ABSTRACT
Context:
There are limited data in the literature about the relationship between neonatal seizures and subsequent epilepsy.
Aims:
This study aimed to identify the predictive value of perinatal factors, etiologies, electroencephalography (EEG), and cranial ultrasonography (USG) for future epilepsy after neonatal seizures.
Materials and Methods:
A total of 92 children with epilepsy who had seizures during their neonatal period were retrospectively evaluated whether the contribution of perinatal, natal, and postnatal risk factors confining clinical, laboratory, EEG, and imaging to subsequent epilepsy. Chi-square, uni, and multivariate logistic regression were applied to find out predictive factors for subsequent epilepsy.
Results:
The rate of epilepsy was 57.6 % during 1–6 years follow-up. Birth weight, Apgar scores at first and fifth minutes, resuscitation history, abnormal neurological examination, etiology, response to the treatment, abnormal EEG, or USG findings were the most important risk factors for future epilepsy in univariate analysis (P < 0.05). Furthermore, asphyxia, fifth minute Apgar scores, response to the treatment, USG, and EEG were independent predictors (P < 0.05) for subsequent epilepsy in multivariate logistic regression. No relationship was found between subsequent epilepsy and mode of delivery, seizure onset time, and seizure types (P > 0.05).
Conclusion:
Although there are recent promising and advanced techniques in neonatal intensive care units, asphyxia is still one of the most important risk factors for not only poor neurological conditions but also for future epilepsy after neonatal seizures. Apgar scores, treatment with multiple antiepileptic drugs, poor background EEG activity, and abnormal neuroimaging seem to have strong predictive values for developing subsequent epilepsy. Therefore, patients with a history of neonatal seizures should be closely followed up to decrease the risk of long-term outcomes and early detection of epilepsy.
KEYWORDS: Epilepsy, newborns, perinatal injury, risk factors, seizures
INTRODUCTION
Neonatal seizures are one of the most common reasons for the future poor neurological condition and subsequent epilepsy.[1,2,3,4,5,6] Although severely affected newborns can be survived thanks to using advanced techniques in neonatal intensive care units (NICUs), neurological sequels may be confronted as a long-term consequence of those complicated cases.[4,5,6,7] The incidence of seizure of newborns varies between 2 and 15 per 1000 live births.[1,2,3,4,8] Recurrent seizures can be frequently observed in NICUSs and may lead to further irreversible detrimental effects on maturational stages of the younger brain.[8,9,10,11,12] Therefore, epilepsy remains the most important issue after neonatal seizures with a higher ratio of 10%–50% when compared to the patients who had their first seizure in older ages than the neonatal period.[1,2,3,4,6,9,13]
There are limited and conflicted data regarding adverse outcomes of neonatal seizures and subsequent epilepsy.[7,8,11] Some factors such as gestational age and birth weight, Apgar scores, resuscitation, etiology, seizure semiology, response to the treatment, electroencephalography (EEG), and neuroimaging seems to be related to adverse outcomes of neonatal seizures. However, many of those factors were globally investigated for outcomes instead of separate items for future epilepsy in many studies.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31] Even though there have been some efforts to develop scoring systems for predicting future neurological outcomes,[7,8,11] there is still a lack of consistency to be able to establish a reliable scoring system for subsequent epilepsy.[8,11,12,14,20,24] Therefore, etiology and risk factors should be comprehensively evaluated to be able to provide early preventive approaches for decreasing neurological complications like epilepsy.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]
Our purpose was to determine the relationship between neonatal seizures and future epilepsy by investigating the possible contribution of independent risk factors including perinatal, etiological, EEG, and neuroimaging findings.
MATERIALS AND METHODS
Patients
The data and chart review of 108 patients have gathered department of NICU at Gazi University School of Medicine from January 2007 to December 2012 retrospectively. The inclusion criteria were the presence of seizures during neonatal periods, followed up at least 1 year in the department of pediatrics. Information for prenatal, natal, and postnatal periods was obtained from the chart reviews. After excluded the patients from the study who had insufficient information or died before the study, the remaining 92 children were comprehensively investigated in terms of perinatal risk factors such as gestational age, type of delivery, birth weight, Apgar scores at first and fifth minutes, history of resuscitation, as well as detailed etiologic factors, time of seizure onset, seizure types, the presence of status epilepticus, response to the treatment, EEG, and cerebral ultrasonography (USG).
Perinatal risk factors
Gestational age was categorized into two groups as younger or older than 37 weeks and birth weights were grouped as greater or less than 2500 g. The type of delivery was described as a cesarean section (C/S) or normal spontaneous vaginal delivery (NSVD). Resuscitation history was also noted. Apgar scores at the first and fifth minutes were determined as lower as or higher than 7 points. Concurrent neurological examinations were appreciated as normal or abnormal depending on the following data: moderately abnormal: hypo- or hypertonia, decreased spontaneous movements, or lethargy; severely abnormal: no movement, inactive, coma.[32]
Etiology
Blood glucose and electrolyte levels, cerebrospinal fluid, arterial blood gas, and acid-base levels, serum ammonia, urine organic acid, and lactate were checked to identify both the degree of asphyxia and hypoxic-ischemic encephalopathy (HIE). The presence of infection, sepsis, and meningitis inherited metabolic disorders or transient metabolic disturbances were also analyzed. The diagnosis of HIE was based on four criteria: severe metabolic acidosis (umbilical cord or first neonatal blood sample pH of <7.0); fifth minute Apgar score <6; fetal distress (abnormal fetal heart rate or meconium-stained amniotic fluid); and neonatal seizures within the first 24h after delivery. In cases with no clear reason, the etiology was assigned to as “unknown” category. Etiologies were grouped into the following two categories for statistical purposes: (1) HIE and intracranial hemorrhage; and (2) meningitis, sepsis, inherited metabolic disorders, transient metabolic disturbances, genetic disorders, cerebral dysgenesis, and unknown etiology.
Cranial ultrasound
Cranial USG was performed by the method of multifrequency, 5–10 MHz sector probes, and 7.5–12 MHz linear probes. The findings were appreciated as abnormal for stages 1 and 2: intraventricular hemorrhage; and stage 3: intraparenchymal hemorrhage, transient periventricular echo densities, borderline ventricular dilatation; periventricular leukomalacia (PVL), structural malformations, and other lesions.
Electroencephalography
Electroencephalograms were recorded for at least 60 min at a paper speed of 30 mm/s and an amplitude of 70 mV ¼ 10 mm by Nihon–Kohden Neurofax EEG 1200. Extraocular and ECG leads were applied for identifying sleep and wakefulness. Electrodes were placed on the surface of the scalp according to the International 10/20 system modified for neonates. A placement with fewer electrodes was preferred because of the small head circumferences of the patients as suggested by Tekgul et al.[33] The findings were grouped into two categories: 1: normal and slightly abnormal background rhythms: mildly increased sharp wave activity; 2: moderately or severely abnormal EEG: voltage/period asymmetry, frequent multiregional spikes or sharp waves, prolonged silent period, lack of electroencephalogram maturation patterns, or persistent low-voltage basal rhythm, burst suppression pattern, and electro-cerebral inactivity.[33]
Seizure types, timing, and treatment
Seizure types were categorized according to Volpe’s[34] classification as clonic (Focal, multifocal), tonic (focal, generalized), myoclonic, and subtle events observed by consulting pediatric neurologists, neonatologists, residents, and neonatal nursing staff. We assigned the most prominent seizure type (i.e., the one that arose most often) in cases that experienced multiple seizure types. Nevertheless, if multiple seizures were prominent, they were recorded as a separate category Benign neonatal sleep myoclonus was excluded from the study by clinical and EEG criteria. Subtle seizures were defined as a constellation of paroxysmal events comprising eye movements, oral automatism, bicycling, some other unusual movements, apnea, and tachycardia.[34]
Seizure onset time was categorized concerning appearing within the first 48h or afterward. The main antiepileptic drugs (AEDs) were recorded either phenobarbital or phenytoin. Levetiracetam, topiramate, or carbamazepine were administrated as add-on therapies, whereas midazolam and lidocaine were applied as a rescue approaches in case of status epilepticus. All AED and rescue medications were administered at an appropriate dosage for the neonatal age group.[35] The treatment options were grouped depending on the response to the AEDs. The responsive group was defined as the patients who had no seizures on one AED, whereas the unresponsive group was comprised of patients requiring two or more AEDs to obtain satisfactory seizure control or those with epileptic encephalopathy.
Epilepsy and outcome
Postneonatal epilepsy was diagnosed if the patient experienced at least two afebrile and unprovoked seizures over the 24h after the neonatal period. All perinatal risk factors, etiologies, features of the seizures, EEG, and USG results were compared to predict the possibility of future epilepsy. Therefore, gestational age, type of delivery, birth weight, Apgar score at 1 and 5min, a history of resuscitation at birth, time of seizure onset, seizure types, the presence of status epilepticus, treatments, EEG, cerebral USG results, and detailed etiologic factors were applied to univariate logistic regression, and then meaningful results were analyzed by multivariate logistic regression to predict possible future epilepsy.
Statistical analysis
Statistical analysis was performed with Statistical Package for the Social Sciences (SPSS Inc., Chicago, Illinois) version 20.0 for Windows. Data were expressed as mean ± standard deviation. Categorical data were evaluated by chi-square comparison between the epileptic and nonepileptic groups. Univariate logistic regression was performed to find a predictive value of the variables for future epilepsy. Finally, the meaningful data from the univariate analysis were then applied to multivariate logistic regression to establish a model for predicting independent factors for postneonatal epilepsy. Odds ratios and 95% confidence intervals (CI) were also calculated for each of these parameters. A value of P < 0.05 was considered statistically significant.
This study was approved by the Ethics Committee of the Gazi University School of Medicine.
RESULTS
A total of 92 children, 41 girls (44.5%), and 51 boys (55.4%) were followed up between 12 and 72 months (median: 36 months). The incidence of epilepsy was 57.6% in the mix gestational age of newborns, whereas 70.6% in premature newborns and 50% in term newborns separately (P < 0.05).
Perinatal factors, etiology, and ultrasonography
Almost 60% of the patients were term, whereas 40% were preterm. Birth weight was between 680 g and 3700 g (median: 2790 g). Both younger ages and having lower birth weight were significantly associated with a higher rate of subsequent epilepsy (P < 0.05). C/S was two times higher (68%) than NSVD (31.5%); however, later outcomes did not differ in terms of having epilepsy (P > 0.05) [Table 1].
Table 1.
Demographics, perinatal, natal, and postnatal risk factors
| Variables Total n: 92(%) | Without epilepsy n (%) | With epilepsy n (%) | P* | Preterm n: 34 | Term n: 58 | P** |
|---|---|---|---|---|---|---|
| Gestational age | ||||||
| <37 week: 34 (37) | 10 (29.4) | 24 (70.6) | 0.043 | 34 (37) | ||
| ≥37 week: 58 (63) | 29 (50) | 29 (50) | 58 (63) | |||
| Birth weight, g | ||||||
| <2500: 31 (33.7) | 8 (25.8) | 23 (74.2) | 0.018 | 28 (82.4) | 3 (5.2) | 0.000 |
| ≥2500: 61 (66.3) | 31 (50.8) | 30 (49.2) | 6 (17.6) | 55 (82.4) | ||
| Mode of delivery | 0.652 | |||||
| NSVD: 29 (31.5) | 11 (37.9) | 18 (62) | 7 (20.6) | 22 (37.9) | ||
| C/S: 63 (68.5) | 28 (44.4) | 35 (55.6) | 27 (79.2) | 36 (62.1) | ||
| 1st minute Apgar scores | ||||||
| <7: 56 (60.9) | 17 (30.4) | 39 (69.6) | 0.003 | 24 (70.6) | 32 (55.2) | |
| ≥7: 36 (39.1) | 22 (61.1) | 14 (38.9) | 10 (29.4) | 26 (44.8) | ||
| 5th minute Apgar scores | ||||||
| <7: 51 (55.4) | 13 (25.5) | 38 (74.5) | 0.000 | 22 (64.7) | 29 (50) | |
| ≥7: 41 (44.6) | 26 (63.4) | 15 (36.6) | 12 (35.3) | 29 (50) | ||
| Need for resuscitation | ||||||
| No: 45 (48.9) | 26 (57.8) | 19 (42.2) | 13 (38.2) | 32 (55.2) | ||
| Yes: 47 (51.1) | 13 (27.7) | 34 (72.3) | 0.003 | 21 (61.8) | 26 (44.8) | |
| Neurological examination | ||||||
| Normal: 45 (48.9) | 25 (55.6) | 20 (44.4) | 16 (47.1) | 29 (50) | ||
| Abnormal: 47 (51.1) | 14 (29.8) | 33 (70.2) | 0.011 | 18 (52.9) | 29 (50) | |
| Seizure onset time | ||||||
| <48 h: 49 (53.3) | 17 (34.7) | 32 (65.3) | 11 (32.4) | 32 (55.2) | ||
| ≥48 h: 43 (46.7) | 22 (51.2) | 21 (48.8) | 0.083 | 23 (67.6) | 26 (44.8) | 0.028 |
| Seizure types | ||||||
| Clonic: 10 (10.9) | 3 (30) | 7 (70) | 0.313 | 2 (5.9) | 8 (13.8) | |
| Myoclonic: 23(25) | 8 (34.8) | 15 (65.2) | 0.273 | 9 (26.5) | 14 (24.1) | |
| Tonic: 24 (26.1) | 9 (37.5) | 15 (62.5) | 0.375 | 11 (32.4) | 13 (22.4) | |
| Subtle seizures: 19 (20.7) | 14 (73.7) | 5 (26.3) | 0.002 | 6 (17.6) | 13 (22.4) | |
| Multiple seizure types: 20 (21.7) | 9(45) | 11 (55) | 0.493 | 10 (29.4) | 10 (17.2) | |
| Status epilepticus: 4 (100) | 0 | 4 (100) | 2 (5.9) | 2 (3.4) | ||
| Treatment | ||||||
| Responder: 53 (57.6) | 34 (64.2) | 19 (35.8) | 17 (50) | 36 (62.1) | ||
| Not responder: 39 (42.4) | 5 (12.8) | 34 (87.2) | 0.000 | 17 (50) | 22 (37.9) | |
| EEG | ||||||
| Normal–mildly abnormal: 74 (80.4) | 38 (51.4) | 36 (48.6) | 26 (76.5) | 48 (82.8) | ||
| Moderate–severe abnormal:18 (19.6) | 1 (5.6) | 17 (94.4) | 0.000 | 8 (23.5) | 10 (17.2) | |
| Cranial USG | ||||||
| Normal: 44 (47.8) | 26 (59.1) | 18 (40.9) | 12 (35.3) | 32 (55.2) | ||
| Abnormal: 48 (52.2) | 13 (27.1) | 35 (72.9) | 0.002 | 22 (64.7) | 26 (44.8) | |
| Etiology | ||||||
| Asphyxia: 33 (35.8) | 9 (27.3) | 24 (72.7) | 0.023 | 10 (29.4) | 23 (39.7) | |
| ICH:16 (17.3) | 3 (18.8) | 13 (81.2) | 0.031 | 13 (38.2) | 3 (5.2) | 0.000 |
| Infection:10 (10.8) | 4 (33.3) | 6 (66.7) | 0.493 | 4 | 6 | |
| Inborn error of metabolism: 8 (8.6) | 0 | 8 (100) | 1 (2.9) | 7 (12.1) | ||
| Transient metabolic reasons:38 (41.3) | 15 (39.5) | 23 (60.5) | 0.398 | 19 (55.9) | 19 (32.8) | |
| Structural: 5 (5.4) | 2 (40) | 3 (60) | 2 (5.8) | 3(5) | 0.025 | |
| Unknown:9 (9.7) | 4 (44.4) | 5 (55.6) | 3 (8.8) | 6 (10.3) |
Chi-square, P* shows differences between epilepsy and without epilepsy group
Chi-square, P** shows differences between term and preterm newborns
Apgar scores were lower than 7 points in 33% of the patients at the first minute, whereas 50% in the fifth minute. 69.6% and 74.5% of the patients had future epilepsy for each first and fifth minute Apgar scores, respectively (P < 0.05). The need for resuscitation was significantly higher than in patients with later epilepsy (P < 0.05). Oxygen was applied to 11 (23%), positive pressure ventilation in 9 (19%), endotracheal intubation in 18 (38%), and resuscitation with cardiac massage in 9 (19%) patients. The presence of abnormal neurological examination was remarkably increased in the epilepsy group (70%) compared to developmentally appropriate patients without epilepsy (44%) (P < 0.05) [Table 1].
The most frequent etiology was perinatal asphyxia (35.8%), hemorrhage (17.3%), transient metabolic disorders (41%), and infections (10.8%) (sepsis, meningitis). Intracranial hemorrhage was significantly higher (38.2%) with a poorer prognosis compared to other etiologies in the preterm newborns (P < 0.05). Furthermore, intracranial hemorrhage (81.2%) and perinatal asphyxia (72.7%) were remarkably related to future epilepsy in both preterm and term group together (P < 0.05) [Table 1].
Almost half of the patients (n: 48) had abnormal cranial USG and 73% (n:35) of those significantly associated with future epilepsy compared to the patients (27.1%, n:13) no having epilepsy (P < 0.05). Of the 35 patients (73%) with future epilepsy, 37% had hemorrhage whereas the remaining 62.8% had structural malformations and PVL including infections and metabolic disorders [Table 1].
Seizure types, times, EEG, and treatment
The earlier onset of clinical seizures within the first 48h was seen in 49 infants (53.3%), which was significantly higher in the term group (55.2%) (P < 0.05) but not associated with subsequent epilepsy (P > 0.05). Distribution of the predominant clinical seizures was as follows: tonic (26%), myoclonic (25%), clonic (10%), and subtle seizures (20%). Either any seizure subtypes or having multiple seizure types (20%) were found no correlate with future epilepsy (P > 0.05). Interestingly, subtle seizures were higher in the nonepileptic group with a favorable outcome (P < 0.05). Four patients had status epilepticus with future neurological complications of global developmental delay (50%) or cerebral palsy (50%) in the setting of asphyxia, sepsis, and inborn metabolic disorders [Table 1].
Of 18/92 (20%) patients had moderate to severe EEG abnormalities with 11 (61%) had frequent multiregional spikes and sharp waves, and 7 (38%) had persistent low voltage or background suppression. Almost 95% of those patients had significantly related to future epilepsy with significant power of predictive value (P < 0.05) [Tables 1 and 2].
Table 2.
Predictive values of the perinatal, natal, and postnal factors for future epilepsy
| Variables | Univariate logistic regression | Multivariate logistic regression | ||
|---|---|---|---|---|
| OR (95% CI) | P | OR (95% CI) | P* | |
| Perinatal factors | ||||
| Gestational age <37 weeks | – | 0.054 | – | – |
| Gestational weight <2500 g | 2.97 (1.151–7.668) | 0.024 | – | – |
| Mode of delivery (C/S) | – | 0.557 | – | – |
| Meconium aspiration | – | 0.222 | – | – |
| Need for resuscitation | 3.579 (1.498–8.550) | 0.004 | – | – |
| 1st minute Apgar <7 | 3.605 (1.496–8.687) | 0.004 | – | – |
| 5th minute Apgar <7 | 5.067 (2.071–12.396) | 0.000 | 3.715 (1.089–12.670) | 0.036 |
| Neurological examination | 2.946 (1.249–6.950) | 0.014 | – | – |
| Etiology | ||||
| HIE and hemorrhage | 2.719 (1.140–6.482) | 0.024 | – | – |
| HIE | 2.759 (1.099–6.926) | 0.031 | – | – |
| Hemorrhage | 3.90 (1.028–14.801) | 0.045 | – | – |
| Infection (sepsis and meningitis) | – | 0.642 | – | – |
| Transient metabolic disturbance | – | 0.635 | – | – |
| Inborn metabolic disorders | – | 0.999 | – | – |
| Transfontanel USG | 3.899 (1.620–9.333) | 0.020 | 8.023 (2.090–30.800) | 0.002 |
| Seizures and treatment | ||||
| Onset age <48 h | – | 0.111 | – | – |
| No response to the treatment | 12.168 (4.076–36.331) | 0.000 | 11.803 (2.090–30.800) | 0.000 |
| Tonic seizure | – | 0.573 | – | – |
| Clonic seizure | – | 0.401 | – | – |
| Myoclonic seizure | – | 0.394 | – | – |
| Subtle seizure | 0.186 80.006–0.576) | 0.004 | 0.209 (0.44–0.992) | 0.049 |
| Multiple seizure types | – | 0.709 | – | – |
| Status epilepticus | – | 0.079 | – | – |
| EEG abnormalities | 17. 944 (2.270–141.874) | 0.006 | 32. 946 (2.746–395.291) | 0.006 |
*Negative values represent P > 0.05
Of the 92 patients, 56.7 % of them received one AED (phenobarbital or phenytoin), whereas 42.4% of them needed additional therapy due to unsatisfactory seizure control. 87.2% of the patients had a strong correlation for future epilepsy in the groups of nonresponder to one medication (P < 0.05) [Table 1].
Predictive factors for future epilepsy
Possible factors future epilepsy including perinatal risk factors, etiology, neurological examination, seizure times, types, and treatment, and EEG and USG findings were applied to univariate logistic regression. Birth weight, first and fifth minutes Apgar scores, need of resuscitation, neurological examination, etiology such as asphyxia and hemorrhage; response to the treatment, abnormal EEG, and USG findings were found to have significant predictive value for future epilepsy. As a last step, those 10 factors were analyzed in multivariate logistic regression to determine independent risk factors for subsequent epilepsy. Finally, five factors consisting of fifth minute Apgar scores, subtle seizures, response to the treatment, abnormal USG, and EEG findings were found to be independent predictors for future epilepsy (P < 0.05) [Table 2].
DISCUSSION
Epilepsy still seems one of the adverse complications of neonatal seizures.[4,7,8,9,11,20,24] Diagnosis and immediate interventions should be well established during the neonatal period to be able to prevent future complications.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31] Even though there are well- known established factors for future global neurological conditions, there is a lack of unique data predicting for future epilepsy. In this respect, our study provides a new insight by highlighting important points such as fifth minute Apgar scores, poor response to the treatment, severely abnormal EEG background, and pathologic cranial USG which are independent predictive risk factors for future epilepsy. Furthermore, we found that lower birth weight, history of resuscitation, abnormal neurological examination, and etiology were also important not only for predicting future neurological conditions, also significantly higher in future epilepsy when compared to children without epilepsy after neonatal seizure.
The possibility of postneonatal epilepsy was shown in various range between 18% and 50% in different series.[7,8,9,17,19] Clancy and Legido[9] reported that childhood epilepsy was rather higher at almost 50% after neonatal seizures.[5,8] This was close to our results which were at a fairly high ratio of 57.6% in a mixed group of term and preterm infants, whereas 70.6% in preterm infants and 50% in term infants as separately. Those differences can be explained by various inclusion criteria and settings of the studies.[6,24] As shown in our cohort, mixed, or separate groups of preterm and term infants, different diagnostic criteria such as clinical or EEG findings, or patient selection from hospitals or public basis may independently affect the epilepsy ratios after neonatal seizures.[4,5,6,8,9,12,17,18,24,30,31]
It is a well-known fact that some perinatal factors such as gestational age and weight,[6,7,8,9,25,30] need for resuscitation, Apgar scores,[6,7,8,10,27,28] and also neurological examination[4,7,12,20,24,25] were shown to be related to neonatal seizures. However, predictive value of those parameters is still debatable for subsequent epilepsy.[4,6,7,8,9,11,12,20,21,25,30] Although Soltirovska-Salamon et al.[8] showed that gestational age was the most important predictor for epilepsy, Yıldız et al.[5] failed to reveal this interaction after neonatal seizures. As confirmed by some series for a future neurological condition, we determined that younger gestational age and lower birth weight were associated with future epilepsy (74.2%) not only general neurological condition.[4,7,8,9,11,20,21,30] Therefore, the profound vulnerability can occur during maturation, connectivity, and organization steps in this unique age.[7,8,10,28,30] When other clinical indicators are taken into consideration, one of our important results attributed that history of resuscitation and Apgar scores are sensitive for not only the global neurological outcome but also for future epilepsy.[6,8,9,20,27,28] Soltirovska-Salamon et al.[8] and Garfinkle and Shevell[11] also supported this argument and they confirmed that Apgar scores were significantly associated with postneonatal epilepsy. We also showed that abnormal neurological examination was rather higher in the epileptic groups (70%) by promoting substantial effects for subsequent epilepsy. Similarly, Garcias Da Silva et al.[20] showed that neurological examination is the only factor in multivariate logistic regression for postneonatal epilepsy. Eventually, in the case of a history of resuscitation and lower Apgar scores, we strongly recommend to close follow-up neurological examination which may provide not only short-term assessment but also predict long-term neurological status from the first minute.[4,6,7,9,12,20,25]
Nowadays, there are many advanced delivery techniques and better postpartum care; however, perinatal hypoxia and hemorrhage are still confronted as remarkable reasons which were related to neurological outcome.[4,5,6,8,11,12,20,24,25,27,29] In concordant with the literature, we found neonatal seizures were substantially increased as a consequence of asphyxia (35.8%) and intracerebral hemorrhage (ICH) (17%). Furthermore, our results implied both of those etiologies are strongly associated with subsequent epilepsy. This was supported in the setting of hypoxia by Tekgul et al.,[4] Garfinkle and Shevell,[27] and Glass et al.,[29] whereas in the presence of ICH by Pisani et al.[7] and Yıldız et al.[5] On the contrary, the possibility of future epilepsy can change depending on either reversible or irreversible effects of the reasons.[4,6] However, unknown etiologies still cause unpredictable neurological outcomes and may lead to unsatisfactory interventions during the neonatal period of the seizures.[4,6] In our study, 9.7% of patients did not have a fair reason like in a study by Tekgul et al., who showed 10% of the newborns had no clear etiology for seizures. Overall, etiologies, diagnosis, and inventions during neonatal seizures should be well established to minimize future complications.
At that point, neuroimaging seems to be one of the helpful tools for not only determining etiology but also verifying the severity of the injury and providing reliable follow-up options.[6,7,8,12,18,25,28] Many studies are attributed that abnormal USG were sensitive to predict a neurological outcome, whereas a few series implied to association with epilepsy.[6,7,8,12,22,23,28] Strikingly, we found that USG was contributed not only etiology but also very specific for later epilepsy which seemed a strong independent predictor Moreover, when taking into consideration that many newborns having ventilator support and critical interventions at the same time during the seizures, USG can provide some advantages such that it can be applied bedside without needing anesthesia, not affecting moving artifact, noninvasive, and provides rapid results for deciding a neurological assessment.[7,12,28]
There are controversial results in the relationship between seizure semiology and postneonatal epilepsy.[5,6,7,11,12,14,24,26] Some of those show that multiple and some specific seizure types such as tonic, myoclonic, and subtle seizures are assumed to have some additive effects for further epilepsy,[4,6,7,12,24,26] whereas some of them failed to show this association.[8] Interestingly, even if we cannot show any predominant neonatal seizure types relationship with subsequent epilepsy, subtle seizures had a better outcome for not having epilepsy contrary to previous results.[7] This controversy may be a consequence of the diagnosis of seizures depending on the clinical definition or EEG proven.[9,11,13] In a different view of aspect, due to maturational step and immature connections, generalized seizures may point to focal origin, whereas bilaterally distributed conditions can be presented as the focal seizures which should be taken in mind in this particular age. Related to this concept, the contribution of multiple seizure types for developing epilepsy is debatable.[9,24]
On the contrary, the neonatal period is a particular time for suspicious and subclinical seizures which may be under or overestimated ratios.[9,24] Likewise, earlier onset of seizures in our term newborns (55.2%) than preterm suggested us to an increased possibility of subclinical seizures without motor findings in premature infants as a consequence of profound depressed cerebral functions.[5,6,7,9,11,12,24,28] Therefore, supplementary techniques such as EEG and video EEG monitoring seem to be important tools for an accurate diagnosis.[5,6,7,9,11,12,24,28] Background patterns such as burst suppression, persistent low amplitude, periodic patterns, and multifocal discharges were found related to developmental delays and cerebral palsy beyond to future epilepsy.[4,5,6,7,8,9,11,12,24] Garfinkle[11] and Soltirovska-Salamon et al.[8] showed background EEGs were strong factors of the scoring system for the neurological outcome and future epilepsy. In concordant with this argument,[4,5,6,7,8,9,12,20] we attributed background suppression and severe multifocal frequent discharges were associated 30 times greater than future epilepsy. Therefore, instead of a single recording, long-term monitoring should be preferred to be captured of EEG abnormalities and seizures especially in encephalopathic newborns.[7,9,27]
Seizure burden, response to the treatment, timing, frequency, duration of the seizures, and presence of status epilepticus were suggested to be contributing variables for future epilepsy in different settings.[5,6,7,9,10,11,12,14,24,25,26,31] In support of those findings, four of our patients had status epilepticus and not only developed future epilepsy but also had global developmental delays and cerebral palsy. The most striking point of those four patients was that they had severe brain damage including asphyxia, sepsis, and inborn metabolic disease as pointed by Pisani and Spagnoli[6] and Pisani et al.[7,12,14,25] Consequently, uncontrolled and prolonged seizures may lead to disruption of the processing and interaction of neuronal circuits in immature brains which is a sensitive period for developing neuronal connections, maturations, and plasticity.[8,11,12,14,25,31] In this respect, the quality of response to the treatment and capability of subsidizing of seizures can affect the possibility of future epilepsy and complications.[6,7,8, 9,11,12,13,20,24] Pisani et al.[12] and Garcias Da Silva et al.[20] showed that response to the therapy was the only independent powerful factor subsequent epilepsy.[12,20] We also found that unsatisfying response to treatment and failure to response to at least two AEDs is one of the strong independent parameters for suggesting the likelihood of worsening seizure control and the probability of epilepsy.[8,9,12,20]
Recently, there have been some efforts to develop the scoring system for neurological outcomes after neonatal seizures.[7,8,11] In this concept, a constellation of clinical, electrographic, and radiologic tools can provide accurate and easier diagnosis, for interventions, and it might be also a chance for predicting subsequent epilepsy from the first minute of the seizures.[7,8,11] Pisani et al.[7] found six criteria consisting of birth weight, first minute Apgar score, neurological exam, status epilepticus, response to AEDs, and USG findings are valuable for scoring system to predict future neurological condition. Likewise, Garfinkle and Shevell[11] showed that delivery mode, seizure type and timing, EEG background, and etiology can provide a reliable model for the future outcome. In a different aspect, Soltirovska-Salamon et al.[8] aimed to specify those scoring systems for predicting only epilepsy. However, not enough amount of the items can be eligible for scoring; furthermore, they fail to apply for multivariate logistic regression.[8] Alternatively, they found some different items such as gestational age and duration of seizures as independent factors for the scoring system of postneonatal epilepsy.[8] As a new perspective, we showed that fifth minute Apgar scores, response to the treatment, abnormal USG, and EEG findings with 30 times strong power as distinct and reliable factors for being a part of a future potential scoring system for predicting future epilepsy beyond the neurological condition.
CONCLUSION
Epilepsy still seems an important consequence of neonatal seizures. Even though there are some studies which show a relationship between neonatal seizures and future neurological outcome, there is a lack of information for subsequent epilepsy. Therefore, our study is one of the rare and unique efforts for this important result of neonatal seizures. We found important factors including fifth minute Apgar scores, subtle seizures, response to the treatment, USG, and EEG findings which may be strong independent predictors for predicting future epilepsy beyond the assessment of neurological condition. Hence, we suggested that clinical, electrographic, and radiological findings are needed to be combined for not only accurate diagnose but also prompt interventions to prevent future complications and epilepsy. These results would give a new perspective and promise a basis for multicenter, prospective, and large cohort studies for developing a reliable scoring system for future epilepsy after neonatal seizures.
Financial support and sponsorship
Nil.
Conflicts of interests
There are no conflicts of interest.
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