A Scoring System for Early Prognostic Assessment After Neonatal Seizures

7/30/2019 A Scoring System for Early Prognostic Assessment After Neonatal Seizures

1/10

DOI:10.1542/peds.2008-2087published online Sep 14, 2009;Pediatrics

Francesco Pisani, Lisa Sisti and Stefano SeriA Scoring System for Early Prognostic Assessment After Neonatal Seizures

http://www.pediatrics.orglocated on the World Wide Web at:

The online version of this article, along with updated information and services, is

rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright 2009 by the American Academy of Pediatrics. Alland trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published,PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

. Provided by Indonesia:AAP Sponsored on September 16, 2009www.pediatrics.orgDownloaded from
http://www.pediatrics.org/http://www.pediatrics.org/http://www.pediatrics.org/http://www.pediatrics.org/http://www.pediatrics.org/http://www.pediatrics.org/


2/10

A Scoring System for Early Prognostic Assessment

After Neonatal Seizures

WHATS KNOWN ON THIS SUBJECT: Only 1 article has reported ascoring system to predict the outcome of neonates with seizures;

however, this previous score was developed on clinical detection

of the seizures and did not consider ultrasound examination of the

brain.

WHAT THIS STUDY ADDS: We developed a scoring system to

predict neurologic outcome in neonates with seizures. A

composite score accurately predicted favorable outcome in 29 of

36 and unfavorable outcome in 60 of 70 of the infants.

abstractOBJECTIVE: The aim of this study was to devise a scoring system that

could aid in predicting neurologic outcome at the onset of neonatal

seizures.

METHODS: A total of 106 newborns who had neonatal seizures and

were consecutively admitted to the NICU of the University of Parma

from January 1999 through December 2004 were prospectively

followed-up, and neurologic outcome was assessed at 24 months

postconceptional age. We conducted a retrospective analysis on this

cohort to identify variables that were significantly related to adverseoutcome and to develop a scoring system that could provide early

prognostic indications.

RESULTS: A total of 70 (66%) of 106 infants had an adverse neurologic

outcome. Six variables were identified as the most important indepen-

dent risk factors for adverse outcome and were used to construct a

scoring system: birth weight, Apgar score at 1 minute, neurologic ex-

amination at seizure onset, cerebral ultrasound, efficacy of anticonvul-

sant therapy, and presence of neonatal status epilepticus. Each vari-

able was scored from 0 to 3 to represent the range from normal to

severely abnormal. A total composite score was computed by addi-

tion of the raw scores of the 6 variables. This score ranged from 0 to 12.A cutoff score of4 provided the greatest sensitivity and specificity.

CONCLUSIONS: This scoring system may offer an easy, rapid, and reli-

able prognostic indicator of neurologic outcome after the onset of

neonatal seizures. A final assessment of the validity of this score in

routine clinical practice will require independent validation in other

centers. Pediatrics2009;124:e580e587

AUTHORS: Francesco Pisani, MD,a Lisa Sisti, MD,a and

Stefano Seri, MD, FRCPb

aChild Neuropsychiatric Unit, University of Parma, Parma, Italy;

andbSchool of Life and Health Sciences, Clinical

Neurophysiology Unit, Aston University, Birmingham, United

Kingdom

KEY WORDS

neonatal seizures, neurodevelopmental outcome, newborns,

preterm infants

ABBREVIATIONS

EEG electroencephalography

GA gestational age

ROCreceiver operating characteristic

AUCarea under the curve

NPVnegative predictive value

PPVpositive predictive value

IVHintraventricular hemorrhage

CI confidence interval

www.pediatrics.org/cgi/doi/10.1542/peds.2008-2087

doi:10.1542/peds.2008-2087

Accepted for publication May 29, 2009

Address correspondence to Francesco Pisani, MD, University of

Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail:

[email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2009 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have

no financial relationships relevant to this article to disclose.

e580 PISANI et al. Provided by Indonesia:AAP Sponsored on September 16, 2009www.pediatrics.orgDownloaded from
http://www.pediatrics.org/http://www.pediatrics.org/


3/10

Neonatal seizuresareconsidered an epi-

phenomenon of the underlying neuro-

logic pathology. Despite improved peri-

natal care, mortality and incidence of

neurologic sequelae in the seizing new-

born remain high. The identification of

early predictors of short-term and long-term neurodevelopmental outcome af-

ter neonatal seizures could be a valuable

tool in providing supportive indicators

for an early referral for long-term

follow-up and habilitative intervention.

Clinical studies have suggested that

the cause of neonatal seizures is the

most important factor in influencing

outcome.15 Other prognostic factors

reported in the literature are the ictal

semeiology and an early onset of sei-zures.6,7 Reliability of both of these

characteristics can be limited and

strongly depends on the seizure type

(clinical, electroclinical, or only electri-

cal); the gestational age of the new-

born (in the preterm newborn, sei-

zures are usually difficult to detect);

and the modality of seizure identifica-

tion, whether it is only clinical or with

temporally related video electroen-

cephalography (EEG).7,8 The latter con-sideration is particularly important,

given that in some newborns the clini-

cal manifestation of the seizures can

be subtle or even only electrical and

therefore clinically silent. Evidence on

the prognostic significance of specific

seizure types is not univocal6,7,911 be-

cause multiple seizure types often co-

exist in the same patient, and duration

of seizures can also play a nonnegli-

gible role.2,1114 Clinical variables suchas gestational age, Apgar score, birth

weight, the need for resuscitation ma-

neuvers, neurologic examination,2,4,15,16

and instrumental findings such as EEG

and cerebral ultrasonographynow

routinely available in most NICUs

have been attributed a significant

prognostic role.11,1720

Development of a neonatal scoring sys-

tem has been attempted in the past,

but the diagnosis of neonatal seizures

was based on clinical criteria only and

the studies did not include neuroimag-

ing data.21,22 To address these issues,

we conducted a hospital-based study

to devise a clinically viable risk scoring

system and assess its properties inearly prediction of adverse outcome of

newborns with neonatal seizures.

METHODS

Sample

The study was conducted on data from

a neonatal seizure database that con-

sisted of 106 newborns who were con-

secutively admitted to the NICU of Uni-

versity of Parma from January 1999

through December 2004 and followed

up by the Department of Child Neurol-

ogy. Details on the clinical characteris-

tics of the sample have been described

in a previous publication.14 Candidate

variables were selected on the basis of

a literature review and of their routine

availability in the initial days after hos-

pital admission (Table 1).2327 Data col-

lected included gestational age (GA),

type of delivery, birth weight, Apgar

score at 1 and 5 minutes, and the need

for and type of resuscitation immedi-

ately after birth. Time of seizure onset

was divided in before or after the first

24 or 48 hours of life. On the basis of

seizure semeiology, patients were

classified as having 1 type of seizure or

multiple seizure types.28 Electroclinical

and/or electrographic only seizures

were considered. Status epilepticus

was recorded as present or absent

and defined as continuous seizure ac-

tivity for at least 30 minutes or recur-

rent seizures that lasted a total of30

minutes without definite return to the

baseline neurologic condition between

seizures.14 Neurologic examination

was evaluated clinically. Video EEG and

the cerebral ultrasound, which are

considered important prognostic indi-

cators,2932 were included in the analy-

sis. The first video EEG monitoring was

started at a mean age of 6.36 days of

postnatal life (median: 2.00; SD: 12.17):

in preterm infants at a mean age of

6.98 of postnatal days (median: 2.00;

SD: 8.98) and in term newborns at a

mean age of 5.8 days of postnatal life

(median: 2.00; SD: 14.57).

A clinical scoring system and prog-

nostic cutoff values were defined by

assigning a value from 0 to 3 to the

clinical variables by increasing level

of severity. The composite score for

all newborns was subsequently eval-

uated in relation to developmental

outcome. General development was

assessed using the Griffiths Mental

Development Scale33 and classified

as normal when the developmentquotient was 80 and abnormal

when 80.34

The neurodevelopmental outcome was

classified as favorable or adverse and

was based on data that were system-

atically collected by a multidisci-

plinary team that was responsible

for the longitudinal follow-up pro-

gram under the auspices of the local

health authority. The definition of fa-

vorable outcome included normalneurologic development or mild

muscle tone and/or reflex abnormal-

ities, whereas an adverse outcome

included death, cerebral palsy, de-

velopmental delay, chronic epilepsy,

blindness, or deafness.

The relationship between scores on

the chosen variables and neurodevel-

opmental outcome at 2 years of age

was investigated. Receiver operating

characteristic (ROC) curves were con-

structed to measure the performance

of our scoring system in predicting the

outcome at 2 years of age. The ROC

curve was chosen to show how sensi-

tivity (vertical axis) changed with re-

spect to the false-positive estimate

(horizontal axis; 1-specificity), because

the decision criterion was varied. The

area under the curve (AUC) is consid-

ered a better indicator of predictive

ARTICLES

PEDIATRICS Volume 124, Number 4, October 2009 e581. Provided by Indonesia:AAP Sponsored on September 16, 2009www.pediatrics.orgDownloaded from
http://www.pediatrics.org/http://www.pediatrics.org/http://www.pediatrics.org/


4/10

accuracy than fixed sensitivity and

specificity because it yields an index

that is independent of the cutoff point.

In addition, ROC curves were used to

determine the cutoff values with the

best sensitivity and specificity in dis-

criminating between patients with agood outcome from those who had an

unfavorable outcome. The negative

predictive value (NPV) and the posi-

tive predictive value (PPV) were also

analyzed.

The Students t test for unpaired data

was used to compare differences in

the mean value of continuous vari-

ables of subcategories of patients.

Nominal data were analyzed by using

2 test and, when necessary, Fishersexact test for 2-by-2 comparisons. The

variables with a Pvalue of.01 on uni-

variate analysis were included in a

multiple logistic regression analysis. A

multiple logistic regression model was

applied to determine independent risk

factors for adverse neurodevelopmen-

tal outcome. Statistical analysis was

performed by using SPSS 15.0.1 for

Windows.35

For the statistical analysis, EEG find-

ings were grouped into 2 categories:

1 normal or mildly abnormal when

there was excess sharp activity, ab-

sence or decreased frequency of nor-

mal patterns, excessively long low-

voltage periods, or overall slightly

decreased voltage; and 2 moder-

ately or severely abnormal when there

was asymmetries in voltage or fre-

quencies, asynchrony for age, low-

voltage invariant activity, burst-suppression pattern, or permanent

discontinuous activity. Ultrasound

findings were grouped into 3 catego-

ries: I normal; II intraventricular

hemorrhage (IVH) of degree 1 or 2,

transient periventricular echodensi-

ties, borderline ventricular dilatation;

and III IVH of degree 3 or 4, intrapa-

renchymal hemorrhage, periventricu-

lar leukomalacia, and brain malforma-

TABLE 1 Sample Characteristics

Variable Favorable

Outcome, n(%)

Unfavorable

Outcome, n(%)

Total P

Delivery .219

Spontaneous 18 (41.0) 26 (59.0) 44

Cesarean delivery 18 (29.0) 44 (71.0) 62

GA, wk .007a

29 4 (14.0) 25 (86.0) 272933 1 (5.0) 18 (95.0) 19

3436 6 (27.3) 16 (72.7) 22

37 26 (47.0) 29 (53.0) 55

Birth weight, g .001a

1000 2 (9.0) 20 (91.0) 22

10001499 3 (30.0) 7 (70.0) 10

15002499 3 (15.0) 17 (85.0) 20

2500 28 (52.0) 26 (48.0) 54

Apgar score at 1 min .001a

03 7 (18.0) 31 (82.0) 38

47 5 (18.0) 23 (82.0) 28

810 24 (60.0) 16 (40.0) 40

Apgar score at 5 min .019a

03 1 (8.0) 11 (92.0) 12

47 10 (26.0) 29 (74.0) 39

810 25 (45.0) 30 (55.0) 55

Reanimation maneuver .007a

Ordinary assistance 23 (55.0) 19 (45.0) 42

Oxygen supplementation 1 (25.0) 3 (75.0) 4

Resuscitation1 min with positive-

pressure ventilation

2 (17.0) 10 (83.0) 12

Endotracheal intubation 7 (18.0) 31 (82.0) 38

Cardiac massage and/or drug therapy 3 (30.0) 7 (70.0) 10

Etiologyb .001a

II 12 (17.0) 58 (83.0) 70

I 12 (54.5) 10 (45.5) 22

0 12 (86.0) 2 (14.0) 14

Seizure onset, h .213

48 17 (41.0) 24 (59.0) 41

48 19 (29.0) 46 (71.0) 65Seizure type, n .390

1 15 (41.0) 22 (59.0) 37

1 21 (30.0) 48 (70.0) 69

Anticonvulsant therapy efficacy .001a

Immediate response 30 (53.0) 27 (47.0) 57

Partial response 4 (19.0) 17 (81.0) 21

No response 2 (7.0) 26 (93.0) 28

Neurologic examination .001a

Normal/mild abnormal 24 (56.0) 19 (44.0) 43

Moderately abnormal 10 (29.4) 24 (70.6) 34

Severely abnormal 2 (6.9) 27 (93.1) 29

Ultrasound brain scanc .001a

I 18 (67.0) 9 (33.0) 27

II 17 (55.0) 14 (45.0) 31

III 1 (2.0) 47 (98.0) 48

EEG findingsd .001a

I 27 (60.0) 18 (40.0) 45

II 9 (15.0) 52 (85.0) 61

Status epilepticus .001a

Present 1 (4.0) 25 (96.0) 26

Absent 35 (44.0) 45 (56.0) 80

a Significant on univariate analysis.b 0 indicates unknown or transient metabolic disorder; I, mild or moderate hypoxic-ischemic encephalopathy or IVH of

degree 1 or 2; II, meningitis, severe hypoxic-ischemic encephalopathy, brain malformation, sepsis, IVH of degree 3 or 4, or

intracerebral hemorrhage.c I indicatesnormal; II,IVH of degree1 or 2, transient periventricularechodensities,or borderlineventricular dilation;III, IVH

of degree 3 or 4, intraparenchymal hemorrhage, periventricular leukomalacia, or brain malformation.d I indicates normal or mildly abnormal; II, moderately or severely abnormal.



5/10

tions. Etiologies were grouped in the

following 3 categories: 0 unknown

or transient metabolic disorder; 1

mild or moderate hypoxic-ischemic en-

cephalopathy or IVH of degree 1 and 2;

and 3 meningitis, severe hypoxic-

ischemic encephalopathy, brain mal-formation, sepsis, degree 3 to 4 IVH, or

intracerebral hemorrhage.

RESULTS

Birth weight, GA, Apgar scores at 1

minute, need for resuscitation, cause

of seizure, neurologic examination,

presence of status epilepticus, efficacy

of the anticonvulsant therapy, the

background EEG activity, and the ce-

rebral ultrasound scans were the

most significant risk factors in the

univariate analysis (Tables 1 and 2).

Exploratory factor analysis (Principal

Axis Factorialization, eigenvalues 1)

showed that the variable pairs GA and

birth weight, as well as Apgar score at

1 minute and resuscitation had unifac-

torial saturation on a unique latent

component (0.743 and 0.648, and 0.831

and 0.853, respectively). Birth weight is

an objective and easily available mea-sure, unlike GA, which is anamnestic

and can be less reliable. In light of

these considerations, GA was excluded

from additional analysis. The variables

Apgar score at 1 minute and resuscita-

tion showed a non-Gaussian bimodal

distribution. When both variables were

simultaneously considered, this led to

inadequateROC curves, with loss of the

concavity and therefore a lesser accu-

racy of the cutoff. Given the statisticalproperties highlighted by factor analy-

sis and that Apgar score, when added

to other clinical variables, led to the

construction of more accurate ROC

curves, we decided to use this variable

in the final analysis and to exclude the

variable resuscitation. Seizure onset

did not reveal any prognostic power

with both a cutoff age of 24 (P .495)

and 48 hours (P .213).

The best outcome predictors on multi-

ple logistic regression were birth

weight, Apgar score at 1 minute, preic-

tal neurologic examination and ultra-

sound at seizure onset, efficacy of the

anticonvulsant therapy, and presence

of status epilepticus. These were fur-

ther used to devise 2 scoring systems

in which the variable background EEG

activity was added only to the second

(Tables 3 and 4).

In the first scoring system, the minimum

possible total score was 0 and the maxi-

mum was 12 (Tables 4 and 5). This score

was highly accurate, with an AUC corre-

sponding to 0.917 (95%confidence inter-

val [CI]: 0.858 0.975; P .001) and with

a cutoff of4 that provided the best

compromisewith a sensitivity of 85.7%, a

specificity of 80.6%, and a PPV of 89.6%.

Results indicated that the model accu-

rately predicted outcome in 74.4% (29 of

TABLE 2 Potential Predictors of Adverse Outcome (Univariate Analysis)

Variable OR 95% CI P

GA, wk .00700

37 1.000

3036 2.391 0.8147.021 .11300

29 5.603 1.72018.250 .00400

Birth weight, g .00100

2500 1.000

15002499 6.103 1.60023.269 .00800

10001499 2.513 0.58710.756 .21400

500999 10.769 2.28950.661 .00300

Apgar score at 1 min .00006

810 1.000

47 6.900 2.17321.914 .00100

03 6.643 2.35818.715 .00000

Etiologya .00600

0 1.000

I 5.000 0.89927.815 .06000

II 29.000 5.734146.666 .00005

Reanimation maneuver .00700

0 ordinary assistance 1.000

1 oxygen supplementation 3.632 0.34937.826 .28100

2 resuscitation1 min with positive-pressure ventilation

6.053 1.18031.055 .03100

3 endotracheal intubation 5.361 1.93214.878 .00100

4 cardiac massage and/or drug therapy 2.825 0.64112.442 .17000

Anticonvulsant therapy efficacy .00004

0 immediate response 1.000

1 partial response 4.722 1.41215.787 .01200

2 no response 14.444 3.13066.661 .00100

Cerebral ultrasound findingsb .00000

I 1.000

II 1.647 0.5664.792 .36000

III 94.000 11.101795.933 .00000

EEG findingsc .00000

I 1.000

II 8.667 3.43521.865 .00000

Neurologic examination .00000

Normal 1.000

Moderately abnormal 3.032 1.1707.855 .02200

Severely abnormal 17.053 3.59380.933 .00000

Status epilepticus .00000

Absent 1.000

Present 19.444 2.511150.591 .00400

a 0 indicates unknown or transient metabolic disorder; I, mild or moderate hypoxic-ischemic encephalopathy or IVH of

degree 1 or 2; II, meningitis, severe hypoxic-ischemic encephalopathy, brain malformation, sepsis, IVH of degree 3 or 4, or

intracerebral hemorrhage.b I indicatesnormal;II, IVHof degree1 or 2, transient periventricularechodensities,or borderlineventricular dilation;III, IVH

of degree 3 or 4, intraparenchymal hemorrhage, periventricular leukomalacia, or brain malformation.c I indicates normal or mildly abnormal; II, moderately or severely abnormal.

ARTICLES



6/10

36) of the newborns with favorable out-

come and in 89.6% (60 of 70) of those

with unfavorable outcome.

When we included background EEG ac-

tivity, not significant on the multiple

logistic regression but used in the

study as a criterion for case definition,

the maximum possible total score

reached 13 (Tables 4 and 6). This score

had a comparable accuracy, with an

AUC of 0.919 (95% CI: 0.864 0.974; P

.001). Considering a cutoff of5, the

score presented a sensitivity of

81.4%, a specificity of 83.3%, and a

PPV of 90.5%. Results indicate that

69.8% (30 of 36) of the infants with

favorable outcome and 90.5% (57 of70) of those with unfavorable out-

come were correctly predicted.

Moreover, the comparison of the AUC

of both scores did not show any dif-

ference (nonsignificant).

DISCUSSION

Despite the improvement in perinatal

care,36 mortality and above all the inci-

dence of neurologic sequelae in new-

borns with seizures remain high.5 It istherefore paramount for neonatolo-

gists to have early and accurate prog-

nostic indicators of short-term and

long-term outcome to plan diagnostic,

therapeutic, and habilitative interven-

tion. Given the paucity of available

studies, we tried to devise a scoring

system based on a set of clinical and

instrumental variables that are easily

available in the NICU and have been

shown in previous studies to bestrongly correlated with neurodevel-

opmental outcome.21,22,37

The clinical score was designed to be

easily applicable in the first days after

the onset of the neonatal seizures and

accurate in identifying as early as pos-

sible newborns who have seizures and

will have an unfavorable outcome. In

our cohort, only 10 newborns with a

score 4 had neurologic sequelae. A

score of4 provided a sensitivity of85.7%, a specificity of 80.6%, and a PPV

of 89.6%, confirming its potential use-

fulness as a prognostic indicator.

The variables chosen forthis study had

3 main properties: they were available

at the earliest stages after seizure on-

set; had a priori an early prognostic

value2,4,9,1416; and, for the instrumental

investigations, were routinely avail-

able in NICUs. Comparing our scoring

TABLE 3 Final Multiple Logistic Regression Model to Predict Adverse Outcome

Variable OR 95% CI P

Birth weight, g

15002499 42.003 2.710651.002 .008

500999 202.731 3.82210 752.230 .009

Apgar score at 1 min

47 29.725 1.842479.688 .017

Anticonvulsant therapy efficacyNo response 63.637 2.3291738.554 .014

Cerebral ultrasound findings

IVH of degree 3 or 4, intraparenchymal hemorrhage,

periventricular leukomalacia, or brain

malformation

108.905 5.9302000.080 .002

Neurologic examination

Moderately abnormal 30.201 2.123429.688 .012

Status epilepticus

Present 51.787 1.2562135.550 .038

TABLE 4 Clinical and Instrumental Variables Scored

Variable Score 1 Score 2

Birth weight, g1000 3 3

10001499 2 2

15002499 1 1

2500 0 0

Apgar at 1 min

03 2 2

47 1 1

810 0 0

Neurologic examination

Severely abnormal 2 2

Moderately abnormal 1 1

Normal or mildly abnormal 0 0

Background EEG activity

Asymmetries in voltage or frequencies, asynchrony for age, isoelectric or

low-voltage invariant activity, burst-suppression pattern, permanent

discontinuous activity

1

Normal or excessive sharp activity, absence or decreased frequency of

normal patterns, excessively long low-voltage periods or overall

slightly decreased voltage

0

Anticonvulsant therapy efficacy

No response 2 2

Partial response 1 1

Immediate response 0 0

Ultrasound brain scan

IVH of degree 3 or 4, intraparenchymal hemorrhage, periventricular

leukomalacia, or brain malformation

2 2

IVH of degree 1 or 2, transient periventricular echodensities, or

borderline ventricular dilation

1 1

Normal 0 0Status epilepticus

Present 1 1

Absent 0 0

Total 012 013



7/10

system with the only one currently

available,21,22 a difference in ascertain-

ment method emerges. Inclusion of pa-

tients with neonatal seizures was

based only on clinical criteria without

synchronized video EEG recording. This

technique has since become an essen-

tial tool in confirming the epileptic na-

ture of neonatal paroxysmal events.

This limitation might have resulted in

the inclusion of neonates with nonepi-

leptic paroxysmal events, who are

known to have different prognoses, or

exclusion of patients with very subtle

or electrical only seizures. Differences

in ascertainment methods could

have resulted in either an overesti-

mation or an underestimation of the

incidence of the neonatal seizures,

which has been reported to range

between 0.5% and 22.2%.38 This wide

variability is likely to be related to

different inclusion criteria and can

make the comparison between avail-

able studies quite challenging.

PPV and NPV are indicators of the use-

fulness of a diagnostic tool, and both

measures are related to the preva-

lence of the disease. In the absence of

population-based data on the preva-

lence of unfavorable outcome of new-

borns with neonatal seizures in Italy,

we chose to rely on clinical data from

our center14 rather then adopt data

collected in countries with potentially

different standards of service provi-

sion. Although on the basis of the rela-

tively low prevalence of neonatal sei-

zures we might have legitimately

expected a low PPV in our study, our

scoring system was very robust with

values as high as 89.6%. Although the

exact prognostic value of the presence

of specific seizure types remains a

challenge forthe clinician, a number of

studies converge in reporting that pa-

tients with subtle seizures have a

worse outcome compared with those

with clonic seizures.6,7,9 In the only cur-

rently available scoring system, neo-

natal seizures were scored as follows:

0 for the subtle seizures, 1 for the focal

clonic or multifocal clonic seizures,

and 2 for the tonic or myoclonic sei-

zures.21,22 In our study, despite the im-

provement in ascertainment methods

and a nonnegligible sample size, we

could not draw any conclusion on the

effect of specific seizure types on neu-

rodevelopmental outcome, and this led

us to the choice not to include seizure

semeiology in the scoring system.

Seizure duration is an additional impor-

tant point to consider. Prolonged or

recurrent seizures are thought to be

associated with poor neurologic out-

come2,11,13,14; however, an accurate quan-

tification of seizure duration requires a

time-consuming calculation and a sys-

tematic datacollection of the duration of

each individual seizure. We adopted a

less ambitious but more realistic vari-

able: the presence/absence of status

epilepticus. Although we are aware that

a definition of neonatal status epilepti-

cus is far from being universally ac-

cepted, the one that we used was in line

with that adopted by our group in a pre-

viousstudy14 and by others and was used

to allow some comparison with existing

literature. An additional element that weconsidered in our decision was that pro-

longed seizures can be related to spe-

cific clinical conditions with a known fa-

vorable outcome, as for focal clonic

seizure in neonatal hypocalcemia,

whereas neonatal status epilepticus is

almost always of symptomatic origin

and is more likely to be related to diffuse

and extensive structural brain injury,

which is likely to have a significant influ-

ence on outcome. With regard to the in-strumental investigations, the only cur-

rently available scoring system21,22 did

not include neuroimaging data, which

have since become commonly applied in

NICUs. In particular, cerebral ultrasound

is now readily available at the bedside of

the newborn; it is cost-efficient and

noninvasive, and its prognostic value

for later neurologic sequelae has

already been suggested by several stud-

ies.39,40 MRI-based techniques, includingdiffusion-weighted imaging and mag-

netic resonance spectroscopy, are the

new frontier in neonatal brain imaging.

Their use is particularly promising in

periventricular white matter lesions,41

but theystill presentinherentdifficulties

in patient preparation, safety, timing,

and sequence optimization. Further-

more, although some abnormalities are

better detected by magnetic resonance

techniques, cerebral ultrasound will besensitive enough to identify most abnor-

malities that are known to be associated

with adverse neurologic outcome.42,43 In

light of these considerations and our

goal for the score to be easily applicable

in daily clinical routine, we chose to limit

the imaging variable to the traditional ul-

trasound methods.

The proposed score is able to identify

only 3 of 4 infants with good outcome

TABLE 5 Score 1

Cutoff Sensitivity Specificity Accuracy PPV NPV

3 0.957 0.694 0.825 0.859 0.893

4 0.857 0.806 0.831 0.896 0.744

5 0.757 0.917 0.837 0.946 0.660

AUC: 0.917; SE: 0.030; P .001; 95% CI: 0.858 to 0.975.

TABLE 6 Score 2

Cutoff Sensitivity Specificity Accuracy PPV NPV

4 0.900 0.778 0.839 0.887 0.800

5 0.814 0.833 0.823 0.905 0.698

6 0.743 0.917 0.830 0.945 0.647

AUC: 0.919; SE: 0.028; P .001; 95% CI: 0.864 to 0.974.

ARTICLES



8/10

with a sensitivity of 85% and a specific-

ity of 80%. On the basis of these prop-

erties, we emphasize that the pro-

posed scoring system should not be

used in decisions on discontinuation of

care or any form of euthanasia.

An additional element of debate lies indefinition of outcome and the choice of

24 months as follow-up interval. Out-

come after neonatal seizures is char-

acterized by a wide spectrum of clini-

cal situations. Disabilities lie in a

continuum and can involve multiple

domains of development. For this rea-

son, categorical classification can be

challenging, hence our choice of using

only favorable or adverse as levels of

the variable outcome. Significantlylarger sample size will allow future

studies to be focused on 1 outcome

category only such as ongoing sei-

zures/chronic epilepsy. The choice of

the 24-month cutoff was motivated by

two main considerations. First, obser-

vational studies are somewhat limited

to short follow-up times, and this hasprovided limited information on the

timing of emergence of neurologic def-

icits. A second factor in the choice of a

cutoff of 2 years is its theoretical ad-

vantage in identification of the severity

and the type of pathologies such as ce-

rebral palsy and mental retardation

more reliably.

CONCLUSIONS

We propose this scoring system fornewborns with seizures because of

its immediate availability, its relative

simplicity, and its potential for pro-

viding early prognostic information

on the neurodevelopmental out-

come. If confirmed with prospective

studies, then the scoring system has

the potential to become a useful toolfor neonatologists in guiding treat-

ment and follow-up of neonates with

seizures. The proposed scoring

model needs prospective validation

in a new sample of newborns. A pro-

spective study in a small network of

NICUs with a different set of patients

is due to start this year to increase

our understanding of the potential

role of the proposed scoring method

outside our immediate workingenvironment.

REFERENCES

1. Holden KR, Mellits ED, Freeman JM. Neonatal seizures: I correlation of prenatal and perinatal

events with outcomes. Pediatrics. 1982;70(2):165176

2. Mellits ED, Holden KR, Freeman JM. Neonatal seizures: IIa multivariate analysis of factors

associated with outcome. Pediatrics. 1982;70(2):177185

3. Scher MS. Neonatal seizures and brain damage. Pediatr Neurol. 2003;29(5):381390

4. TekgulH, Gauvreau K, Soul G, et al.The current etiologicprofile andneurodevelopmental outcome

of seizures in term newborn infants. Pediatrics. 2006;117(4):12701280

5. Volpe JJ. Neonatal seizures. In: Neurology of the Newborn. 4th ed. Philadelphia, PA: WB Saunders;

2001:178214

6. Brunquell PJ, Glennon CM, DiMario FJ Jr, Lerer T, Eisenfeld L. Prediction of outcome based on

clinical seizures type in newborn infants. J Pediatr. 2002;140(6):707712

7. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology. 1987;

37(12):18371844

8. Sheth RD, Hobbs GR, Mullet M. Neonatal seizures:incidence, onset, and etiology by gestational age.

J Perinatol . 1999;19(1):40 43

9. Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal

seizures. Neurology. 2007;69(19):18161822

10. McBride MC, Laroia N, Guillet R. Electrographic seizures in neonates correlate with poor neuro-

developmental outcome? Neurology. 2000;55(4):506513

11. Bye AM, Cunningham CA, Chee KY, Flanagan D. Outcome of neonates with electrographically

identified seizures, or at risk of seizures. Pediatr Neurol. 1997;16(3):225231

12. Scher MS, Hamid MY, Steppe DA, Beggarly ME, Painter MJ. Ictal and interictal electrographicseizures duration in preterm and term neonates. Epilepsia. 1993;34(2):284288

13. Pisani F, Copioli C, Di Gioia C, Turco E, Sisti L. Neonatal seizures: relation of ictal video-EEG findings

with neurodevelopmental outcome. J Child Neurol. 2008;23(4):394398

14. Pisani F, Cerminara C, Fusco C, Sisti L. Neonatal status epilepticus vs recurrent neonatal seizures:

clinical findings and outcome. Neurology. 2007;69(23):21772185

15. Bergman I, Painter MJ, Hirsch RP, Crumrine PK, David R. Outcome in neonates with convulsions

treated in an intensive care unit. Ann Neurol. 1983;14(6):642647

16. Sun Y, Vestergaard M, Pedersen CB, Christensen J, Olsen J. Apgar scores and long-term risk of

epilepsy. Epidemiology. 2006;17(3):296301

17. Legido A, Clancy RR, Berman PH. Neurologic outcome after electroencephalographically proven

neonatal seizures. Pediatrics. 1991;88(3):583596

18. Rowe JC, Holmes GL, Hafford J, et al. Prognostic value of the electroencephalogram in term and



9/10

preterm infants following neonatal seizures. Electroencephalogr Clin Neurophysiol. 1985;60(3):

183196

19. Connell J, Oozeer R, de Vries L, Dubowitz LM, Dubowitz V. Continuous EEG monitoring of neonatal

seizures: diagnostic and prognostic considerations. Arch Dis Child. 1989;64(4):452458

20. Ancel PY, Livinec F, Larroque B, et al. Cerebral palsy among very preterm children in relation to

gestational age and neonatal ultrasound abnormalities: the EPIPAGE cohort study. Pediatrics.

2006;117(3):828 835

21. Ellison PH, Largent JA, Bahr JP. A scoring system to predict outcome following neonatal seizures.J Pediatr. 1981;99(3):455459

22. Ellison PH, Horn JL, Franklin S, Jones MG. The results of checking a scoring system for neonatal

seizures. Neuropediatrics. 1986;17(3):152157

23. European Community collaborative study of outcome of pregnancy between 22 and 28 weeks

gestation. Working Group on the Very Low Birthweight Infant. Lancet. 1990;336(8718):782784

24. KramerMS, DemissieK, Yang H, Platt RW,Sauve R, ListonR. Thecontribution of mild andmoderate

preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal

Surveillance System. JAMA. 2000;284(7):843849

25. Mercuri E, Rutherford M, Barnett A, et al.MRI lesions andinfants with neonatal encephalopathy:is

the Apgar score predictive? Neuropediatrics. 2002;33(3):150156

26. WoodNS, Marlow N, Costeloe K, Gibson AT, WilkinsonAR. Neurological and developmentaldisability

after extremely preterm birth. N Engl J Med. 2000;343(6):378384

27. Sun Y, Vestergaard M, Pedersen CB, Christensen J, Basso O, Olsen J. Gestational age, birth weight,

intrauterine growth, and the risk of epilepsy. Am J Epidemiol. 2008;167(3):262270

28. Lombroso CT, Neonatal seizures: a clinician overview. Brain Dev. 1996;18(1):128

29. Holmes GL, Lombroso CT. Prognostic value of background patterns in the neonatal EEG. J Clin

Neurophysiol. 1993;10(3):323352

30. Ortibus EL, Sum JM, Hahn JS. Predictive value of EEG for outcome and epilepsy following neonatal

seizures. Electroencephalogr Clin Neurophysiol. 1996;98(3):175185

31. Amess PN, Baudin J, Townsend J, et al. Epilepsy in very preterm infants: neonatal cranial ultra-

sound reveals a high-risk subcategory. Dev Med Child Neurol. 1998;40(11):724730

32. de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using ultrasound. Behav Brain

Res. 1992;49(1):1 6

33. Griffiths R. The Abilities of Young Children. London, England: Child Development Research Centre;

1970

34. Ivens J, Martin N. A common metric for the Griffiths Scales. Arch Dis Child. 2002;87(2):109110

35. SPSS Professional Statistics Edition [computer program]. Version 15.0.1. Chicago, IL: SPSS Inc;

2006

36. Stoelhorst GM, Rijken M, Martens SE, et al. Changes in neonatology: comparison of two cohorts of

very preterm infants (gestational age 32 weeks)the Project on Preterm and Small for Ges-

tational Age Infants 1983 and the Leiden Follow-up Project on Prematurity 19961997. Pediatrics.

2005;115(2):396 405

37. Portman RJ, Carter BS, Gaylord MS, Murphy MG, Thieme RE, Merenstein GB. Predicting neonatal

morbidity after perinatal asphyxia: a scoring system. Am J Obstet Gynecol. 1990;162(1):174182

38. Scher MS. Neonatal seizures classification: a fetal perspective concerning childhood epilepsy.

Epilepsy Res. 2006;70(suppl 1):S41S57

39. Ment LR, Bada HS, Barnes P, et al. Practice parameter: neuroimaging of the neonatereport of

the Quality Standards Subcommittee of the American Academy of Neurology and the Practice

Committee of the Child Neurology Society. Neurology. 2002;58(12):17261738

40. Leijser LM, de Vries LS, Cowan FM. Using cerebral ultrasound effectively in the newborn infant.Early Hum Dev. 2006;82(12):827835

41. Mirmiran M, Barnes PD, Keller K, et al. Neonatal brain magnetic resonance imaging before dis-

charge is better than serial cranial ultrasound in predicting cerebral palsy in very low birth

weight preterm infants. Pediatrics. 2004;114(4):992998

42. Leijser LM, de Bruine FT, Steggerda SJ, van der Grond J, Walther FJ, van Wezel-Meijler G. Brain

imaging findings in very preterm infants throughout the neonatal period: part Iincidence and

evolutionof lesions, comparisonbetweenultrasound and MRI. Early HumDev. 2009;85(2):101109

43. Leijser LM, Steggerda SJ, de Bruine FT, van der Grond J, Walther FJ, van Wezel-Meijler G. Brain

imaging findings in very preterm infants throughout the neonatal period: part IIrelation with

perinatal clinical data. Early Hum Dev. 2009;85(2):111115

ARTICLES



10/10

DOI:10.1542/peds.2008-2087published online Sep 14, 2009;Pediatrics

Francesco Pisani, Lisa Sisti and Stefano SeriA Scoring System for Early Prognostic Assessment After Neonatal Seizures

& Services

Updated Information

http://www.pediatrics.org

including high-resolution figures, can be found at:

Permissions & Licensing

http://www.pediatrics.org/misc/Permissions.shtmltables) or in its entirety can be found online at:Information about reproducing this article in parts (figures,

Reprintshttp://www.pediatrics.org/misc/reprints.shtml

Information about ordering reprints can be found online:

. Provided by Indonesia:AAP Sponsored on September 16, 2009www.pediatrics.orgDownloaded from
http://www.pediatrics.org/http://www.pediatrics.org/http://www.pediatrics.org/misc/Permissions.shtmlhttp://www.pediatrics.org/misc/Permissions.shtmlhttp://www.pediatrics.org/misc/Permissions.shtmlhttp://www.pediatrics.org/misc/reprints.shtmlhttp://www.pediatrics.org/misc/reprints.shtmlhttp://www.pediatrics.org/misc/reprints.shtmlhttp://www.pediatrics.org/http://www.pediatrics.org/http://www.pediatrics.org/misc/reprints.shtmlhttp://www.pediatrics.org/misc/Permissions.shtmlhttp://www.pediatrics.org/

A Scoring System for Early Prognostic Assessment After Neonatal Seizures

Documents

Transcript of A Scoring System for Early Prognostic Assessment After Neonatal Seizures