52
PEDIATRICS
Vol. 76 No. 1 July1985Stability
in Waking-Sleep
States
in Neonates
as a Predictor
of Long-Term
Neurologic
Outcome
Cesare
T. Lombroso,
MD, PhD,
and Yoichi
Matsumiya,
PhD
From the Seizure Unit and Division of Neurophysiology, Department of Neurology, The
Children’s Hospital, and Department of Neurology, Harvard Medical School, Boston
ABSTRACT. Thirty-three full-term neonates were ranked
blindly on a scale ranging from the least to the highest
“risk” for future neurologic complications on the basis of
available perinatal biographies, tests, and examinations
performed during the newborn period. Four prolonged
polygraphic-behavioral recordings were obtained one
week apart beginning at ten days after birth. Five waking
and sleep states were scored in each session as
percent-ages of total observation time, giving a total of 20 scores
for each baby to be subjected to analysis of variance. These measures also provided individual profile
consist-ency or variability in maintaining waking-sleep states
over the selected period of postnatal time. The whole
cohort, except three infants who could not be followed
adequately, was then reexamined periodically over a
pe-nod ranging from 3 to 4 years (±6 months) for neurologic
and developmental assessments. Except for two scores
that produced a low level of statistical significance (P <
.05), the other 18 scores were found to be not associated
with long-term outcomes. Even the first two scores were
not satisfactory discriminators for the outcome of the
individual babies. However, when coefficients of
concord-ance (W) were computed from each individual baby
pro-file, significant statistics (P < .001) emerged to indicate
good correlations between high or low W values in the
newborn period and long-term outcomes. All 17 newborns
who had W scores greater than 0.9 were found to be
normal at follow-up regardless of the poor ranking given
several of them during the newborn period. Among the
13 newborns who had W scores less than 0.9, 11 had a
poor clinical outcome at follow-up, though several had
been ranked initially as falling within the least “risk”
group. Pediatrics 1985;76:52-63; newborns at risk,
wak-ing-sleep profiles, neurologic assessment.
Neonatal EEGs provide noninvasive diagnostic
clues and have been shown by many to be a powerful
Received for publication May 6, 1983; accepted Aug 14, 1984. Reprint requests to (C.T.L.) Seizure Unit, The Children’s Hos-pital, Boston, MA 02115.
PEDIATRICS (ISSN 0031 4005). Copyright © 1985 by the American Academy of Pediatrics.
tool to suggest short- and long-term outcomes.’2
In our investigations during the past two decades,
we classified newborn polygraphic EEG recordings
according to the presence or absence of (1)
abnor-malities in background EEG activities, (2) ictal
abnormalities, and (3) abnormalities in the
orga-nization of “states” (for a definition of “states,” see
references 12 to 17) and in some specific EEG
maturational indices.12’18’19 We were able to
estab-lish their consistency or inconsistency by serial
tests during the newborn period and to correlate
them with clinical outcomes in prospective studies.
We obtained some significant statistical
correla-tions between these groups of recordings and
long-term outcomes in various cohorts of infants “at
high risk.”
These correlations, however, refer to groups of
babies, not to individuals. Whereas we might
pre-dict what outcome awaits a group of babies at high
risk, we are often unable to determine how an
individual baby might fare. The purpose of the
present study was to seek new strategies for
obtain-ing more individual long-term prognosis.
Neonates with known anomalies in their CNS
show deviations in the duration of their sleep
states or in some specific components of the
lat-ter.’2’4”8’2025 We thought that we might enhance
our ability to predict individual outcome by
system-atically measuring for a period of postnatal life a
baby’s consistency in maintaining its states.
Most investigations have dealt with the more
easily qualifiable and quantifiable sleep states and
the transitions between them. We chose to include
waking states as well. Although these have been the
subject of fewer controlled studies, we assumed that
their inclusion might more fully demonstrate how
predetermined inborn schedules interact with, and
are modified by, exogenous and endogenous factors.
Kleitman,26 Prechtl et al,’3 and Wolff’5 were some
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ARTICLES 53
of the early authors to include waking states in
their studies, they established some of the
taxon-omy, and they reached some conclusions about
waking-sleep organization and about how it could
be influenced by morbidity.
MATERIALS
AND METHODS
Population
Thirty-three full-term newborns were studied;
three were eliminated from the study because they
were lost at follow-up. We studied a population of
babies that were waiting for adoption and, hence,
they were kept at their nurseries for a longer time
than usual. Selection depended on the availability
of required information and access. The scope of
the study was described to appropriate guardians.
Care was taken to stress that this was an
investi-gative endeavor and that the only benefits to the
babies were inherent in their being followed
regu-larly and, if abnormal signs or symptoms developed,
appropriate measures were to be taken. The
gesta-tion, age, sex, and prenatal, perinatal, and postnatal
status of each infant are shown in the Table.
Rating
of Population
To minimize selection biases and to avoid the
risk in arbitrarily assigning each infant to discrete
categories (“normal,” “at risk,” “at high risk,” etc),
we adopted a method of rank order. Three pediatric
neurologists were given the information shown in
the Table except for the long-term outcomes listed
in the column on the right (a single-blind design).
They were asked to project by a ranking method
the degree of future risk for neurodevelopmental
deficits for each subject, considering the given data
on the prenatal, perinatal, and postnatal biography,
tests, and clinical status. Their task was to arrange
the series of neonates in a scale ranging from the
infant thought to be at “the least risk” to the one
considered to be at “the highest risk.” Then the
whole population was arranged in a serial order,
assigning number 1 to the subject rated as being
least at risk progressively to the one considered to
be most at risk. There was a good agreement among
the three raters (r = .70). As shown in the Table,
the subjects are arranged according to the sum of
the three ranked values given by the three raters so
that the first subject in the list (baby 1) received
the best combined rank (least risk) and was given
a new rank of 1, and the last one (baby 29) received
the worst combined rank (highest risk) and was
given a new rank of 30. The new ranking order
based on the combined ranks is shown in the
col-umn on the left. Within the group of newborns
ranked at low risk, the EEG findings obtained
within the first week after birth were normal except
for five infants: in one newborn there was an
ex-cessive number of apneic episodes of “central type”
during non-rapid eye movement (NREM) sleep,
with some rolandlic isolated sharp waves; in two
infants there were dysmaturity indices of a
tran-sient nature189; two newborns had excessive
ro-landic and/or multifocal spikes, with otherwise
nor-ma! background and sleep states. Within the group
of newborns ranked at progressively higher risk,
genera! and neurologic examinations during the
newborn period, however, revealed no unequivocal
evidence of obvious, severe CNS impairment such
as persistent and marked hypotonia, continuing
seizures, or evidence of persistent brainstem
dys-function. Three infants actually had borderline
neurologic assessments, but they were classified as
at risk because of their morbid histories. The
neu-rologic examinations utilized the techniques of
Amiel-Tison, modified according to states (see
Lombroso,8 Prechtl’6). EEG findings were
abnor-ma! initially in 13 babies, but six of these infants
subsequently
had normal EEG findings. AbnormalEEG findings showed only in four infants some of
the patterns that, in previous studies, suggested
profound CNS compromise.’’2
TESTING
AND FOLLOW-UP
Polygraphic recordings, with behavioral
obser-vations by a technologist well trained in
interpret-ing neonatal EEGs, were performed during seven
consecutive hours at about i-week intervals, four
times after birth. The recordings were obtained in
the same surroundings in the nursery and at the
same time of day. Although previous routine EEGs
had been obtained in several infants during their
first week of life, the initial session for this study
was begun at the second week of life. The routines
of feeding, cuddling, and diaper changing were
maintained; but patting, rocking, and use of
paci-fiers and of toys were discouraged during the
re-cording sessions. None of the infants or their
moth-ers were receiving drugs at the time the
investiga-tion began. Some of the babies had received
pheno-barbital or Dilantin, but in all babies the drugs were
discontinued within 1 week after birth, and blood
levels at the time ofthe po!ygraphic recordings were
less than values known to influence states.
Five states were selected for scoring (modified
from the scales of Wolff15 and of PrechtP6): state
1-awake, active, and crying; state 2-awake,
ac-tive, but quiet; state 3-awake, quiet, possibly
drowsy; state 4-rapid eye movement (REM), or
active sleep; and state 5-NREM, or quiet sleep.
(The criteria for scoring these states were: state
i-eyes open, moving, crying or fussing, EEG
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3 yr, nl; DQ 110 3.5 yr, nl; DQ 98
4 yr, ni; DQ 108
8 mo, satisfactory; 18 mo, walked, language devel delay; 3.6 yr, mild diparesis, abn gross & fine coord, Neg CT scan, DQ 70
2.9 yr, ni; DQ 90
3.2 yr, nl; DQ 100
8 mo onset IS with hypsar, neg w/
U, Rx ACTH, cessation IS; 2.9
yr, mild quadriplegia; DQ 60 1.2 yr, F#{176}T/C convulsions; not walking; HC 25%; 3.0 yr,
nonfo-cal szs (tonic/atonic/myoclonic); extrapyramidal signs moderate;
DQ 76
2.8 yr, ni; DQ 112
3.7 yr, nl; DQ 108
3.4 yr, ni; DQ 110
1.8 yr, onset Rt focal szs; NE, nl;
DQ 84; 3.0 yr, szs controlled by
DPH; NE Rt hemiparesis; DQ 80
3.6 yr, severe diparesis, language devel delay, HC 10%, EEG abn;
DQ 85
2.9 yr, ni; DQ 96
2.6 yr, HC 50%, neg CT scan,
EEG; (mild global delay); DQ <
88
3.1 yr, ni; DQ 105
2.9 yr, nl; DQ 110
54
TABLE. Data for 30 Infants Ranked According to Future Risk for Neurodeveloprnental Deficits (Least Risk
[Infant 1] to Most Risk [Infant 30])*
Infant’s Infant Gesta- Sex Prenatal, Perinatal, and Outcome
Rank No. tional Postnatal Status
of Age
Risk (wk)
1 1 40 F Neg P & Del; Neg NE & EEG
2 2 41 M Neg P & Del; SIB 12%; Rx with lights; Neg NE & EEG
3 11 40 F Neg P & Del; wt 1,350 g; Neg NE & EEG
4 23 40#{189} F URI with fever at 6 mo; LF Del; SIB 18%;
Rx Pb, lights x 5 d; Neg sepsis w/u, NE,
sono, ECG, EEG, CSF
5 10 39 M Multiple misc; Neg P & Del; pH 7.2; Neg
w/u, NE & EEG
6 20 39 M Bleed 7 mo; Neg Del; ? szs 4th d; Neg w/u,
CSF, sono, CT scan, EEG, NE
7 13 39#{189} M Neg P & Del; IAA; EEGs “transient dysma-turity”
8 21 39 F Neg P & Del; Mild meconium stain; Apgar:
7 at 1 mm and 8 at 5 mm; SIB 17%; Rx with lights; NE some jitteriness, ? szs;
EEG wnl; Neg sono, NE except
jitteri-ness
9 6 39 F Neg P & Del; PRM; Neg sepsis w/u; PDA
& RDS 5 d; Neg NE, EEG, sono
10 22 38 M Neg P & Del; pulmonary hypertension,
re-solved 10th d; Neg CT scan, BAEP, CEP,
EEG; NE jitteriness, obligatory TNR, no
tracking, ? blink to light
11 7 40 F Neg P & Del; apnea 1 wk; Neg w/u; EEG
central-type apnea; Neg sepsis w/u, CSF,
NE, CT scan; EEG abn (absent NREM
& excess F sharp transients)
12 30 38#{189} M Neg P & Del; Apgar: 6 at 1 mm and 8 at 5 mm; PDA; mild RDS; several apneic spells 3rd d; Neg EEG, ECG,
pneumo-gram, sepsis w/u, chemistries, BS; NE
slight jitteriness 48 h, responsive, good
tone, Moro, suck, placing, eye tracking;
NE at discharge wn! with slight increase
DTR LE
13 3 39 F Neg P; brief decel ht monit; pH 7.2; RDS; 2
szs 3rd d; Rx Pb x 7 d; Neg w/u, NE,
sono; EEG abn (focal ictal discharge, nl
bkgd)
14 18 40 F Neg P; prolonged 2nd stage labor; marked
late meconium; pH 6.9; resusc at 3 mm &
off 24 h later; Neg NE, sono 7th d; EEG
abn (some burst suppression in NREM)
15 4 41 M Maternal DM; LF Del; resusc at 6 mm with
resp assist 4 d; NE floppy w/clonus; Neg
w/u & sono, but BS 20 mg/dL; no known szs; NE moderate hypotonia with brisk
DTR, good Moro, suck; Neg sono, BAEP;
EEG abn (brief low-frequency ictal
dis-charge)
16 17 39 F Mild late preeclampsia; CS; BW 2,100 g;
few apneas, nonictal, resolved 6th d; Neg
sepsis w/u & CSF; NE mild hypotonia,
depressed suck; Neg sono; EEG excessive
rolandic spikes
17 16 40 M Neg P; Del pelvic disproportion; fetal
dis-tress; CS; resusc at 10 mm with resp
as-sist 1 wk; RDS; apnea (nonictal) 2 wk; Neg CT scan, sono; NE mild hypotonia, lethargy, poor suck, obligatory TNR;
EEGs “transient dysmaturity”
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TABLE-Continued
Infant’s Infant Gesta- Sex Prenatal, Perinatal, and Outcome
Rank No. tional Postnatal Status
of Age
Risk (wk)
18 5 38 F Moderate ethanol in P; LF Del; jitteriness 3 3.2 yr, nl; DQ > 90
d; DIC; renal failure resolved 4th d; NE
floppy, poor suck; EEG abn 3rd d; Neg
NE, EEG, BAEP, CT scan 6th d
19 8 39 M Neg P; decel ht monit; pH 6.9; resusc at 5 3.0 yr, quadriparesis w/Lt
hemi-mm with resp assist 10 d; mu!tifoca! szs 2 paresis, EEG abn; DQ < 80
d; Rx Pb & DPH; Ca 5, BS 18 mg/dL;
Rx Pb & DPH discontinued 8th d; no
recurrence of szs; Neg sono, ECG, NE;
EEG abn (ictal multifocal discharge 2nd
d; wnl 5th d)
20 14 38 F Moderate toxemia; Abr plac; CS; Rt pneu- 2.6 yr, global devel delay, CT scan mothorax; resusc at 7 mm; PDA; Ca 6.6; bilateral mild atrophy; DQ < 80 3 clonic szs; Rx Pb, Ca & glucose; NE
hypertonic, mild obligatory TNR, good suck, Moro, eye tracking, but lethargic;
EEG abn (poor state differentiation)
21 12 41 F Bleed 3rd T; Preeclampsia; Del late, 2.8 yr, HC 3%, hemiparesis, TIC
marked meconium; pH 7.1; fever & Esch- szs, CT scan Rt hemisphere
atro-erichia coli; Neg CSF, CT scan; RDS; phy, EEG abn; DQ < 70 dysmorphic features; apnea ? ictal; EEG
abn; NE lethargic, hypotonic, poor
plac-ing, Moro, & suck, clonus, plantar
flex-ors; Neg EEG 6th d
22 24 41 F Vaginal bleed 3rd mo; fetal distress; HF 3.0 yr, very mild quadriparesis,
Del; resusc at 4 mm with resp assist 1 EEG nl; DQ 90
wk; PDA; sepsis; ? meningitis; CSF
pleo-cytosis (TP 150); multifocal szs x 2 wk;
Neg CT scan; NE mildly floppy, DTR nl,
poor Moro, good eye movement; Neg
EEG, BAEP, CEP
23 15 39 F Neg P; Del breech, heavy meconium; decel 1.4 yr, delayed motor; 3 yr, very
ht monit; pH 7; DIC; renal failure; HBP; mild hemiparesis; DQ 100
CT scan and sono Rt cerebellar
hemor-rhage & mild ventricular dilation; clonic
szs 3rd d; Rx Pb 6 d; NE lethargy;
unsus-tamed bilateral clonus; repeat CT scan
mild hydrocephalus; EEG abn; Neg NE &
EEG 10th d
24 19 38#{189} M Gestational DM, bleed 6th mo; nuchal cord 3.2 yr, severe TIC szs; global devel
X2; fetal distress; pH 6.9; resusc with delay, EEG abn; DQ <60
resp assist X 5 d; SIB 15%; NE
hypo-tonia, lethargy, clonus; Neg CT scan,
CSF, BAEP; EEG abn (burst
suppres-sion) 1st d, 5th d borderline
25 26 38#{189} M Eclampsia 6th mo (BP 200/95; 1 T/C sz, 1.5 yr, nl except ? language devel
Rx conservative); Labor decel ht monit; delay; 3.1 yr, nl; DQ 104
MF Del; umbilical cord; pH 6.9; heavy
meconium; Apgar: 2-5-5 at 1-5-10 mm;
Resusc at 11 mm with resp assist 38 h; sepsis w/u pos blood culture E coli; LP
neg; sono Neg; apneic episodes ? szs;
EEG abn 4th d, nl 7th d; NE at discharge
2 wk later hypotonia, asymmetrical
Moro, poor suck, poor placing,
hyperac-tive DTR LE>UE, clonus sustained Rt
foot
26 9 38#{189} M Neg P & Del; 1 tonic sz at 46 h; LP blood 2.9 yr, nl; DQ 108
CT scan & sono grade II IVH; Rx
con-servative (no hydrocephalus); NE
hyper-tonic 4th d, exaggerated TNR, poor suck,
central apneas; Neg BAEP, CEP; EEG
abn (“marked dysmaturity”); NE still
hy-pertonic 8th d, scissoring, clonus, no placing, asymmetrical TNR, Moro; EEG
still mild dysmaturity 8th d
55
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nh,
mii diplegia; 2.3yr, nl;DQ 92
3.5 yr, ni; DQ 96
1 yr, one febrile convulsion, NE, nl; 3.6 yr, nl; DQ 98
1.8 yr, onset Rt focal szs, NE, nl;
DQ 84; 3.0 yr, szs controlled with
DPH, NE, Rt hemiparesis; DQ
80
TABLE-Continued
56
Infant’s Infant Gesta- Sex Prenatal, Perinatal, and Outcome
Rank No. tional Postnatal Status
of Age
Risk (wk)
27 28 41 M Bleed 5th mo; NegL& Del; BW 2,650 g;
Apgar: 5 at 1 mm and 7 at 5 mm; focal sz
at i5 h; Nl electrolytes and BS; Neg sep-tic w/u; LP slight pleocytosis, TP 90, sugar 50; 2nd LP neg; szs persisted de-spite good Pb & DPH levels; CT scan
edema & ? Rt F infarct, 2nd CT scan Rt
F atrophy; EEG x 3 1st 2 wk abn (poor states; ictal runs Lt F-P in 1st EEG, 2nd
EEG better states, dysmature indices;
asymmetrical with decreased voltage Rt F); NE at discharge marked hypertonicity w/bilateral clonus, poor Moro,
asymmet-rical TNR, poor visual responses
28 27 39 F Neg P; Long Del (no monitor); CS; severe meconium stain; Umb cord; pH 7; Apgar: 3 at 1 mm and 6 at 5 mm; szs multifocal at 12 h; Ca 6.8; BS 20 mg/dL; szs for 10 d despite good Pb & DPH levels, then szs discontinued; Neg w/u; NE at discharge floppy, lethargic, brisk DTRS with clonus
poor tracking with nl doll’s responses,
poor suck & placing; 3 EEGs 1st d to
13th d abn (persistent dysmaturity
indices, nl states, persistent Rt & Lt
spikes C-P-O)
29 25 40 F Neg P; long 1st stage labor, ruptured
mem-brane, CS at 12 h; Apgar: 1 at 1 mm and
3 at 5 mm; pH 6.8; Resusc 5 mm; focal szs at 6 h; Ca 6, BS 15 mg/dL; Rx Cat,
glucose, Pb (10 mg/kg x 3 d); szs
discon-tinued; EEG abn 2nd d; Neg sono, LP;
CT scan 5th d ? edema; 2nd EEG abn
7th d; NE lethargy, hypotonic, poor suck,
poor Moro, brisk DTR, poor tracking,?
doll’s responses; Neg BAEP, vestibular test
30 29 42#{189} M Neg P; Del lost fetal heart monitor, CS;
Umb cord; pH 6.2; BW 3,840 g; Apgar: 3
at 1 mm and 3 at 5
mm;
Resusc at 5 mmwith resp assist; RDS; LP marked
xan-thochromia in 3 tubes; Hct 29; Sono IVH
grade 3; myoclonic sz, apnea, & posturing 26th h; EEG abn (ictal t discharge, Lt
P-0, poor states); szs persisted 4 d despite
good level Pb, then discontinued with
di-azepam; 2nd LP xanthochromia; TP 200,
S 60; Off resp assist 10th d; NE at
dis-charge (2 wk) marked hypotonia,
de-pressed sensorium, poor Moro, suck, &
placing; frequent vomiting; EEG abn
(ab-sent NREM, excess spikes awake &
REM over P-T with Pos sharp waves Lt
C
* Abbreviations used are: abn, abnormal; Abr plac, abruptio placenta; ACTH, adrenocorticotropic hormone; BAEP,
brainstem auditory evoked potentials; bkgd, background; BS, blood sugar; BW, birth weight; C, central; CEP, cerebral evoked potentials; coord, coordination; CS, cesarean section; CSF, cerebrospinal fluid; CT, computed tomography;
decel ht monit, decelerated heart monitor; Del, delivery; devel, developmental; DIC, disseminated intravascular
coagulation; DM, diabetes mellitus; DPH, diphenylhydantoin; DQ, developmental quotient; DTR, deep tendon reflexes;
F, frontal; HBP, high blood pressure; HC, head circumference; HF, high forceps; hypsar, hypsarrhythmia; IAA, internal
aortic arch; IS, infantile spasms; LE, lower extremities; LF, low forceps; LP, lumbar puncture; Lt, left, MF, mid
forceps; misc, miscarriage; NE, neurologic examination; Neg, negative; ni, normal; NREM, non-rapid eye movement;
0, occipital; P, pregnancy, PDA, patent ductus arteriosus; Pos, positive; PRM, premature ruptured membranes; RDS,
respiratory distress syndrome; REM, rapid eye movement; resp assist, respiratory assistance; resusc, resuscitated; Rt, right; Rx, therapy; SIB, serum indirect bilirubin; sono, ultrasound scan; szs, seizures; T, temporal; T/C, tonic/clonic; TNR, tonic neck reflex; TP, total protein; UE, upper extremities; URI, upper respiratory tract infection; wnl, within
normal limits; w/u, work-up.
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ARTICLES
57
mostly obscured by artifact; state 2-eyes open, notcrying or fussing, moving and responsive to visual
stimuli, EEG with continuous irregular background
with mixed frequencies from fi to t5, voltages of 20
to 100 ;zV, no clear gradients, often
electromy-ographic (EMG) artifact and eye movements; state
3-eyes open, but rarely moving or responsive to
visual stimuli, not crying or fussing, EEG similar
to state 2, but with intermittent frontoposterior
gradient, with higher voltages and slower
frequen-cies in anterior gradients; state 4 or REM
sleep-eyes closed, intermittent phasic body/limb
move-ments, grimacing, smiling, sucking, clusters of eye
movements, irregular respiration, lowered EMG
tonic activity, EEG similar to that of state 2 during
the initial or first REM period, in subsequent REM
periods showing continuous, lower-voltage (20 to
50 tV) background with prevailing f, t frequencies;
state 5 or NREM sleep-eyes closed, quiescence of
body, limbs, face, and eye movements except for a
rare startle or a rare slow eye movement, regular
respiration, increased tonic EMG activity, EEG
either discontinuous with bursts of higher-voltage
(50 to 200 V) t5, t waves with some sharp transients
separated by decreased mixed-frequency
back-ground (20 to 50 j.tV, four- to ten-second duration)
or with more continuous and higher-voltage (50 to
200 V) background with prevailing frequencies in
the #{246},0 range. These two EEG patterns are called,
respectively, “trace alternant” and “continuous
slow wave” patterns, and they occur in NREM sleep
in variable percentages, the trace alternant
prevail-ing at birth and progressively decreasing with the
continuous slow wave progressively increasing
dur-ing the first 4 to 6 weeks after birth. For a more
detailed description of both states and
accompany-ing EEG patterns, see Parmelee and Stern,14
Wer-ner et al,17 and Lombroso.’2 In some epochs during
sleep in which babies had closed eyes and, hence,
were considered to be asleep, the other criteria for
defining REM or NREM were incomplete. This
represents what has been called “transitional sleep
state.” For the purpose of our analysis, we
elimi-nated these epochs from our scoring. In this
popu-lation, such epochs never exceeded more than 5%
of the total sleep recorded.)
Times spent by each infant in each one of these
five states were scored as percentages of the total
recording periods at each ofthe four sessions. Thus,
we obtained for each baby a total of 20 scores that
could be subjected to various analyses of variance
between the normal and at risk groups. Further, for
each infant, it was feasible to establish the degree
of variability for each selected
state
from session tosession; this resulted in an individual profile of the
stability or instability of the selected states (profile
consistency). All babies were reexamined at
6-month intervals (±2 weeks) by the same observer
(C.T.L.), and a final neurologic reevaluation was
performed at periods varying from 2 years 4 months
to 4 years. In some, a computed tomographic (CT)
scan was repeated. All obtained full developmental
evaluations at the end of the study (Table).
RESULTS
AND ANALYSIS
The clinical outcomes for the whole group are
summarized in the Table. In the first analysis, we
examined whether any scores of particular states at
any of the weekly recording sessions offered
mdi-vidual prognostic clues. Of the 20 scores obtained
(five awake-sleep states times four recording
ses-sions), two statistical significances were found
be-tween the normal and abnormal outcomes.
Awake-Quiet percentages between the normal and
abnor-ma! populations in the first week recordings are
shown in Fig 1. A statistically significant difference
is present
at this
time
(P < .05). However, if wetake the normal mean, -2 SD, as a criterion for
“normality,” only 2/il babies in the abnormal
group had values outside the criterion, whereas all
the others had values within the criterion. If the
abnormal mean, +2 SD, is used as a criterion for
“abnormality,” only 3/19 in the normal group had
values outside the criterion. The other group
com-parison that showed statistical significance was
NREM in the second week (P < .05). The group
with normal outcome had a higher NREM
percent-age than the abnormal group, but the
discrimina-tory power of the mean ±2 SD was similarly poor.
Thus, it became clear that this type of intergroup
analysis was not particularly promising to refine
our “group-prognostications.”
We noted that there was a genera! tendency for
the normal group to show approximately the same
percentages of sleep-waking states at different
re-cordings, whereas the risk group exhibited higher
variability. Hence, we proceeded to analyze the
consistency profiles of the individual babies and
their long-term clinical outcomes.
Two examples, one chosen as the best case of
state consistency throughout the four separate
ses-sions and the other chosen as an extreme example
of state variability, are shown in Fig 2.
The consistency measurement of a given subject
on the state profile over the four repeated
obser-vations is expressed by an index
W,
which is acoefficient of concordance derived from an analysis
of variance applied to the 20 points (five states
times four repetitions) in a given individual data
matrix. Because these points are in a percentage
form, ie, the length of time spent in each state
divided by the total observation time, the totals of
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1ST WEEK ? BORDERLINE
U ABNORMAL
10
5
p <
0.05
- 2SD
W0.9965
#2
INITIALLY: NORMAL
60 - OUTCOME: NORMAL
-I
% 40
-20
-0
60
% 40
20
0
the repetition rows ofthis analysis are always 100%,
which makes the sum of squares (55) for the
repe-tition (SSr) to zero. Hence, the total 55 (SSt) is
composed of the 55 between states (SSs) and the
55 within
states
(SSe).
If each
repetition
produces
the same percentage to a given state that every
other repetition produces, and if the same is
re-peated in the other four states, the SSe becomes
zero, and SSs =
SSt,
which
is a case
of the perfect
concordance. As the degree of lack of concordance
increases, the SSr decreases, while SSe increases.
The
W
is defined as SSr/SSt and is a parametricequivalent to Kendall’s method, which used a
non-parametric technique.27 It is obvious that when the
profiles between the four recordings approach
iden-tity, W approaches the value of 1 (SSr = SSt); and
if the state percentages are distributed as if
ran-domly assigned, W approaches the value of 0 (SSr
U = 0).
I P III IV V The results of this analysis for the entire cohort
of neonates are summarized in Fig 3. The babies
are lined up in the abscissa from the most normal
(baby 1) to the highest risk (baby 29), using the
combined ranking method described earlier. In
gen-era!, there is a weak association between initial
normality or abnormality and good or bad
long-term outcomes. However, there are many
excep-tions (see the Table). For example, baby 13, whose
initial neonatal findings were benign, developed
infantile spasms with hypsarrhythmia in his EEG
at 8 months, with quadriparesis and a
developmen-tal quotient of 60 at 2.9 years; baby 21, located close
to the normal end in the newborn period, developed
I AWAKE, CRY IV ASLEEP. REM
II AWAKE, QUIET V ASLEEP. NON-REM
AWAKE - QUIET
U NORMAL OUTCOME
58
WAKING-SLEEP
STATES
IN NEONATESr.:j#{149}
+ 2SD#{149}1
;‘I
.
. normaI mean (x);:
‘ I:0rmaI
mean
(y)0±
___
Fig 1. One of two examples in which statistically significant value was found when
comparing outcomes. At first week of testing, percentage scores in Awake-Quiet state were
significantly different between normal and abnormal outcomes (P < .05). However, this
is a group difference. Taking normal mean -2 SD values as criterion, only two abnormal outcomes could be identified; the other nine values were within 2 SD. Taking abnormal
mean +2 SD, three normal outcome values were outside of this criterion.
I I I I I
I Ii III IV V
#19
INITIALLY: AT RISK
- OUTCOME: ABNORMAL 3
O.73O1 f\ I i
- /, %,#{149}_
, ..
.4 %% 2
- //41 4
III AWAKE, DROWSY
Fig 2. Two examples of state profiles. Percentage time
spent in each awake-sleep state is plotted on vertical axis;
horizontal axis shows five awake-sleep states. Solid,
dot-ted, coarse, broken, and fine broken lines represent
mea-sures obtained on first, second, third, and fourth sessions,
respectively. Top, Profile ofneonate with highest W value
is shown; bottom, profile of neonate with lowest W value is shown.
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LONG TERM OUTCOME
#{149}
ABNORMAL? BORDERLINE
1.00
0.90
0.80
0.70
121212 2 3 1 11 112112 2222
121 30 031627 038476 584245998 759
PROFILE CONSISTENCY
ARTICLES
59
>-C)
z
w
U)
Cl)
z
0
C)
z
II
0
0 0
.(
II
0 0
U NORMAL
NORMAL TO BORDERLINE TO AT RISK
ASSESSMENT IN NEWBORN PERIOD
Fig 3. Assessment of profile consistency in newborn period. State profile consistency is expressed by W on vertical axis. On horizontal axis, baby who was thought to have least risk (baby 1) was placed at left end, and other neonates were arranged according to their ranking for increasing risk obtained through single-blind method. Thus, baby rated as
having highest risk (baby 29) is located at extreme right. With two exceptions (babies 16
and 20), high W values (>90) are associated with normal outcomes, whereas low W values
(<.90) are associated with abnormal outcomes. Two borderline cases (babies 4 and 24) also had relatively high W values.
nonfebrile seizures and at age 3 years had
my-oclonic, tonic, and atonic epilepsy, with
extrapyr-amidal signs and a developmental quotient of 76;
baby 23, who received the fourth highest rank in
normality during the newborn period, was
motori-cally delayed with mild diparesis and a
developmen-tal quotient of
70 at 3.6 years.
Babies
30 and 3, who
are located slightly to the left of the midpoint in
the scale (hence, ranked as relatively normal
new-borns) also had poor outcomes. A!! five infants had
shown low-consistency profiles during their
neo-natal period. All others who were normal at final
assessment had shown good state consistency with
the exception of baby 20. Baby 16, ranked at some
risk initially, had a low consistency profile, but a
good outcome. Conversely, babies 26, 9, 28, 25, and
29 were initially considered to have high risks, but
were found to be neurologically intact on follow-up.
As shown in Fig 3 and detailed in the Table, these
five babies had demonstrated high state consistency
profiles in spite of their low initial ranking, hence,
rated at significant risk for future outcome. Baby
24 at 3 years had some motor deficits, but normal
development; baby 4 was questionably
compro-mised. They had been ranked initially within the
at-risk group; both, however, showed consistent
state profiles, and their final clinical outcome may
be considered as borderline, at worst.
In summary, all 17 babies who had the 17 highest
w
values were found to be normal later (includingthe two borderline ones), whereas among the 13
babies who had the lowest 13
W
values, 1 1 werefound to be abnormal and two normal at final
assessment (P < .001). The results are shown in
Fig 4 (right columns). Hence, compared with the
future risk predictions by the neurologists on the
basis of prenatal, perinatal, and postnatal clinical
information (Fig 4, left columns), the profile
con-sistency method (W) appears to be vastly superior
for long-term prognosis.
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1
10
20
30
BORN PERIOD RANKED
.
I
I
.
I
N
0 N N
A
A
I N
I
!
I
I’
I
I
I
I
III C H
1
I
w
I
ABNORMAL NORMAL
.
.
ABNORMAL NORMAL
ASSESSMENT IN
NEW-RANKED
60
WAKING-SLEEP
STATES
IN NEONATES
N
A
N
K
S
LONG TERM OUTCOME
Fig 4. Assessment of long-term outcome. In two columns on right, all babies’ values are
aligned from highest W (top) to lowest W (bottom). There is clear correlation between
high W values and normal outcomes and, conversely, correlation between low W values
and abnormal outcomes. Two dots with question mark are borderline cases. In contrast
with these positive correlations, prognostic profiles suggested by clinical assessment during
newborn period often proved to be wrong. This is indicated by entirely overlapping
distributions of dots in columns on left. Baby who was thought to be least at risk is ranked
at top of column, and one thought to be most at risk is ranked at bottom.
DISCUSSION
Early investigators who demonstrated the
recur-rence of relatively homogenous, short and simple
cycles of wakefulness-sleep states in the human
newborn were already aware that these states are
sensitive to exogenous and endogenous factors. In
1967, Parmelee et al alluded to the lability of sleep
cycles in grossly abnormal babies. Deviations in
sleep states or in some of their components have
been
described by other investigators.’3”20’22’23’33These included most heterogenous groups of
patho-logic
conditions:
asphyxia;
Down
syndrome;
hypo-thyroidism; stress; heroin-addicted mothers or
mothers with diabetes or toxemia; kernicterus;
gen-era! sepsis; seizures; surgical problems with no
evi-dence of CNS involvement.
These studies dealt with sleep states only.
Be-cause full-term, normal neonates spend about 60%
to 70% oftheir time in sleep during their first weeks
of life, it is natural that investigations focused
mainly on sleep states. This was especially true of
investigations using serial EEG recordings.
A major
problem
confronting observations onsleep states is that they use “group” rather than
“individual” measures. For example, normal
full-term newborns during their first 4 weeks of life
spend nearly half of their total sleep time in REM
and slightly less time in NREM. These are average
percentages; in fact, they may vary 20% to 30% in
either direction between babies. Hence, reliable
normal values, even values that are only for sleep
states, show marked individual fluctuations, often
overlapping with those obtained in impaired
new-borns. Further, different values are reported
ac-cording to whether these states were scored by
simple observation or by polygraphy, and, hence,
they may vary from study to study according to
predefined criteria set by individual investigators.
Not only do we deal with large normal standard
deviations, but we know also that these sleep states
can be influenced, even if transiently, by several
variables.’2 For example, there are reports stating
that newborns with seizures exhibit decreased REM
sleep time. Yet these reports do not include
infor-mation about use of anticonvulsants. It is known
that diazepam or phenobarbital prolong NREM
sleep at the expense of REM.’2 Even greater
van-abilities may be expected in the waking states in
which so many more interactions take place with
hard-to-control environmental stimuli.
Thus, in our attempt to evaluate degrees of
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ARTICLES
61
bility in wakefulness-sleep state organization as apossible predictive measure for at-risk newborns,
we were confronted by several problems. We could
not find published data on a cohort of normal babies
that included polygraphic recordings in both
wak-ing and sleep over a period of time after birth.
Although sleep patterns of normal infants from
birth to several months have been carefully
stud-ied,16’3436 these do not include waking states nor do
they focus on neurologic clinical correlates. No data
covering a sufficiently long period of waking-sleep
recordings and long-term clinical correlations are
available for at-risk neonates. There are, of course,
exceptions for babies already known to have severe
CNS disorders and who show aberrations in their
sleep-state cycling. These have been described
an-ecdotally in neonates known to have congenital
brain malformations and in infants with
hypothy-roidism, phenylketonuria, or severe kernicterus and
in “other grossly abnormal babies.* Once we
ex-dude this population of clearly affected neonates,
there remains a large group of infants in whom
either biographic events or neurologic and other
examinations suggest less clear risk factors. This
population, comprising our group, rarely has those
constellations of abnormal parameters that would
reliably indicate long-term clinical outcome.
Experimental studies of Waite et a!39 suggested
that sleep stability in newborn rabbits appeared to
have high predictability in terms of their normal
development. Our pilot study, begun in 1973, of two
small groups of full-term human neonates
consid-ered, respectively, as normal or at risk suggested
that this strategy of studying individual
waking-sleep state stability over time was promising.4#{176}
Tho-man et a!41 studied a sample of 22 “healthy
full-term babies” by measuring percentages of six
be-haviora! states between the second and fifth week
after birth. Their conclusions were that infants with
most stable state consistency developed better than
those with least stable state consistency. Their
follow-up covered about 30 months, and their main
correlations were with developmental scales. Some
deviant cases were found, and some clinical
corre-lates appear obscure, such as those of a baby with
the lowest profile consistency developing an
aplas-tic anemia at 30 months. Our pilot study4#{176}and the
present one differ in terms of populations and
methodologies from that of Thoman et al,41 but
there is general agreement in that quantitative
in-dices of stability over time in behavioral states
demonstrate a generally positive correlation with
later clinical outcomes.
A ranking scale from normal to highest risk was
*References 3, 4, 11, 20-23, 30, 37, 38.
used in our study to minimize bias. It became
evident that the at-risk population tended to cluster
around extreme values. This suggested that the
individual state consistency profile over time,
sub-mitted to Mann-Whitney U-test, would provide a
clear difference between the groups. Indeed, this
difference emerged (P < .01, Fig 3). Five babies
ranked within the lowest risk cluster, exhibited
some of the lowest consistency profiles and, on
long-term follow-up, had clearly poor clinical
out-comes. Eight neonates who were ranked by the
blind scores within the group at risk had, instead,
good profiles and fared well on follow-up. Some of
these babies had worrisome neonatal problems,
from hypoxic-ischemic states with early seizures,
to meningitis, to intraventricular hemorrhage as
well as abnormal findings on neurologic
examina-tions and tests during the newborn period.
Inter-estingly, three newborns ranked at moderate to
high risk (babies 3, 8, and 15) had borderline or
normal findings on neurologic assessments at
dis-charge, but showed poor state consistency profiles
and were neurologically impaired when reexamined
at age 3 years. Some deviant cases should be pointed
out: within the least-risk group, baby 20 had a low
consistency quotient, but at 3.2 years was normal.
Conversely, one infant ranked within the greater
risk range (baby 16) developed into an essentially
normal toddler, but had a low quotient.
There was a high statistical difference between
the normal and abnormal outcomes (P < .01). If
values for the two babies with normal outcome but
with low W-va!u#{234}s are excluded, the mean values
for the normal and abnormal groups became .9851
and .8738, respectively (P < .001). The standard
deviations are .0102 and .0740, respectively. Thus,
if the normal mean +2 SD is used as the normal
criterion
(W
= .9647), ii infants with normal valuesand two infants with borderline values are within
this criterion. Therefore, with this criterion,
pre-dictability of the future normalcy is 82.6% (19/23).
If normal and borderline cases are combined, such
predictability rises to 91.3%, with two
false-nega-tive cases (8.7%).
One might say that because the distribution of
these data points is more Poisson in type, normal
mean +2 SD would not be appropriate as criterion
values. However, because with the exceptions of
babies 20 and 16, there is a clear separation between
the two groups, any criterion values between .96
(the lowest value for normal outcome) and .91 (the
highest value for abnormal otucome) are probably
good for discriminating purposes.
We recognize that our study did not control a
number of variables that might be relevant,
partic-ularly with regard to the waking states. Our
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62
WAKING-SLEEP
STATES
IN NEONATES
graphic data indicate a period of total sleep greater
than that reported by direct observation. We do not
dispute the question raised by WolW2 of whether
polygraphic recordings are necessarily superior to
careful visual observation of the waking-sleep
be-havioral states of these infants. We think that, as
far as sleep states are concerned, the availability of
other parameters offered by polygraphy is, indeed,
a better method for both qualification and
quanti-fication of sleep states. Regarding the waking
states, however, polygraphy is of doubtful value. As
we mentioned in the introduction, the study of
consistency in the various waking states may
ac-quire greater value in detecting subtle dysfunctions
of the developing CNS, as they may offer more
information on how pre-determined biologic
sched-ules may be modified by organic as well as by
environmental variables.
CONCLUSION
This investigation was focused on the proposition
that prolonged and repeated measurement of the
ability of a baby to maintain fairly constant state
organization might indicate that baby’s neurologic
outcome. It is clear that the data reported in this
study with relatively small numbers of neonates
will require further confirmation and refinement in
design. Meanwhile, the results obtained appear
en-couraging and, if confirmed, we would have
avail-able an economical tool for prognostic profiles of
newborns at risk. Parents and/or other observers
could, in fact, be trained to recognize and score
these waking-sleeping states, without the need of
the more expensive polygraphic recording, and thus
prolonged profiles of state consistency or variability
could be obtained by simple observation.
ACKNOWLEDGMENTS
We thank Drs Karl Kuban and Shozo Nakano,
De-partment of Neurology, Harvard Medical School, and Dr
Ritsuko Sawa, Department of Pediatrics, Jichi Medical
School (Japan), who helped in assessment of neonates.
We also thank Dr Russel M. Church, Department of
Psychology, Brown University, for his advice on
statis-tical procedures.
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19. Lombroso CT: Quantified electroencephalographic scales in 10 preterm healthy newborns followed up to 40-53 weeks CA by serial polygraphic recordings. Electroencephalogr Clin Neurophysiol 1979;46:460-473
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27. Edwards AL: Statistical Methods for the BehavioralScien-tists, ed 6. New York, Rinehart, 1958
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Amsterdam, Elsevier Biomedical Press, 1982, pp 652-663 41. Thomas EB, Denenberg VH, Sievel J, et al: State
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42. WolffPH: Organization ofbehavior in the first three months of life, in: Early Development, Research Publications of Association for Research in Neurological and Mental Dis-eases (ARNMD). New York, 1973, vol 51, chap 7, pp 132-153
GROWTH
HORMONES
The days when we thought we knew how to use human growth hormone
(hGH) are over: the prospect of growth-hormone-releasing hormone (GHRH)
and genetically engineered biosynthetic hGH in unlimited quantities raises a
new set of questions. . . . The comfortable situation which we enjoyed when we
thought we were using a safe preparation for clear clinical indications with a
reasonably assured outcome has been shattered. We do not know who needs
GH and we do not know what will happen when we give it to normal short
children. We have about two years to find the answers to these questions before
hGH is available in large quantities and consumer pressure begins to rise.
Submitted by Student
From Editorial: Who needs growth hormones? (Lancet 1984;2:1189-1190).
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1985;76;52
Pediatrics
Cesare T. Lombroso and Yoichi Matsumiya
Outcome
Stability in Waking-Sleep States in Neonates as a Predictor of Long-Term Neurologic
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Pediatrics
Cesare T. Lombroso and Yoichi Matsumiya
Outcome
Stability in Waking-Sleep States in Neonates as a Predictor of Long-Term Neurologic
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