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Official Journal of the European Paediatric Neurology Society
Orginal article
Neonatal status epilepticus: Differences between preterm and term newborns Elena Pavlidis a,*, Carlotta Spagnoli a, Annalisa Pelosi b, Silvia Mazzotta a, Francesco Pisani a a b
Child Neuropsychiatry Unit, Neuroscience Department, University of Parma, Italy Psychometrics, Neuroscience Department, University of Parma, Italy
article info
abstract
Article history:
Background: Despite the many studies on neonatal seizures, neonatal status epilepticus
Received 31 July 2014
(NSE) remains a controversial entity, with no general consensus about its definition. We
Received in revised form
report the characteristics of newborns with NSE in order to assess whether they showed
2 December 2014
homogeneous features or displayed clinical and/or instrumental differences depending on
Accepted 4 January 2015
gestational age (GA). Preterm and term neonates were compared and risk factors for adverse outcome evaluated.
Keywords:
Methods: From 154 newborns with video-EEG confirmed neonatal seizures admitted to the
Neonatal status epilepticus
NICU of Parma University Hospital between January 1999 and December 2012, we collected
Status epilepticus
a cohort of 47 newborns (19 preterm, 28 full-term) with NSE. NSE was defined as continuous
Neonatal seizures
seizure activity for at least 30 min or recurrent seizures lasting a total of 30 min without
Outcome
definite return to the baseline neurologic condition between seizures. Outcome was assessed at least at one year. We applied the c2 test to compare nominal data, and multivariate logistic regression analysis to determine independent risk factors for adverse outcome. Results: Only Apgar scores and neurologic examination (p .02) were different between the groups. None of the preterm newborns had a favourable outcome compared to 25% of the full-term ones (p ¼ .032). Moreover, 52.6% of preterm neonates died compared to 17.8% of the full-term newborns (p ¼ .01; OR ¼ 5.11). The only variable related to outcome was Apgar score at 5 min (p ¼ .02). Conclusion: Newborns with NSE represented a quite homogeneous group regardless of the GA. Outcome was unfavourable in most of the subjects; however adverse outcome and death were more represented in preterm newborns. © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Abbreviations: GA, gestational age; IVH, intraventricular hemorrhage; NS, neonatal seizures; NSE, neonatal status epilepticus; PVL, periventricular leukomalacia; US, cerebral ultrasound; v-EEG, video-electroencephalogram. * Corresponding author. U.O. di Neuropsichiatria Infantile, Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126 Parma (PR), Italy. Tel.: þ39 521702205; fax: þ39 521704708. E-mail address: [email protected] (E. Pavlidis). http://dx.doi.org/10.1016/j.ejpn.2015.01.002 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
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1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 5 ) 1 e6
Introduction
Neonatal status epilepticus (NSE) is still a controversial entity, for which a specific and worldwide accepted definition does not exist. However, different definitions,1e7 mostly arbitrary and based on temporal criteria, have been applied to define this entity and several studies showed a wide variety of NSE percentage in newborns with neonatal seizures (NS), ranging from 8% up to 43%.4,8 This variability is probably due to the different definitions and inclusion criteria used to diagnose NSE. In older ages, status epilepticus was usually defined as a continuous seizure activity lasting for at least 30 min, or recurrent seizures lasting 30 min or more from which the patient does not regain consciousness.9 A more operational definition was proposed for generalized, convulsive status epilepticus in adults and children, being a continuous seizure or two or more discrete seizures between which there is incomplete recovery of consciousness for 5 min.10 However, it is still debated if these definitions are applicable to newborns.11e17 Beyond the adopted definition, it seems that the effects of prolonged seizures on the developing brain lead to a poor outcome.1,2,5,18e20 This study, focused on newborns with status epilepticus, evaluates the differences between preterm and full-term newborns and also the risk factors for an adverse outcome have been analysed.
2.
Methods
We selected 47 newborns with NSE out of 154 newborns with video-EEG (v-EEG) confirmed NS, selected among the 5100 neonates consecutively admitted to the NICU of Parma University Hospital, between January 1999 and December 2012. NSE was defined as continuous seizure activity for at least 30 min or recurrent seizures lasting a total of 30 min without definite return to the baseline neurologic condition of the newborn between seizures, in any 1-h period (hourly seizure burden range: 50%e100%).9,19,21 The following inclusion criteria were applied: 1) v-EEG confirmed NS; 2) more than one cerebral ultrasound (US) examination performed up to term age and at least one computed tomography and/or cerebral MRI within the first year of life; 3) a follow-up of at least 12 months. All newborns at high risk of seizures due to predisposing factors such as birth asphyxia, sepsis, meningitis, metabolic disorders, brain malformations, intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL) on brain US scans, or in the presence of clinical signs suggestive of seizures, underwent serial EEGs during the neonatal period. NS were classified according to Volpe's classification modified by Lombroso22 and had to be associated with electrographic changes. Polygraphic v-EEG were obtained at the bedside and, depending on infants' head size, 21 or 10 cerebral electrodes were applied according to the 10e20 International System. Electrocardiogram, lateral eye movements, chin electromyographic activity, and abdominal respiration were the other physiologic variables most frequently monitored. The recordings continued until a complete cycle of awake, quiet, and active sleep were captured, or, if these were not clearly distinguishable, the recording continued for at least 60 min
and could be further prolonged on the basis of seizures course and clinical needs. Moreover, almost all the subjects with NSE underwent at least one follow-up EEG recording during the subsequent 24 h from the first one. Standardized agedependent criteria were applied to assess EEG background activity.23 The study was conducted on data from a NS database, continuation of a database whose clinical features have been previously described.19,24 Outcome was assessed at discharge, 3, 6, 9, 12 months and afterwards every six months with a follow-up from a minimum of 12 months to a maximum of 13 years according to clinical conditions. Neuromotor assessment was based on clinical criteria,25,26 and general development was assessed using the Griffiths' Mental Developmental Scale and, after 2007, the Bayley Scales of Infant and Toddler Development II.27,28 The neurodevelopmental outcome was classified as favourable or adverse. A favourable outcome was defined as normal neurologic development or mild muscle tone and reflexes abnormalities and isolated speech delay, whereas adverse outcome was identified as involvement resulting in death, cerebral palsy, developmental delay, epilepsy, blindness, or deafness.
2.1.
Statistical analysis
Nominal data were analysed using the c2 test, and if necessary, the Fisher exact test for two-by-two comparisons. A univariate logistic regression model to determine which independent variable(s) were related to outcome was used. Variables with a p value < .05 on univariate analysis were included in a multiple logistic regression analysis. The multiple logistic regression analysis was performed to detect independent risk factors for adverse outcome. For these purposes, adverse outcome and death were considered as a single group. In all instances, a p value of less than .05 was considered to be significant. Statistical analysis was performed using the Statistical Package for the Social Sciences (Version 20.0; IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp, 2011).29 For the statistical analysis, the first neurologic examination findings, evaluated according to GA, were grouped in three categories (modified from Legido 199130): 1) normal or mildly abnormal; 2) moderately abnormal, such as hypotonia/hypertonia, decreased muscle active movements, lethargy; and 3) severely abnormal, such as flaccid, inactive and coma. EEG findings were grouped into two categories: 1) normal or mildly abnormal (normal or excess sharp activity, absence or decreased frequency of normal patterns, excessively long lowvoltage periods or overall slightly decreased voltage); and 2) moderately or severely abnormal (asymmetries in voltage or frequencies, asynchrony for age, or isoelectric/low-voltage invariant activity, burst-suppression pattern, permanent discontinuous activity). US findings were grouped into three categories: I) normal; II) IVH of degree I or II, transient periventricular echodensities; and III) IVH of degree III or IV, intraparenchymal hemorrhage, PVL, brain malformations. Aetiologies were grouped in the following three categories: hypoxiceischaemic encephalopathy, cerebral hemorrhage, and others (congenital metabolic and transient metabolic disorders, infectious diseases, brain malformations, unknown causes).
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
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3.
Results
Table 1 e Sample characteristics PT vs FT with NSE. NSE (n ¼ 47)
Variables We collected a cohort of 154 newborns with NS among the 5100 admitted to our centre (3%). From those, we further select 47 newborns who experienced NSE, confirmed at v-EEG recording of at least 1 h (range: 1 he5 h 48 min). They represented the 0.9% of the population admitted to our NICU and the 30.5% of those with NS. The findings of the newborns with NSE are reported in Table 1. They were 19 preterm (mean GA of 29.6 weeks; range: 23e36) and 28 full-term neonates (mean GA of 39.7 weeks). Hypoxiceischaemic encephalopathy was the most frequent aetiology (17/47; 36.1%), followed by cerebral hemorrhage in 13 subjects (27.6%). Other aetiologies were infections (5/47; 10.6%), inherited metabolic disease (7/47; 14.9%), and cerebral malformations in 2 (4.2%). Aetiology remained unknown in 3 patients (6.4%). Twenty-four subjects (51%) showed severely abnormal US brain scans, equally distributed between full-term and preterm newborns, however normal US findings were only found in full-term newborns (7/28). The majority of subjects with NSE presented a moderately/severely abnormal background EEG activity (43/ 47; 91.5%). Normal pre-ictal neurologic examination was seen only in 5 subjects (10.6%, 4 full-term). Only 7 full-term newborns (14.9%) had a normal outcome. Death occurred in 15/47 newborns (31.9%), ten of whom were preterm infants (66.7%). In 19 infants (40.4%), we observed cerebral palsy. Developmental delay was observed in 46.8% newborns (22/47) and was associated with cerebral palsy in 17 subjects; epilepsy developed in16 subjects, 15 of whom associated with cerebral palsy and/or developmental delay (total ¼ 16/47; 34%) (Fig. 1). The only different clinical variables between preterm and term neonates were Apgar scores at any time and neurologic examination (respectively, p ¼ .016; .010; .024; .020), being the worst scores mainly represented in preterm infants (Table 1). Furthermore, all preterm newborns had an unfavourable outcome (100% vs 75%; p ¼ .032) (Fig. 2), and 10 of them died (52.6%) compared to 5 (17.8%) of the full-term newborns (p ¼ .01) (Fig. 3). The univariate analysis revealed that only Apgar score at 5 min was related to the outcome (p ¼ .02). Multivariate analysis did not find out any independent risk factor for adverse outcome.
4.
Discussion
Despite many studies on NS, few papers have focused on NSE and moreover they adopt different inclusion criteria with no general consensus on its definition. It is not possible to find a specific and widely accepted definition for NSE yet, however a temporal criterion has been used by several Authors in order to characterize this entity. At the end of the sixties, Monod defined NSE as the repetition of clinical or subclinical seizures with abnormal interictal neurologic status, occurring for at least a few hours,1 subsequently Mora used the same definition, changing the duration and adding the following neurophysiological criteria: 1) generalized high-voltage paroxysmal discharges, 2) two or more discharges occurring every 10 s, 3) with these abnormalities persisting for at least 20 min2 Afterwards, Scher defined NSE like a continuous seizure activity
Delivery Cesarean Spontaneous Gender Male Female Gestational age 29 wk 30e36 wk 37 wk Birth weight 48 h 48 h Seizure type 1 type >1 type Electrographic only Neurologic examination Normal/mildly abnormal Moderately abnormal Severely abnormal EEG findings I II Ultrasound brain scans Normal II III Outcome Normal Adverse Death Present Absent Postneonatal epilepsy Present Absent
PT (n ¼19)
FT (n ¼ 28)
12 7
15 13
7 12
15 13
8 11 0
0 0 28
7 1 9 2
0 0 3 25
13 4 2
8 8 12
3 11 5
2 6 20
10 9
5 23
7 8 4
10 5 13
9 10
12 16
4 15 0
7 20 1
3 4 12
14 7 7
1 18
3 25
0 7 12
7 9 12
0 19
7 21
10 9
5 23
6 3
10 13
P
.561
.373
.016
.010
.024
.109
.775
.657
.020
.638
.057
.032
.012
.431
PT ¼ preterm newborns; FT ¼ full-term newborns. EEG findings: I ¼ normal/mildly abnormal; II ¼ moderatly/severely abnormal. Cerebral ultrasound scan findings: II ¼ IVH of degree I or II, transient periventricular echodensities; III ¼ IVH of degree III or IV, intraparenchymal hemorrhage, PVL, brain malformation. Bold and italics indicates significant values.
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
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Fig. 1 e Outcome in subjects with NSE.
for at least 30 min or recurrent seizures for greater than or equal to 50% of the recording time (1e3 h).3 Different criteria where suggested by Wertheim and colleagues, that used the definition of a continuous EEG seizure-type activity in one or more channels for at least 4 h or separated for only a short period by activity with frequent sharp waves or spikes.4 However, later Ortibus suggested almost the same criteria as Scher considering NSE when: 1) total seizure duration was greater than 30 min or 2) the sum of seizure duration and periodic discharges exceeded 50% of the EEG recording.5 Later on, Yamamoto and colleagues stressed the concept of refractoriness to therapy, proposing the definition of NSE when the following criteria were present: 1) prolonged or frequently repeated seizures lasting more than 15 min, 2) refractory to treatment with conventional anticonvulsants (Diazepam, Phenobarbital and Phenytoin), 3) no response to glucose, calcium and magnesium, 4) mechanical ventilation required during seizures, and 4) further therapeutic options for Midazolam or Lidocaine needed.6 Moreover, other Authors simply defined status epilepticus as repeated seizures longer than 1 hour.7 Therefore, the adopted temporal criterion varies among authors from 15 min to a few hours. In our study, in accordance with the most accepted definition on neonatal status epilepticus3 and on status epilepticus9 and in agreement with our previous study,19 we considered NSE as continuous seizure activity lasting for at least 30 min or intermittent seizures lasting 30 min from which the patient
Fig. 2 e Outcome in preterm and full-term newborns with NSE.
Fig. 3 e Mortality in preterm and full-term newborns with NSE.
does not regain consciousness. However, newborns have peculiar characteristics both for their basal clinical conditions (the concept of consciousness is not the same as in the older ages and it is more difficult to assess) and for the electroclinical findings of the NS.11e17 These peculiarities are even more evident in preterm neonates, thus increasing difficulties to find a general consensus on NSE. Despite all these considerations, we recommend to maintain the same definition of NSE for both preterm and full-term newborns. In fact, comparing our newborns with NSE, particularly preterm versus full-term neonates, we did not find any significant clinical differences apart from the Apgar scores and for the neurological examination that appeared obviously worst in the preterm babies. However, all preterm newborns showed an unfavourable outcome and, moreover, presented a higher mortality rate. These appear to be consistent with previous studies that showed high rate of mortality and severe morbidity in preterm newborns after NS31,32 and might indicate seizures as a risk factor for long-term major impairments in preterm newborns.33 Moreover, the adverse effects of NSE and NS on the developing brain have been largely debated and there is a general agreement among several studies that NSE is related to an adverse outcome, that is reported in more than 60% of these newborns.1,2,5,18e20 This datum is confirmed in several studies despite the different definitions and inclusion criteria used. Most of our patients with NSE presented severe brain injury, in fact most of them, for instance preterm newborns, were at high risk of death or of adverse outcome, which occurred in 85% of the subjects. Although it is difficult to disentangle how much the prognosis depends on the underlying aetiologies or on the direct effect of the NS, animal models seem to suggest that NS and especially NSE could increase the underlying brain damage or could be even harmful per se.34e40 Studies on human newborns seem to confirm this,8,41e43 even if there is no general agreement.44,45 In our sample, characterized by newborns with NSE, only Apgar score at 5 min seems to be related to the outcome and no other independent risk factors for adverse outcome were found. This might depend on the relative homogeneity of the sample that highlights how patients with NSE share a common clinical background, characterized by a severe neonatal encephalopathy that unavoidably leads to an adverse outcome. Based on the evidence above reported, we would recommend a
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 5 ) 1 e6
shorter temporal criterion for the definition of NSE. Furthermore, because of the possible adverse effect of NSE on immature brain, it is mandatory in clinical practice to stop a seizure activity as soon as possible, thus leading to consider any first seizure recorded in an encephalopatic newborn as the potential onset of NSE.12 For adults and children older than 5 years old with generalized convulsive status epilepticus an operational definition has already been proposed,10 whereas for newborns the temporal criteria used for the NSE vary from 15 min to several hours.1e7,19 However, studies evaluating the mean duration of NS report that they vary from a minimum of 2 min to a maximum of 19 min3,5,46,47 It is also reported that 97% of newborns present seizures lasting less or up to 9 min and only .4% of them have seizures lasting more than 30 min.46 Moreover, seizures tend to recur very often in the same newborn mainly at the onset. This is a retrospective study using a database of 154 newborns collected over a 14 years period. While this is a strength of the present study, it represents also a limitation. Indeed, the study typology (retrospective), the long period of data collection (1999e2012), and the absence of a continuous EEG monitoring over a period of days, could not supply some more precise information on NSE duration and course. Thus, further studies are needed on this topic.
5.
Conclusions
Considering the existing data on NS duration and trend, and the adverse effects of prolonged and recurrent seizures on neonatal brain, it is advisable to adopt a shorter temporal criterion that allows early therapeutic intervention. It is also true that for NSE no standard treatment protocols exist, leading to a lack of a targeted intervention and no effective anticonvulsant drugs are available at the moment. However, before the right therapeutic approach, a correct definition of this clinical entity with a shorter temporal criterion would be the first step towards a proper treatment.
Conflict of interest None.
Funding source No funding was secured for this study.
references
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26. Dubowitz LMS, Dubowitz V, editors. The neurological assessment of the preterm and full-term infant. Clinics in developmental Medicine N/79. SIMP/Heinemann: London. Philadelphia: Lippincott; 1981. 27. Griffiths R. The abilities of young children. London: Child Development Research Centre; 1970. 28. Bayley N. Bayley scales of infant development Manual. 2nd ed. San Antonio: The Psychological Corporation; 1993. 29. IBM SPSS. Statistics for windows, version 20.0. Armonk, NY: IBM Corp; 2011. 30. Legido A, Clancy RR, Berman PH. Neurologic outcome after electroencephalographically proven neonatal seizures. Pediatrics 1991;88:583e96. 31. Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal seizures: a populationbased study. Neurology 2007;69:1816e22. 32. Pisani F, Barilli AL, Sisti L, Bevilacqua G, Seri S. Preterm infants with video-EEG confirmed seizures: outcome at 30 months of age. Brain Dev 2008;30:20e30. 33. Teune MJ, van Wassenaer AG, van Dommelen P, Mol BW, Opmeer BC, Dutch POPS-19 Collaborative Study Group. Perinatal risk indicators for long-term neurological morbidity among preterm neonates. Am J Obstet Gynecol 2011;204:396e1e396e14. 34. Jensen FE. Acute and chronic effects of seizures in the developing brain: experimental models. Epilepsia 1999;40:S51e8. 35. Holmes GL. Effects of seizures on brain development: lessons from the laboratory. Pediatr Neurol 2005;33:1e11. 36. Holmes GL, Ben-Ari Y. Effects of seizures on developmental processes in the immature brain. Lancet Neurol 2006;5:1055e63. 37. McCabe BK, Silveira DC, Cilio MR, Cha BH, Liu X, Sogawa Y, et al. Reduced neurogenesis after neonatal seizures. J Neurosci 2001;21:2094e103. 38. Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res 2001;50:445e54.
€ rkman ST, Miller SM, Rose SE, Burke C, Colditz PB. Seizures 39. Bjo are associated with brain injury severity in a neonatal model of hypoxia-ischemia. Neuroscience 2010;166:157e67. n HB, Ruohonen S, Kukko-Lukjanov TK, Virta JE, 40. Laure € nman M, Lopez-Picon FR, et al. Status epilepticus alters Gro neurogenesis and decreases the number of GABAergic neurons in the septal dentate gyrus of 9-day-old rats at the early phase of epileptogenesis. Brain Res 2013;1516:33e44. 41. Miller SP, Weiss J, Barnwell A, Ferriero DM, Latal-Hajnal B, Ferrer-Rogers A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58:542e8. 42. Glass HC, Glidden D, Jeremy RJ, Barkovich AJ, Ferriero DM, Miller SP. Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxicischemic brain injury. J Pediatr 2009a;155:318e23. 43. Wyatt JS, Gluckman PD, Liu PY, Azzopardi D, Ballard R, Edwards AD, et al., CoolCap Study Group. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics 2007;119:912e21. 44. Nagarajan L, Ghosh S, Palumbo L. Ictal electroencephalograms in neonatal seizures: characteristics and associations. Pediatr Neurol 2011;45:11e6. 45. Kwon JM, Guillet R, Shankaran S, Laptook AR, McDonald SA, Ehrenkranz RA, , et alEunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Clinical seizures in neonatal hypoxicischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial. J Child Neurol 2011;26:322e8. 46. Clancy RR, Legido A. The exact ictal and interictal duration of electroencephalographic neonatal seizures. Epilepsia 1987;28:537e41. 47. Pisani F, Copioli C, Di Gioia C, Turco E, Sisti L. Neonatal seizures: relation of ictal video-electroencephalography (EEG) findings with neurodevelopmental outcome. J Child Neurol 2008;23:394e8.
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
Official Journal of the European Paediatric Neurology Society
Orginal article
Neonatal status epilepticus: Differences between preterm and term newborns Elena Pavlidis a,*, Carlotta Spagnoli a, Annalisa Pelosi b, Silvia Mazzotta a, Francesco Pisani a a b
Child Neuropsychiatry Unit, Neuroscience Department, University of Parma, Italy Psychometrics, Neuroscience Department, University of Parma, Italy
article info
abstract
Article history:
Background: Despite the many studies on neonatal seizures, neonatal status epilepticus
Received 31 July 2014
(NSE) remains a controversial entity, with no general consensus about its definition. We
Received in revised form
report the characteristics of newborns with NSE in order to assess whether they showed
2 December 2014
homogeneous features or displayed clinical and/or instrumental differences depending on
Accepted 4 January 2015
gestational age (GA). Preterm and term neonates were compared and risk factors for adverse outcome evaluated.
Keywords:
Methods: From 154 newborns with video-EEG confirmed neonatal seizures admitted to the
Neonatal status epilepticus
NICU of Parma University Hospital between January 1999 and December 2012, we collected
Status epilepticus
a cohort of 47 newborns (19 preterm, 28 full-term) with NSE. NSE was defined as continuous
Neonatal seizures
seizure activity for at least 30 min or recurrent seizures lasting a total of 30 min without
Outcome
definite return to the baseline neurologic condition between seizures. Outcome was assessed at least at one year. We applied the c2 test to compare nominal data, and multivariate logistic regression analysis to determine independent risk factors for adverse outcome. Results: Only Apgar scores and neurologic examination (p .02) were different between the groups. None of the preterm newborns had a favourable outcome compared to 25% of the full-term ones (p ¼ .032). Moreover, 52.6% of preterm neonates died compared to 17.8% of the full-term newborns (p ¼ .01; OR ¼ 5.11). The only variable related to outcome was Apgar score at 5 min (p ¼ .02). Conclusion: Newborns with NSE represented a quite homogeneous group regardless of the GA. Outcome was unfavourable in most of the subjects; however adverse outcome and death were more represented in preterm newborns. © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Abbreviations: GA, gestational age; IVH, intraventricular hemorrhage; NS, neonatal seizures; NSE, neonatal status epilepticus; PVL, periventricular leukomalacia; US, cerebral ultrasound; v-EEG, video-electroencephalogram. * Corresponding author. U.O. di Neuropsichiatria Infantile, Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126 Parma (PR), Italy. Tel.: þ39 521702205; fax: þ39 521704708. E-mail address: [email protected] (E. Pavlidis). http://dx.doi.org/10.1016/j.ejpn.2015.01.002 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
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1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 5 ) 1 e6
Introduction
Neonatal status epilepticus (NSE) is still a controversial entity, for which a specific and worldwide accepted definition does not exist. However, different definitions,1e7 mostly arbitrary and based on temporal criteria, have been applied to define this entity and several studies showed a wide variety of NSE percentage in newborns with neonatal seizures (NS), ranging from 8% up to 43%.4,8 This variability is probably due to the different definitions and inclusion criteria used to diagnose NSE. In older ages, status epilepticus was usually defined as a continuous seizure activity lasting for at least 30 min, or recurrent seizures lasting 30 min or more from which the patient does not regain consciousness.9 A more operational definition was proposed for generalized, convulsive status epilepticus in adults and children, being a continuous seizure or two or more discrete seizures between which there is incomplete recovery of consciousness for 5 min.10 However, it is still debated if these definitions are applicable to newborns.11e17 Beyond the adopted definition, it seems that the effects of prolonged seizures on the developing brain lead to a poor outcome.1,2,5,18e20 This study, focused on newborns with status epilepticus, evaluates the differences between preterm and full-term newborns and also the risk factors for an adverse outcome have been analysed.
2.
Methods
We selected 47 newborns with NSE out of 154 newborns with video-EEG (v-EEG) confirmed NS, selected among the 5100 neonates consecutively admitted to the NICU of Parma University Hospital, between January 1999 and December 2012. NSE was defined as continuous seizure activity for at least 30 min or recurrent seizures lasting a total of 30 min without definite return to the baseline neurologic condition of the newborn between seizures, in any 1-h period (hourly seizure burden range: 50%e100%).9,19,21 The following inclusion criteria were applied: 1) v-EEG confirmed NS; 2) more than one cerebral ultrasound (US) examination performed up to term age and at least one computed tomography and/or cerebral MRI within the first year of life; 3) a follow-up of at least 12 months. All newborns at high risk of seizures due to predisposing factors such as birth asphyxia, sepsis, meningitis, metabolic disorders, brain malformations, intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL) on brain US scans, or in the presence of clinical signs suggestive of seizures, underwent serial EEGs during the neonatal period. NS were classified according to Volpe's classification modified by Lombroso22 and had to be associated with electrographic changes. Polygraphic v-EEG were obtained at the bedside and, depending on infants' head size, 21 or 10 cerebral electrodes were applied according to the 10e20 International System. Electrocardiogram, lateral eye movements, chin electromyographic activity, and abdominal respiration were the other physiologic variables most frequently monitored. The recordings continued until a complete cycle of awake, quiet, and active sleep were captured, or, if these were not clearly distinguishable, the recording continued for at least 60 min
and could be further prolonged on the basis of seizures course and clinical needs. Moreover, almost all the subjects with NSE underwent at least one follow-up EEG recording during the subsequent 24 h from the first one. Standardized agedependent criteria were applied to assess EEG background activity.23 The study was conducted on data from a NS database, continuation of a database whose clinical features have been previously described.19,24 Outcome was assessed at discharge, 3, 6, 9, 12 months and afterwards every six months with a follow-up from a minimum of 12 months to a maximum of 13 years according to clinical conditions. Neuromotor assessment was based on clinical criteria,25,26 and general development was assessed using the Griffiths' Mental Developmental Scale and, after 2007, the Bayley Scales of Infant and Toddler Development II.27,28 The neurodevelopmental outcome was classified as favourable or adverse. A favourable outcome was defined as normal neurologic development or mild muscle tone and reflexes abnormalities and isolated speech delay, whereas adverse outcome was identified as involvement resulting in death, cerebral palsy, developmental delay, epilepsy, blindness, or deafness.
2.1.
Statistical analysis
Nominal data were analysed using the c2 test, and if necessary, the Fisher exact test for two-by-two comparisons. A univariate logistic regression model to determine which independent variable(s) were related to outcome was used. Variables with a p value < .05 on univariate analysis were included in a multiple logistic regression analysis. The multiple logistic regression analysis was performed to detect independent risk factors for adverse outcome. For these purposes, adverse outcome and death were considered as a single group. In all instances, a p value of less than .05 was considered to be significant. Statistical analysis was performed using the Statistical Package for the Social Sciences (Version 20.0; IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp, 2011).29 For the statistical analysis, the first neurologic examination findings, evaluated according to GA, were grouped in three categories (modified from Legido 199130): 1) normal or mildly abnormal; 2) moderately abnormal, such as hypotonia/hypertonia, decreased muscle active movements, lethargy; and 3) severely abnormal, such as flaccid, inactive and coma. EEG findings were grouped into two categories: 1) normal or mildly abnormal (normal or excess sharp activity, absence or decreased frequency of normal patterns, excessively long lowvoltage periods or overall slightly decreased voltage); and 2) moderately or severely abnormal (asymmetries in voltage or frequencies, asynchrony for age, or isoelectric/low-voltage invariant activity, burst-suppression pattern, permanent discontinuous activity). US findings were grouped into three categories: I) normal; II) IVH of degree I or II, transient periventricular echodensities; and III) IVH of degree III or IV, intraparenchymal hemorrhage, PVL, brain malformations. Aetiologies were grouped in the following three categories: hypoxiceischaemic encephalopathy, cerebral hemorrhage, and others (congenital metabolic and transient metabolic disorders, infectious diseases, brain malformations, unknown causes).
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
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3.
Results
Table 1 e Sample characteristics PT vs FT with NSE. NSE (n ¼ 47)
Variables We collected a cohort of 154 newborns with NS among the 5100 admitted to our centre (3%). From those, we further select 47 newborns who experienced NSE, confirmed at v-EEG recording of at least 1 h (range: 1 he5 h 48 min). They represented the 0.9% of the population admitted to our NICU and the 30.5% of those with NS. The findings of the newborns with NSE are reported in Table 1. They were 19 preterm (mean GA of 29.6 weeks; range: 23e36) and 28 full-term neonates (mean GA of 39.7 weeks). Hypoxiceischaemic encephalopathy was the most frequent aetiology (17/47; 36.1%), followed by cerebral hemorrhage in 13 subjects (27.6%). Other aetiologies were infections (5/47; 10.6%), inherited metabolic disease (7/47; 14.9%), and cerebral malformations in 2 (4.2%). Aetiology remained unknown in 3 patients (6.4%). Twenty-four subjects (51%) showed severely abnormal US brain scans, equally distributed between full-term and preterm newborns, however normal US findings were only found in full-term newborns (7/28). The majority of subjects with NSE presented a moderately/severely abnormal background EEG activity (43/ 47; 91.5%). Normal pre-ictal neurologic examination was seen only in 5 subjects (10.6%, 4 full-term). Only 7 full-term newborns (14.9%) had a normal outcome. Death occurred in 15/47 newborns (31.9%), ten of whom were preterm infants (66.7%). In 19 infants (40.4%), we observed cerebral palsy. Developmental delay was observed in 46.8% newborns (22/47) and was associated with cerebral palsy in 17 subjects; epilepsy developed in16 subjects, 15 of whom associated with cerebral palsy and/or developmental delay (total ¼ 16/47; 34%) (Fig. 1). The only different clinical variables between preterm and term neonates were Apgar scores at any time and neurologic examination (respectively, p ¼ .016; .010; .024; .020), being the worst scores mainly represented in preterm infants (Table 1). Furthermore, all preterm newborns had an unfavourable outcome (100% vs 75%; p ¼ .032) (Fig. 2), and 10 of them died (52.6%) compared to 5 (17.8%) of the full-term newborns (p ¼ .01) (Fig. 3). The univariate analysis revealed that only Apgar score at 5 min was related to the outcome (p ¼ .02). Multivariate analysis did not find out any independent risk factor for adverse outcome.
4.
Discussion
Despite many studies on NS, few papers have focused on NSE and moreover they adopt different inclusion criteria with no general consensus on its definition. It is not possible to find a specific and widely accepted definition for NSE yet, however a temporal criterion has been used by several Authors in order to characterize this entity. At the end of the sixties, Monod defined NSE as the repetition of clinical or subclinical seizures with abnormal interictal neurologic status, occurring for at least a few hours,1 subsequently Mora used the same definition, changing the duration and adding the following neurophysiological criteria: 1) generalized high-voltage paroxysmal discharges, 2) two or more discharges occurring every 10 s, 3) with these abnormalities persisting for at least 20 min2 Afterwards, Scher defined NSE like a continuous seizure activity
Delivery Cesarean Spontaneous Gender Male Female Gestational age 29 wk 30e36 wk 37 wk Birth weight 48 h 48 h Seizure type 1 type >1 type Electrographic only Neurologic examination Normal/mildly abnormal Moderately abnormal Severely abnormal EEG findings I II Ultrasound brain scans Normal II III Outcome Normal Adverse Death Present Absent Postneonatal epilepsy Present Absent
PT (n ¼19)
FT (n ¼ 28)
12 7
15 13
7 12
15 13
8 11 0
0 0 28
7 1 9 2
0 0 3 25
13 4 2
8 8 12
3 11 5
2 6 20
10 9
5 23
7 8 4
10 5 13
9 10
12 16
4 15 0
7 20 1
3 4 12
14 7 7
1 18
3 25
0 7 12
7 9 12
0 19
7 21
10 9
5 23
6 3
10 13
P
.561
.373
.016
.010
.024
.109
.775
.657
.020
.638
.057
.032
.012
.431
PT ¼ preterm newborns; FT ¼ full-term newborns. EEG findings: I ¼ normal/mildly abnormal; II ¼ moderatly/severely abnormal. Cerebral ultrasound scan findings: II ¼ IVH of degree I or II, transient periventricular echodensities; III ¼ IVH of degree III or IV, intraparenchymal hemorrhage, PVL, brain malformation. Bold and italics indicates significant values.
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
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Fig. 1 e Outcome in subjects with NSE.
for at least 30 min or recurrent seizures for greater than or equal to 50% of the recording time (1e3 h).3 Different criteria where suggested by Wertheim and colleagues, that used the definition of a continuous EEG seizure-type activity in one or more channels for at least 4 h or separated for only a short period by activity with frequent sharp waves or spikes.4 However, later Ortibus suggested almost the same criteria as Scher considering NSE when: 1) total seizure duration was greater than 30 min or 2) the sum of seizure duration and periodic discharges exceeded 50% of the EEG recording.5 Later on, Yamamoto and colleagues stressed the concept of refractoriness to therapy, proposing the definition of NSE when the following criteria were present: 1) prolonged or frequently repeated seizures lasting more than 15 min, 2) refractory to treatment with conventional anticonvulsants (Diazepam, Phenobarbital and Phenytoin), 3) no response to glucose, calcium and magnesium, 4) mechanical ventilation required during seizures, and 4) further therapeutic options for Midazolam or Lidocaine needed.6 Moreover, other Authors simply defined status epilepticus as repeated seizures longer than 1 hour.7 Therefore, the adopted temporal criterion varies among authors from 15 min to a few hours. In our study, in accordance with the most accepted definition on neonatal status epilepticus3 and on status epilepticus9 and in agreement with our previous study,19 we considered NSE as continuous seizure activity lasting for at least 30 min or intermittent seizures lasting 30 min from which the patient
Fig. 2 e Outcome in preterm and full-term newborns with NSE.
Fig. 3 e Mortality in preterm and full-term newborns with NSE.
does not regain consciousness. However, newborns have peculiar characteristics both for their basal clinical conditions (the concept of consciousness is not the same as in the older ages and it is more difficult to assess) and for the electroclinical findings of the NS.11e17 These peculiarities are even more evident in preterm neonates, thus increasing difficulties to find a general consensus on NSE. Despite all these considerations, we recommend to maintain the same definition of NSE for both preterm and full-term newborns. In fact, comparing our newborns with NSE, particularly preterm versus full-term neonates, we did not find any significant clinical differences apart from the Apgar scores and for the neurological examination that appeared obviously worst in the preterm babies. However, all preterm newborns showed an unfavourable outcome and, moreover, presented a higher mortality rate. These appear to be consistent with previous studies that showed high rate of mortality and severe morbidity in preterm newborns after NS31,32 and might indicate seizures as a risk factor for long-term major impairments in preterm newborns.33 Moreover, the adverse effects of NSE and NS on the developing brain have been largely debated and there is a general agreement among several studies that NSE is related to an adverse outcome, that is reported in more than 60% of these newborns.1,2,5,18e20 This datum is confirmed in several studies despite the different definitions and inclusion criteria used. Most of our patients with NSE presented severe brain injury, in fact most of them, for instance preterm newborns, were at high risk of death or of adverse outcome, which occurred in 85% of the subjects. Although it is difficult to disentangle how much the prognosis depends on the underlying aetiologies or on the direct effect of the NS, animal models seem to suggest that NS and especially NSE could increase the underlying brain damage or could be even harmful per se.34e40 Studies on human newborns seem to confirm this,8,41e43 even if there is no general agreement.44,45 In our sample, characterized by newborns with NSE, only Apgar score at 5 min seems to be related to the outcome and no other independent risk factors for adverse outcome were found. This might depend on the relative homogeneity of the sample that highlights how patients with NSE share a common clinical background, characterized by a severe neonatal encephalopathy that unavoidably leads to an adverse outcome. Based on the evidence above reported, we would recommend a
Please cite this article in press as: Pavlidis E, et al., Neonatal status epilepticus: Differences between preterm and term newborns, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/j.ejpn.2015.01.002
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 5 ) 1 e6
shorter temporal criterion for the definition of NSE. Furthermore, because of the possible adverse effect of NSE on immature brain, it is mandatory in clinical practice to stop a seizure activity as soon as possible, thus leading to consider any first seizure recorded in an encephalopatic newborn as the potential onset of NSE.12 For adults and children older than 5 years old with generalized convulsive status epilepticus an operational definition has already been proposed,10 whereas for newborns the temporal criteria used for the NSE vary from 15 min to several hours.1e7,19 However, studies evaluating the mean duration of NS report that they vary from a minimum of 2 min to a maximum of 19 min3,5,46,47 It is also reported that 97% of newborns present seizures lasting less or up to 9 min and only .4% of them have seizures lasting more than 30 min.46 Moreover, seizures tend to recur very often in the same newborn mainly at the onset. This is a retrospective study using a database of 154 newborns collected over a 14 years period. While this is a strength of the present study, it represents also a limitation. Indeed, the study typology (retrospective), the long period of data collection (1999e2012), and the absence of a continuous EEG monitoring over a period of days, could not supply some more precise information on NSE duration and course. Thus, further studies are needed on this topic.
5.
Conclusions
Considering the existing data on NS duration and trend, and the adverse effects of prolonged and recurrent seizures on neonatal brain, it is advisable to adopt a shorter temporal criterion that allows early therapeutic intervention. It is also true that for NSE no standard treatment protocols exist, leading to a lack of a targeted intervention and no effective anticonvulsant drugs are available at the moment. However, before the right therapeutic approach, a correct definition of this clinical entity with a shorter temporal criterion would be the first step towards a proper treatment.
Conflict of interest None.
Funding source No funding was secured for this study.
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