bleedings (lst-2nd trimester), resuscitation bag and mask, severe RDS, CPAP (Ist-6th day), recurrent apnoeas, brief episodes of hypercapnia and hypoxia (1 st week)

PMA 36 weeks: bilateral parietaloccipital PVL

PMA 37 weeks: GMH-IVH grade 2, increased periventricular echogenicity (1 > r); ventricular dilatation (1 > r) grade I1

PVL

PMA 39 weeks: right fronto-parietal

Resuscitation bag and mask, RDS, CPAP (Ist-6th day), prolonged apnoeas, apathy s, Ist-2nd week)

agents (2nd-3rd trimester), two-horned uterus. CS, RDS, CPAP (Ist-5th day) short apnoeas, apathy s.

Vaginal bleedings (I st-2nd3rd trimester). tocolytics

RDS, CPAP (Ist-4th acidosys (ph 7.10)

signs

signs.

(Continued)

Right hemiplegia, conv. strab. DQ 72, hyperactive child

Mild diplegia. reduced visual acuity (1 > r eye) DQ 108

No abnormal DQ 102

Mild diplegia DQ 100

Intermittent conv. strab. DQ 105

No abnormal DQ 102

32.3

33.2

33.5

M

M

F

M

F

F

13

14

15

16

17

18 1780

2200

2200

1900

1570

1025

BW APGAR

6

4

9

7

8

8

(5’)

data

CS, severe RDS, CPAP (2nd5th day), IPPV (5th-9th day); subtle, tonic seizure and comatose s.; 2 severe hypoxic episodes, max. bil. lev. 342 pmolll (5th day)

Severe RDS, IPPV (Ist-1 lth day): CPAP (12th-15th day) status epilepticus (1 st week); right pneumothorax

Resuscitation bag and mask, RDS, CPAP (Ist-4th day), apathy s. (1st week)

Resuscitation bag and mask, mild RDS, CPAP (Ist-3rd day), seizures, hyperexcitability s. (4th-6th day)

Resuscitation bag and mask, hyperexcitability s. (lst-4th day); RDS, CPAP (2nd-5th day); apathy s. (5th-9th day)

CS, acidosis (pH 7.15) hyperexcitability s. (Ist4th day)

Pre and post-natal

PMA 36 weeks: PVL (large and confluent cysts)

PMA 38 weeks: central and subcortical atrophy

PMA 37 weeks: GMH-IVH grade 3

PMA 39 weeks: GMH-IVH grade 3

PMA 38 weeks: right GMH-IVH grade 2; bilateral occipital PVL

PMA 38 weeks: bilateral frontal PVL

US scan findings

at 24 months

signs

signs

CA

ventilation, Max. bil. s. = syndrome.

Quadriplegia conv. strab. DQ 62

Quadriplegia DQ 65

No abnormal DQ 96

No abnormal DQ 108

Mild diplegia DQ 87

No abnormal signs DQ 80, hyperactive child

Outcome

CA = corrected age, CPAP = continuous positive airways pressure, CS = caesarian section, IPPV = intermittent positive pressure lev. = maximal bilirubin level, PMA = post menstrual age, RDS = respiratory distress syndrome, ROP: rethinopathy of prematurity,

34.1

34

33.5

GA

Sex

II (Continued)

Case

TABLE

%

45

The mean PMA at time of recording was 40 weeks for the FT infants, 39.6 weeks for the HP infants and 40 weeks for the PP infants. At the time of recording the infants, clinical condition was good. Body movements (present in State 2, rare in State l), respiration (irregular in State 2, regular in State l), eye movements (present in State 2, absent in State l), opening or closing of the eyes and crying were used for identification of Prechtl’s five behavioural states [32]; these were identified by means of the moving windowmethod [20], which highlights stable parameters while enabling occasional changes in state due to fleeting perturbations of the variables to be ignored. The verticallyaligned profiles of all the variables were then scanned horizontally to indicate the onset and offset of each state. A state was deemed present if, throughout the 3-min period, its configuration met all the criteria required for State 1 or State 2. A transition was considered to have occurred if all three variables changed and a new combination emerged within the 3 min. If criteria for both states were lacking ‘no state identified’ was recorded. EEG patterns were analyzed according to Nolte and Haas [22], whose method is a modification of the original EEG coding system developed by Parmelee et al. [27]. With this method EEG patterns are coded by means of a three-digit code (Fig. l), the first two of which express the maturational variations (maturational code), the approximate PMA being expressed in weeks, while the third refers to the basic pattern type (type code). The patterns were established on the basis of consecutive 1-min EEG epochs. Profiles of EEG age codes, EEG type codes and state sequence, which enable relationships between EEG-pattern sequence and state sequences to be established, were plotted along a time axis (Fig. 7). According to Haas and Prechtl [13], the EEG-code profiles ‘... are superior to the previously employed statistics on age inadequate codes [35] which do not account for the dynamic aspect of the sequence and consistencies of age-inadequate codes in

EEG

EEG

-

TYPE

-

CODES

7

5

3

2

44

447

445

443

442

441

40

407

405

403

402

401

36

367

363

32

327

323

-

MATURATIONAL

-

CODES 28 Fig. 1. Schematic

presentation

of EEG pattern

287 development

in preterm

infants.

.1

46

relation to state and EEG type’. All polygrams were analyzed by the same examiner (A.T.), who was unaware of the infants’ identities and ages. Only EEG epochs free of artifacts were analyzed. The degree of EEG maturity in individual cases was established by calculating the mean ‘bioelectrical age’ (BA) corresponding to the average of age codes. The number of fluctuations from one maturational code to another was counted in State 1 and 2 for both HP and PP infants. In order to determine whether cerebral damage led to specific EEG abnormalities, each EEG was analyzed by a second examiner (F.F.) with a view to detecting the presence, if any, of generalized low voltage with normal background activity; persistent interhemispheric voltage asymmetry of all background rhythms of more than 50%; poorly developed occipital delta [38]; absence of spatial organization [19]; poor interhemispheric synchrony, e.g. synchrony of ‘trace-alternant’ (TA) burst less than 50% (according to Lombroso [16] the percentage of interhemispheric synchrony in normal newborns is 80-100% at 37-39 weeks, 100% at 40-42 weeks PMA); repetitive focal spikes [ 191;poorly represented frontal sharp transient during the first 5-min epochs of State 1 [2]; poorly developed TA (few theta activities within TA bursts). The preterm infants were examined at corrected ages for prematurity of 3, 6, 9, 12, 18 and 24 months. The follow-up examination consisted of a detailed neurological examination and assessment of development according to the Griffiths Scales [ll]. The neurological outcome and developmental quotient (DQ) at 24 months of HP and PP infants, respectively, are listed in Tables I and II. The infants were classified as being normal, having minor handicaps or having major handicaps. An infant was considered normal if his DQ was higher than 85 and showed no neurological abnormalities at 24 months; he was considered as having minor handicaps if his DQ was between 70 and 85 and/or he showed hyperactivity, mild diplegia, allowing independent walking, and mild hemiplegia, with the motor activity of the affected limbs being fairly well preserved; he was considered as having major handicaps if he was mentally retarded, with a DQ of less than 70, and/or exhibited cerebral palsy (severe diplegia or quadriplegia). The data were processed using the SPSS statistics package.

TABLE

III

Analysis of variance of percent time spent in State 1 and State 2 as far as the maturational codes, types codes and EEG patterns (type codes by maturational codes) in the 3 groups of infants are concerned. Effect

Contrast

F

df

P

Maturational codes Type codes

FT-HP HP-PP FT-HP HP-PP FT-HP HP-PP

3.33 2.27 1.43 1.07 2.24 0.65

4.45 4.45 8.41 8.41 8.38 8.38

0.076 0.018 0.215 0.400 0.023 0.135

EEG patterns (type codes by maturational

codes)

41

Results Multivariate analysis of variance was used and two sets of data taken into account, namely, FT versus HP and HP versus PP. The values are quoted in percentage terms to allow comparison between data deriving from recordings of different duration. Time spent in State 1 and State 2 was analyzed for each of the above categories and referred to maturational codes, type codes and EEG patterns (type codes in relation to maturational codes); the results of the analysis of variance being reported in Table III. The average of percentages of artefact-free time spent in State 1 and State 2 was not found to vary significantly between FT and HP, or between HP and PP. Maturational codes Maturational codes corresponding to 3640 and 44 weeks were observed for each group, with a preponderance of codes corresponding to 40 weeks; code 32 was never observed. The mean times spent in the different maturational codes by FT, HP and PP infants are shown in percentage terms in Figs. 2 and 3. FT and HP do not differ significantly with regard to the time spent in maturational codes observed (P = 0.076), whereas there are significant differences (P = 0.018) between HP and PP (Table III) which, according to univariate analysis, can only be attributed to State 1 (P = O.OOl), for in State 1 HP exhibit a higher percentage of mature or advanced codes (40 and 44 weeks) and a lower percentage of immature codes (36 weeks) with respect to PP infants. The amount of time spent in the three EEG maturational codes by individual FT, HP and PP infants in State 1 and State 2 is shown in Fig. 4a, b and c. The percentage of EEG maturational codes observed varied remarkably from individual to individual in all three groups. At least two codes were present in all infants, with the exception of one infant (case no. 14 of the FT group) who presented the 40-week code only. Young maturational codes were observed in the majority of infants (14 out of 16 FT, 13 out of 17 HP and 17 out of 18 PP) and the percentage of these young codes varied remarkably from case to case in all three groups. In the majority of FT and PP infants younger codes were observed both in State 1 and in State 2 (10 out of 14 FT and 14 out of 17 PP). On the other hand, in 7 out of 13 HP infants younger codes were present in one sleep state only, which in 6 out of 7 HP infants was State 2. Older EEG codes were observed less frequently than the young codes (7 FT, 11 HP and 4 PP infants) and were clearly predominant in State 1 among all three groups of infants. Fluctuations When the fluctuations from one maturational code to another in State 1 and 2 (see Fig. 7a, b, c and Fig. 8a, b, c) are compared in HP and PP infants by means of the Mann-Whitney test, PP infants exhibit a significantly-greater number of fluctuations than HP infants in both (Table IV). Type codes The mean time spent in type codes 1,2,3,5, and 7 by the three groups of newborn infants in State 1 and 2 is shown in percentage terms in Fig. 5 and Fig. 6. In all

44

40

maturational

Fig. 2. Mean percentage (HP) and pathological

codes

of time spent in maturational codes 36, 40,44 pretenn

(PP) infants

by fullterm

(FT), healthy

preterm

in state 1.

PP

10

0

L-

maturational

Fig. 3. Mean percentage (HP) and pathological

of time spent in maturational preterm

44

40

36

(PP) infants

codes

codes 36,40,44

in state 2.

by fullterm

(FT), healthy

preterm

49

TABLE

IV

Number of fluctuations from a maturational code to another statistical comparison was performed with the Mann-Whitney Fluctuations

HP

PP

State I Mean

1.42

2.21

S.D.

0.71

1.16

State 2 Mean

0.91

1.9

SD.

0.69

0.91

per 10 min. in HP and PP infants: test.

the

P

0.0017

0.0015

groups, type codes 5 and 7 predominate in State 1, type 2 and 3 in State 2. Comparison between FT and HP and HP and PP infants, respectively, does not reveal any significant differences (Table III). EEG patterns

The mean time spent in each EEG pattern during State 1 and 2 are shown in Table V. The FT-HP comparison (Table III) is statistically significant (P = 0.023) in that, in State 1 (Table V), the HP exhibit a lower incidence of ‘trace alternant’, corresponding to EEG pattern 407 (28.4 versus 48. l), and a higher incidence of ‘high-voltage slow’ EEG corresponding to EEG pattern 405 (22.5 versus 14.8), whereas in State 2 (Table V) they exhibit a lower incidence of EEG pattern 403 (3 1.7 versus 47). The HP-PP comparisons do not indicate any statistically significant differences (Table. III). We looked for specific trends of EEG codes during State 1 and 2. In this regard, Haas and Prechtl [13] found, in a group of at risk infants ‘... at the onset of State 2 epochs, age code 40 dominated while at the end, 36 weeks codes appeared in an increasing number. At the onset of State 1, following the end of State 2, the EEG maturity may then drop to 32 weeks codes’. In our three groups of infants no relationship between EEG codes and onset-offset of the state could be seen. Younger codes (see Fig. 7a, b, c and Fig. 8a, b, c) were found at the beginning and/or in the middle and/or at the end of the state, and this was true even for the same recording from the same infant. Immature EEG codes and duration of the state were also examined to see whether there was any correlation between the two. The manual analysis of the polygraphic profiles failed to find evidence of any such correlation and any further statistical computation was abandoned. Individual polygraphic profiles show whether younger codes are present in all State-l and State-2 epochs from the same recording (Fig. 7 and Fig. 8).

50 STATE1

STATE2

4 6 6 7 6 0 10 11 12 13 14 16

16

16

16 0

10

fi

20

11 80 46

11

SO

60

1

fi

70

60

1

I

80100

%

0

10

20

STATE1

SO

40

50

60

70

60

60

70

60

90 100 %

STATE2

7 6 0 10

10

11

11

12

12

1s

1%

14

14

16

15

16

16

17

17 0

10

20

SO

40

SO

60

70

60

60 100

%

111

0

10

20

1’EBI SO 46

1

60

I,

90 100 %

Fig. 4. (a) Percentage of 36,40 and 44 EEG maturational codes in state 1 and state 2 spent by individual FT infants. (b) Percentage of 36,40 and 44 EEG maturational codes in state 1 and state 2 spent by individual HP infants. (c) Percentage of 36, 40 and 44 EEG maturational codes in state 1 and state 2 spent by individual PP infants.

51 STATE1

STATE2

1 2 3 ??

6 6 7 E6 t 06 10 11 12 18 14 16 16 17

l-l 0

10

20

SO

46

50

60

70

60

60100

%

0

10

20

SO

40

50

60

70

60

60100

%

Fig. 4. (Contimed)

Of the infants with two or more State-l epochs, 1 out of 7 FT, 7 out of 12 HP and 10 out of 12 PP infants exhibited younger codes in all State-l epochs, while of the infants in whom two or more State-2 epochs were recorded 11 out of 15 FT, 11 out of 14 HP and 12 out of 18 PP infants exhibited immature codes in all State-2 epochs. As an additional aspect of the EEG-code profiles, we explored the relationship between EEG codes and EEG types. In State 1, young codes occurred predominantly with type 7, whereas in State 2 young codes appeared predominantly with type 3. There were exceptions to this rule only among the HP group: in State 1, four HP infants (cases 7, 9, 10 and 17) exhibited pattern 367 as well as pattern 363. Older EEG codes (e.g. 44-week code) in State 1 were restricted to type 7 and in State 2 to type 2. Correlations between bioelectrical age (BA) and post-menstrual age (PMA) Bioelectrical age (BA), post-menstrual age (PMA), BA in State 1 (BA I), BA in State 2 (BA 2) and the difference BA-PMA for each subject at the time of recording are shown in Table VI. Each group contains subjects with BA greater than, less than, or equal to PMA. Median BA, median difference and the range between BA and PMA are shown in Table VII. In FT and HP infants, median BA and median BA-PMA are similar. In both groups median BA-PMA is less than 1 week. The range BA-PMA is wider in HP

52

Ez2

3

2 type

5

codes

of time spent in type codes I, 2, 3, 5, 7 by fullterm Fig. 5. Mean percentage and pathological preterm (PP) infants in state 1.

(FT), healthy

preterm

m

3

2

type

PP

(HP)

PP

5

codes

Fig. 6. Mean percentage of time spent in type codes 1, 2, 3, 5, 7 by fullterm and pathological preterm (PP) infants in state 2.

(FT), healthy

preterm

(HP)

V

I

0

0 0

0

0

0.3 f 1.3 f

1.4 5.2

0 0

0.1 f

0 0 0

0.2

0

FT HP PP

44 3.1

4.6 f 3.4 3.6 + 5.2 5.4 + 9.8

41 + 21.3 31.1 + 26.5 21.2 f 19.4

28.8 f 10.9 28.6 + 20.5 23.8 f 28.4

4.9 zt 6.3 4.5 f 16.3 6.8 f 14.3

FT HP PP

40

0.7 f 0

0

0

3.6

1.4 zt

0

0

0

8.9 f 9.4 24.6 f 26.8 31.3 + 21.5

0

0

36

1.9 3 6.2

0.1 ?? 0.2 0.2 f 0.7 0

2 + 6.2 3.6 zk 10.1 0.6 f 1.6

3.2 + 1.2+ 3 +

10 zt 19.2 16.2 f 19.5 2.8 zt 6

48.1 f 24.4 28.4 f 27 21.5 f 25

14.8 zt 11.4 22.5 f 19.6 15.8 f 21.9 0.2 * 0.5 3.9 ?? 9.7 0

15.5 ?? 27.1 40.6 f 29.5

23.5

22.6 f

0 0

I

0

0

0

0

0

0

FT HP PP 0

1.9 ?? 3.3 4.1 zt 8.3 2.1 ?? 5.4

1* 1.5 4.8 zt 8.4 5.9 f 10.9

3.8 0.5

0.9 f 0.1 f

FT

0.5 * 1.2

0

0.7 f

1.8 6.2 11.6

5

HP and PP infants.

HP PP

0

1.9

0.8 f 3.6 f 8.1 f

0

3

I and 2 by FT newborns,

0

2

in States

0

1

Type codes

EEG patterns

HP PP

FT

Subjects

time spent in different

FT HP PP

State 2

44

40

36

Slate

Maturational codes

Mean percent

TABLE

54

a EEG

44

%;E

$,03

TIME

l-l uu

0

I r-l I

uuu

IJ

nil

l-l

50

100

n

150

MIN

b EEG AGE CODE

TIME

$]a. 36

__ ____

0

L

L_-

__._-uu----

50

3

100

.

MIN

C

_._r--

I-

-

LT

--

-

-

1 TIME

0

50

100

I 150 MIN

Fig. 7. EEG and state profiles of FT case 6, PMA at the day of recording 39.4 weeks (a), of HP case 13, PMA 38. 6 weeks (b), of PP case 16, PMA 38.3 weeks (c). Periods with body movements and EEG artifacts, which do not allow EEG coding and EEG type recognition, are indicated by interrupted lines.

55

EEG AGE CODE

40 J 36

EEG TYPE CODE

STATE

a

44 -

7 : 2 1I

J-L-

--.-__r-

J-k

_.._a-

-L-.-----L_

'-:i' 2

TIME

0

50

100

150

MIN

b

7

EEG TYPE CODE

STATE

: 2 1I

y1

2

I 0

TIME

100

50

MIN

C EEG AGE CODE

44 40 36 3

CODE

;j

_

STATE

2 ‘-3

1

TIME

0

-

-

~-L-r--l-r

--J

---

50

100

MIN

Fig. 8. EEG and state profiles of PP case 5, PMA at the day of recording 40.5 weeks (a), of PP case 2, PMA 40.2 weeks (b), of PP case 3, PMA 41.6 weeks (c). Periods with body movements and EEG artifacts, which do not allow EEG coding and EEG type recognition, are indicated by interrupted lines.

VI

39.8 40.8 36.3 42 40.8 37.8 42.7

40.9 41.2 39.8 40 41.4 39.9

39 40.2 38.7 36.9 37.1 40 37.8 31 39.9 38.5 39 31

38.8 38.5 40.3 38.3

40.1 38.7 40.5 40.6

39.5 39 31.5 41.7

39.6 38.1 41.3

38.7 39.4 40.3 38.5 38.3 40.4 40.7 39.2

40.2 39.9 39.9 40

40.6 39.8

3 4 5 6

1 8 9 10

11 12 13 14

I5 16 17 18

40.7 38.1 38.2 36

36.6 40 37.8 37.5

36.2 38.5 39.5 31.3 37.5 38 37.9 40.5 38.1 36.4

38.2 40.5 41.2 38.4 40.9 40.5 41.2 36.3 40.6 41.8

37.7 37.8 37.6 38.3 40.3 31.6 39.3 40.8 42.5 39

37.5 38.6 39.5 38.6 31.2 38.6

39 40.1

38.1 38.7

1 2

PP

HP

FT

HP

FT

PP

BA

Case

BA

1

39.7 39.1

39.4 37.8 31.9 40.8 37.8 38.3 39.3 39.4 38.2 39.1 31.4

31.2 40 31.9 36.8

41.3 41.3

40.6 40.8 41 41

40.2 38 40

38 39.6 39.8 39 38.5 39.6 41 40.2 40 39 38.6 40.8

39.8 40 40 38.6 39 40.3 39 40.3 39.1 38.3 41.2 40.2

-0.4 -0.9 -1.1 -1 -0.7 -1.5

0.4 -0.1 -0.3 0.2 1 -0.9 -0.8 0.2 0.2 -1.4 39 39.2 39.3 39.4 39.1 40.2 40.5 40.6

40.6 40.2 41.6 40.3 40.5 41.3

39.5 39.6 31 39.4 40 40 39.5 37.1

40 41

38.3 38.8

40 39.8 37.3 38.5 40.1 36.9 40 39.2 40.5 40

-0.6 0.1 1.3

-1 -0.9 0.8 -1.1 0.5 -0.7 2.2 -0.9 -0.5 0.4 -0.5 -1.1 0.9

-1.9 -0.3 -1.2 -3.3 0.2 0.2 -2.2 -3.2

-3.1 -1.6 -2.1 -1.7 -3.3 -2.7 -0.8 0.2 -1.3 -1.7

PP

38.2 38.6

39.2 39 39.2 40 40.3 39.4 37.7 39.8 40 39.3 39.9 39.3 40 40

HP

FT

FT

PP

and post-menstrual

FT

bioelectrical

BA - PMA (weeks) PP

between

PMA HP

age (PMA) and difference preterm infants (PP).

BA 2 HP

Bioelectrical age (BA) in State 1 (BA 1) and in State 2 (BA 2) post-menstrual (BA - PMA) in fullterm newborns (FT), healthy preterm (HP) and pathological

TABLE

age

57

TABLE

VII

Median value of bioelectrical age (BA), of difference between bioelectrical and post-menstrual age (BA - PMA) and range of differences observed in fulltem infants (FT), healthy (HP) and pathological (PP) pretenn infants. FT (16) Median BA Median BA - PMA Range BA - PMA

HP (17)

39.85 -0.55 -1.5/+1

PP (18)

39.5 -0.5 -1.1/+2.2

38.6 -1.7 -3.3/+0.2

infants (3.3 versus 2.5). The greatest negative deviation between BA and PMA is equal to 1.5 and 1.1 weeks in the FT and HP.groups, respectively. By comparison with HP infants, PP infants had a lower median BA (38.6 versus 39.5), a greater BA-PMA (1.7 versus 0.5) and a wider range BA-PMA (3.5 versus 3.3) More than 70% of the PP infants have BA-PMA greater than 1.1 weeks. When BA 1 is compared with BA 2 in single cases, marked differences emerge both in HP and PP infants: in 10 HP infants, BA 1 and BA 2 differ by 1.2 weeks or more, and in 6 of these cases the difference is equal to more than 2.9 weeks; in 7 PP infants, this difference is equal to more than 1.4 weeks.

TABLE

VIII

EEG abnormalities

recorded

at 40 weeks PMA age in the PP infants.

Case

BA - PMA

TA

I. SYNCHR.

5 14

-3.3 -3.3

18

+ + + +

6 17

-3.2 -3.1 -2.1 -2.2

+ + + + +

+

+

3 11 10 4

-2.1 -1.9 -1.7 -1.7 -1.6 -1.3 -1.2 -0.8

+ + + +

+ +

2 9 13 7

+ + + +

12 15 8 16

-0.3 0.2 0.2 0.2

1

+ +

FST

OS

+

s +r +r

+ + +

+ +

f

+

TA = ‘trace alternant’ poorly developed (a few theta activities within bursts), I. SYNCHR. = interhemispheric synchrony less than SO%, FST = poorly represented frontal sharp transients, OS = poor spatial

organization,

S = focal spikes.

58

+2

+1

0

-1

-2

-3

Fig. 9. BA-PMA minor handicap;

and developmental outcome (A) major handicap.

at 24 months

in the 3 groups

of infants;

(0) normal;

(A)

EEG abnormalities No EEG abnormalities were noticed among FT infants. Poorly-developed TA and poorly-represented frontal sharp transients were observed in only 2 of the HP infants, both of whom were affected by GMH-IVH grade 1. The EEG abnormalities observed in PP infants are ranked according to BA from most deviant to most age-adequate in Table VIII. The more immature was the EEG, the more numerous were the EEG abnormalities. The most common abnormality was poor interhemispheric synchrony in TA bursts (11 cases), most often associated with poorly-developed TA (10 out of 11 cases) and often with poorly-represented frontal sharp transients (9 out of 11 cases). In two cases with the most-marked bioelectrical immaturity, focal spikes occurred during TA. Abnormalities such as low-voltage EEG, persistent asymmetry or rare occipital delta activity were never detected. Correlations between BA-PMA at term age and developmental outcome at 24 months The correlation between BA-PMA and the developmental outcome at 24 months is shown in Fig. 9. All FT and HP infants developed normally, whereas, of the PP infants, 6 developed normally, 5 had minor handicaps (3 cases of mild diplegia, 1 case of mild hemiplegia, hyperactivity, convergent strabismus and DQ = 72, 1 case of hyperactivity and DQ = 80) and 8 were severely handicapped (4 cases of quadriplegia and mental retardation, 2 cases of quadriplegia, 1 case of diplegia, and 1 of mental retardation). Of the PP group, all with EEG immaturity of more than 2 weeks developed severe handicaps. Of the 8 PP infants with EEG maturity com-

59

prehended within the range of BA found in FT and HP infants (-1.6-0.2) 4 cases were normal but 4 cases developed a minor handicap. Of the 3 cases with EEG immaturity of between 1.6 and 1.9 weeks 1 infant was normal, 1 infant was affected by minor handicap and 1 infant was affected by a severe handicap. Discussion

The comparison between FT and HP infants of the same CA was intended to determine the influence of premature birth on EEG maturation in the absence of perinatal and neonatal pathologies. The similarities between the two groups of infants were greater than the differences. Similarities concerned the amount of time spent in maturational and type codes, the presence of specific types for each sleep state (5-7 in State 1 and 2-3 in State 2), average BA and average BA-PMA. HP infants only differed in that they exhibited a higher, albeit non-significant, incidence of immature EEG codes in State 2 and a different proportion of the EEG patterns appropriate to 40 weeks PMA (less 407 and 403, more 405). We therefore now have confirmation, many years after the first studies [5,27] and using low risk preterm infants selected on the basis of brain ultrasonography scan not available at the time of the above research, that the extra-uterine environment does not accelerate or retard the bioelectric maturation of the CNS. Parmelee’s conclusion 1291that ‘...EEG maturation is largely a function of conceptional age with minimal alteration as a function of extra-uterine existence’ would appear to be confirmed. The comparison between HP and PP infants was intended to illustrate the influence of perinatal and/or neonatal haemorrhagic and/or hypoxiclischaemic cerebral lesions on EEG. Serious abnormalities of the background EEG such as EEG inactive or hypoactive, excessive discontinuous interburst activity, prolonged interburst intervals, interhemispheric asymmetry, interhemispheric asynchrony, low amplitude, discharges, positive rolandic sharps which have been described in early stages of GMH-IVH and/or PVL [3,33,38] were not present in any of the pathological preterm infants; the correlation between type codes and sleep states and between EEG patterns and sleep states was found to be just as good as among HP and PP infants. The most significant aspects of the present study were the high incidence of ‘younger’ maturational codes (e.g. 36-week code) and the greater number of fluctuations between maturational codes observed in the PP infants. The greater number of fluctuations has already been pointed out by Haas and Prechtl [13], in a group of fullterm infants at risk, and also by Nolte [23,24] in high-risk preterm infants. It should be stated that in our group the fluctuations were observed both in State 1 and in State 2, more frequently in State 2, whereas Haas and Prechtl [13] found them predominantly in State 1. EEG immaturity, which has been called age-inadequate patterns [ 13,3 1,331, EEG regression to early maturational levels [14], ‘EEG trop jeune’ [6], EEG dysmature for PMA [38] is a widely-reported phenomenon in high-risk preterm infants. The relationship between this immaturity and sleep states is a moot point, since Dreyfus-

60

Brisac [6] and Haas and Prechtl [13] find immaturity mainly during State 1 while Lombroso [ 161 finds it in State 1 and/or 2. In our PP infants EEG immaturity was found mainly in State 1. The diagnostic and prognostic value of EEG immaturity has recently been studied. Lombroso [ 15,161 considers the percentage of interhemispheric asynchrony and the number of delta brushes as measures of brain maturation. On the basis of these two parameters he distinguishes transient dysmaturity from persistent dysmaturity and maintains that persistent EEG dysmaturity with a deviation of more than two weeks is likely to be followed by abnormal outcomes and should therefore be given a negative prognostic value [17]. Tharp et al. [38] agree with Lombroso and illustrate the negative prognostic bearing of dysmature EEG features. Ellingson and Peters [9], however, are much more prudent as to the diagnostic and prognostic significance of EEG dysmaturity and maintain that dysmaturity, in isolation, cannot be considered as a specific indicator of cerebral disorder unless it is very severe (e.g. of the order of 5 or more weeks). The criteria as to how to evaluate EEG maturation are still being debated. Tharp et al. [39], in a study subsequent to that previously mentioned [38], are very prudent with respect to the recognition of dysmaturity. They state that the criteria for dysmaturity based on the number of delta brushes and interhemispheric synchrony are ‘... often hard to evaluate in the small premature and particularly when one ‘uses eyes only’ quantitative indices’. These authors [38] consider dysmature records moderately abnormal ‘...only when these transients are excessive in EEG performed at 37 weeks CA’. In our study we adopted criteria for the definition of EEG maturity that are quite different from those used by Lombroso [15,16] and by Tharp et al. [39]; also, ours is a transversal and not longitudinal study, which precludes a direct comparison between our findings and theirs. Nevertheless, it is worthy of note that in our investigation of premature pathological infants we too found that EEG immaturity is the most significant sign of cerebral lesion; our study shows that EEG immaturity at term of between 1.6 and 3.3 weeks is observed only in the presence of haemorrhagic and/or hypoxic/ischaemic lesions of the CNS, which never occur in the healthy fullterm newborn or in preterm infants without serious CNS damage when they reach term. The search for other EEG abnormalities, together with, or as alternative to, EEG immaturity, was based on the need to check whether the EEG at term of pathological preterm infants is invariably and exclusively a question of immaturity or whether other types of EEG abnormality are present. In this context, Haas and Prechtl [13] state that ‘... there are infants at term whose EEG is so disturbed that a coding according to type and age patterns no longer possible... Many have abnormal EEG’s that do not resemble younger age codes’. Nolte [23] describes not classifiable EEG codes in high-risk infants. However, the EEG of our PP group were never so disturbed as to make it impossible to assign an EEG code, nor were serious background EEG abnormalities discovered. The kind of EEG abnormalities we found were essentially excessive asynchrony of the ‘trace alternant’, lack of frontal sharp transients, and ‘bouffees’ of the ‘trace alternant’ with little activity at 2-6 c/s. They occurred almost always

61

in association and in the subjects with the most immature EEG codes. Since synchrony of TA, frontal sharp transients and ‘trace alternant bouffees’ are commonly considered as maturational EEG features, we again have confirmation that, even if EEG analysis criteria other than maturation codes are used, the main abnormality present in the EEG patterns of PP infants at term consists of immature EEG patterns. As for abnormal TA we frequently observed monomorphism of the TA ‘bouffees’ and a monotonous rhythm that varied little with time. As for the question of whether the inappropriate EEG patterns show a specific sequence and state relationship as stated above we found no relationship between young EEG codes and onset/offset or duration of the states. Furthermore, young codes were often found in one but not all successive State l-State 2 epochs of the same recording, regardless of groupings, As a practical sequence, the bioelectrical age may vary, in a single infant, according to the duration of the recording and the number of State l-State 2 epochs. In confirmation of previous studies by Dreyfus-Brisac [5,6] and Haas and Prechtl [ 131, we found a clear state relationship between young codes and State 1. Turning finally to the prognostic value of EEG maturation at term, the limited number of subjects studied does not allow us to draw definite conclusions. A bioelectric age appropriate to the PMA, even in the presence of CNS damage, seems to prelude either to a normal development or to minor handicaps, while EEG immaturity of more than 2 weeks always presages greater complications. The outcome of preterm infants with a 1.6-1.9 weeks immaturity is uncertain. Acknowledgements

The Authors gratefully acknowledge Prof. H.F.R. Prechtl who made helpful suggestions and reviewed critically a previous version of the manuscript. We also thank Prof. G.B. Cavazzuti, chief of the Institute of Pediatrics and Neonatal Medicine of Modena University, for his continuous support and encouragement in the research. References Amiel-Tison, C. and Grenier, A. (1985): Evaluation neurologique du nouveau-ni et du nourrisson. Editor: Masson. Paris. Arfel, G., Leonardon, N. and Moussalli, E. (1977): Densite et dynamique des encoches pointues frontales dans le sommeil du nouveau-n6 et du nourrisson. Rev. EEG Neurophysiol., 7, 351-360. Connell, J., Oozer, R, De Vries, LX, Dubowitz, L.M.S. and Dubowitz, V. (1987): Continuous fourchannel EEG monitoring in the evaluation of echodense ultrasound lesions and cystic leukomalacia. Arch. Dis. Child., 62, 1019-1024. Dreyfus-Bri sac, C., Flescher, J. and Plassart, E. (1962): L’ilectroencephalogramme. Critere d’lge conceptionnel du nouveau-m? a terme et premature. Biol. Ntonat., 4, 154-173. Dreyfus-Brisac, C. (1966): The bioelectrical development of the central nervous system during early life. In: Human Development, pp. 286-305. Editor: F. Falkner. Saunders, New York. Dreyfus-Brisac, C. (1977): Conclusions g&r&ales. Rev. EEG Neurophysiol., 7, 3, 416-419. Eisengart, M., Gluck, L. and Glaser, G.H. (1970): Maturation of electroencephalogram of infants of short gestation. Dev. Med. Child Neural., 12, 49-55. Ellingson, R.J. (1964): Studies of the electrical activity of the developing human brain. In: The Developing Brain-Progress in Brain Research, pp. 9-24. Editors: W.A. Himwick and E.H. Himwick. Elsevier, Amsterdam.

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28 29 30 31

32

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34 35 36 31 38

39

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Radvanyi-Bouvet,

M.F. (1988): Valeur prognostique

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of slow-wave

sleep in low-birthweight