http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1010199
ORIGINAL ARTICLE
To study the incidence, etiology and EEG profile of neonatal seizures: a prospective observational study from India Padmani Ghanshyambhai1, Deepak Sharma2, Ankur Patel3, and Sweta Shastri4 J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
1
Bachpan Children Hospital, Surat, Gujrat, India, 2Department of Neonatology, Fernandez Hospital, Hyderabad, India, 3Department of Neonatology, King Edward Memorial (KEM) Hospital and Seth G.S. Medical College, Mumbai, India, and 4ACPM Medical College, Dhule, Maharashtra, India
Abstract
Keywords
Aim: To study the incidence, etiology and electroencephalography (EEG) profile of neonatal seizures and also to study the correlation between clinical picture and EEG appearance. Type of study: Prospective observational cohort study. Study duration: September 2011 to April 2013. Inclusion and exclusion: Seizures within first 28 d of life and seizures documented by doctors. Population: Neonates admitted in intensive care unit: intramural (4412) and extramural (1900) admissions (all together 6312). Materials and methods: One hundred and seventy-two neonates with seizures were enrolled. All the neonates were evaluated with necessary investigation, ultrasound head and CT scan. All the neonates underwent EEG as early as possible with neonatal stabilization. The etiology of neonatal seizures, CT scan and ultrasound head, characteristic of the EEG and neonatal mortality were noted. Results: The incidence of neonatal seizure was 0.77% in the intramural and 7.3% among the extramural neonates. The incidence of seizures in term newborn was 0.7% and in preterm was 1.1%. The most common cause of neonatal seizure was hypoxic ischemic encephalopathy (HIE) followed by hypocalcemia. The predominant seizure type was multifocal (51%) followed by subtle seizure (43%). There was an EEG abnormality in 72% of the total EEG with varied patterns. The mortality rate in the cohort was 15% with HIE being the most common cause. Conclusion: Most common cases of neonatal seizure were HIE and with the most common type being multifocal. EEG was abnormal in the majority of the neonates with various pattern of abnormality.
Electroencephalography, etiology, incidence, mortality, neonatal seizures
Introduction Clinical seizures are defined as a paroxysmal alteration in neurological function, i.e. Behavioral, motor, and/or autonomic dysfunction [1]. The occurrence of neonatal seizures may be the first and only neurological sign, of an underlying central nervous system (CNS) abnormality in a newborn infant, and are viewed as a medical emergency in nursery [2] but due to the different clinical manifestation of this age, it is frequently difficult to recognize [3]. The mortality secondary to neonatal seizures parse has decreased to approximately 15% in the recent few years, with mental retardation and motor deficits being seen as a common sequel in 15–20% of surviving infants [4]. Etiology of the seizure determines the prognosis and outcome and guides therapeutic strategies.
Address for correspondence: Dr. Ankur Patel, MD, DNB (Paediatrics), Department of Neonatology, King Edward Memorial (KEM) Hospital and Seth G.S. Medical College, Mumbai, India. E-mail: [email protected]
History Received 16 December 2014 Revised 30 December 2014 Accepted 18 January 2015 Published online 10 February 2015
Neonatal seizures can be due to various causes like hypoxic-ischemic encephalopathy (HIE), intracranial hemorrhage (IVH), meningitis, hypoglycemia, hypocalcemia, congenital malformations, and so on [5,6]. Patients with HIE, intraventricular hemorrhage (IVH) (Grade III IVH and IVH with Periventricular Hemorrhagic infarcts), and neuronal migration disorder have the worst outcome [7]. Neurological deficits also predict a poor effect. Neonatal seizure needs to be differentiated with other benign condition like benign sleep myoclonus, jitteriness, etc. [8–10]. The most usual design in many neonatal intensive care units is to rely on clinical behaviors to identify seizures, without confirmation by electroencephalography (EEG), this is commonly looked at low income states, while in most developed countries the neonatal seizures are confirmed with bed side EEG monitoring [11]. The clinical appearance should be correlated with EEG and both of them with etiology. Hence a study was carried out in the neonatal intensive care unit of Krishna Institute of Medical Science Ltd, Hyderabad, to evaluate the correlation
2
P. Ghanshyambhai et al.
of EEG with clinical and etiological profile of neonatal seizures.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
Materials and methods This prospective observational study was conducted at the tertiary care level, neonatal intensive care units of the Department of Pediatrics, Krishna Institute of Medical Science Ltd, and Hyderabad. The age group consisted of Neonates admitted in the nursery (intramural and extramural) from September 2011 to April 2013. The study had ethical clearance from the institutional research board. All neonates in the extramural or intramural intensive care unit were included in the study if they satisfied the following criteria: (1) Seizures within first 28 d of life (2) Seizures documented by doctor weather it may be intramural or extramural neonate. A total 172 newborn satisfying our inclusion criteria were enrolled in the study after receiving the written consent from parents on consent performs. A redesigned patient performs was charted out and filled up for each newborn enrolled in the subject. The complete name, sex, address, date of birth and time of birth was noted down. Antenatal history of any infection in the mother, maternal diabetes and history of fever before delivery, previous abortions and history suggestive of fetal distress, instrumental delivery, need for resuscitation in the project room, low APGAR scores of less than or equal to 3 at 1 and 5 min were obtained if available. In case of extramural deliveries, since APGAR was not operable, if in that respect was a history of delayed cry at birth or history of need of resuscitation and if these neonates had postnatal evidence of neurological abnormality in the form of hypotonia of axial musculature, shoulder tone hypotonia, head lag, differential hypotonia, multi-organ dysfunction, they were considered as HIE. A report of seizures associated with poor feeding, prolonged lethargy, recurrent vomiting, with a family history of consanguinity and/or neonatal seizure with early fetal and neonatal death were taken and base-line investigation like serum ammonia, serum lactate, arterial blood gas analysis and urinary ketone and reducing substance were also served to rule out inborn error of metabolism. Day of onset of seizures/ hours of life were accurately recorded along with the duration of each seizure and their frequency. A complete description of the seizure was observed with associated eye movement, restraint of episode by passive flexion limbs, any associated color change or autonomic phenomenon and state of consciousness at the time of the seizure, and the type of seizure was followed. A complete examination of all vital was also done. Neurological examination was done at the time of onset of seizures. Any congenital malformation, cutaneous markers were noted. Stage of consciousness of the patient, condition of anterior fontanel, tone, posture, deep tendon reflexes, neonatal reflexes and papillary reactions were noted. Sarnat and Sarnat score was considered for HIE grading [12]. A complete systemic examination, including the cardiovascular system, signs of respiratory distress, bleeding from the gastrointestinal tract or other sites was particularly noted as
J Matern Fetal Neonatal Med, Early Online: 1–5
signs of multi-system involvement due to asphyxia. All the necessary investigation for evaluation of neonatal seizures, which included complete Blood Counts, C-reactive protein, random blood sugar, serum calcium, magnesium and sodium, Blood urea, serum creatinine, serum bilirubin, blood C/S, CSF examination, ultrasound head, CT scan, MRI (wherever feasible and indicated) and EEG were done as per the neonatal requirement [13]. All the neonatal seizures were management as the standard protocol of the nursery [14,15]. Once the neonate was hemodynamically stable and off intravenous fluids, he/she was transported to the EEG recording at the earliest. EEG was obtained with the RMS EEG machine having 25 leads. The techniques applied were as per guidelines of the American EEG Society for recording EEG in neonates [16]. Neonatal montages were used and 16 leads were used as against the standard of 25 steers in the adult. Trichlorphos was used in the dose of 50 mg/kg/dose for inducing sleep when needed. Children were also subjected to photic stimulation to provoke any abnormalities in brain activity. Each EEG recording was made for 30–40 min in order to wreak the sleep wake cycles in each newborn. Data were recorded on a predesigned detailed proforma and entered on Microsoft Excel worksheet. SPSS version 16 for Windows was used for analysis of the data.
Results During the study period, there were a total of 6312 newborn admitted, of which 4412 were retained in the intramural NICU and 1900 in the extramural NICU. A total of 172 newborns satisfying the inclusion criteria were enrolled in the study. EEG was performed in all neonates of the survey group. The incidence of neonatal seizure was 0.77% in the intramural NICU and 7.3% among the extramural neonates. In the intramural neonates, the incidence of seizures in term newborn was found to be 29/3920 (0.7%) while that among preterm newborns was found to be 5/492 (1.1%). In the extramural neonates the incidence of seizures in term newborn was found to be 133/1180 (11.3%) while that among preterm newborns was found to be 5/720 (0.7%). A total of 121 males and 51 females were enrolled in the cogitation. Male: female ratio was observed to be 2.44:1. On the basis of weight, 87 (2.8%) of the total low birth weight newborns developed neonatal seizures. Early onset seizures (548 hour of life) were found to be the major part of the seizures amounting to 139 (81%) neonates. Away of the 139 patients in our study with early onset seizures, 98 of them had onset of seizures within the first 12 h of life, 88 (90%) of which were due to HIE. Fourteen of these had onset of seizures within the beginning hour of life, the cause being HIE in 10 out of them. A summation of 352 seizures was observed in the 172 babies with an average of 2.03 seizure episodes per child in the first 28 d of life. The median age of onset of the first seizure episode was 38.5 h (38.5 h in term babies and 19.5 h in preterm babies). Among the seizures recorded in our study group, the predominant seizure type was found to be multifocal 180 (51%) followed by subtle seizure 151 (43%). The most common cause of Multifocal seizure was found to be HIE (80%) and the most common cause of subtle seizures was
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DOI: 10.3109/14767058.2015.1010199
also HIE (77%). Tonic seizures were found in 8 (4.6%) of the patients. The most common etiology was found to be hypocalcemia 3 (37.5%) and ICH 2 (25%). Clonic seizures contributed to 0.60% of the total seizures. HIE was honored to be the most frequent etiology of neonatal seizures contributing to 274 (77.9%) of the total seizure episodes. Hypocalcemia 31 (8.7%) formed the next most common instances of neonatal seizures in our study. A sum of 172 EEGs was done out of which 124 (72%) were found to be unnatural. EEG done in 134 neonates with HIE showed abnormality in 110 (82%) of cases with various abnormalities including absent frontal sharp waves, invariant delta background activity suggestive of diffuse encephalopathy, multi-focal discharges with sharp waves from occipital area, burst suppression pattern, isoelectric pattern and also disorganized sleep patterns. At that space was no EEG abnormality noted in the neonates with hypoglycemic seizures. EEGs done in patients with intracranial hemorrhage, 3 (50%) neonates were found to cause an abnormal EEG with invariant delta background activity. The common EEG abnormalities reported with intracranial hemorrhage were inter-hemisphere asymmetries, positive sharp rolandic waves, occipital sharps and positive temporal sharp waves. In our workplace, we could get done ultrasonography of the brain as a function of neonatal seizure work up. Of the total, 103 (60%) experienced no obvious abnormalities. Of the remaining patients, 24 patients showed mild dilatation of the ventricles and 24 patients had IVH (Grade II–III), 8 patients had parenchymal hemorrhage, 12 patients had choroid plexus cysts and 1 patient had cephalhematoma. One hundred and twenty patients had CT scan, out of which 32 patients having a normal CT scan feature. Of the remaining abnormal CT scan, 12 patient had IVH, 4 patients had parenchymal hemorrhage, 3 patient had small cerebral infarcts, which were delivered outside with assisted vacuum delivery (this could be incidental finding as usually prenatal condition which was the indication to perform the vacuum is the cause of brain damage and not the vacuum delivery itself), one patient had hypoglycemic changes (hypo density of parietal and occipital region), one patient had meningitis like picture and rest patient had changes suggestive of hypoxic ischemic changes. On examining our cohort of 172 patients, the mortality rate was found to be 26 (15%). The most usual reason was found to be HIE contributing to 21 (81%) of the mortality.
Discussion Motor or autonomic behavior, may represent normal age and gestation specific behavior, or non-epileptic paroxysmal conditions. Medical personnel also differ significantly in their ability to pick out such behaviors, thus giving to over or under diagnosis [17]. Therefore, verification of suspicious clinical events as seizures using coincident EEG recordings is now strongly advocated. Though EEG provides a useful noninvasive test to diagnose neonatal seizures and evaluate the level of perinatal damage to the genii, as well as long-term prognosis, yet its interpretation is defined by variations in normal brain development process. EEG abnormalities, such as burst suppression, low electric voltage, or multi-focal
Incidence, etiology and EEG profile of neonatal seizures
3
abnormal discharges are associated with abnormal neurological outcome [18]. Neonatal seizures are normally a mutual expression of multiple etiology and neonates need to be assessed for the cause of seizure as treatment and prognosis depend on the etiology of the chapter. The most common case of neonatal seizure noted in our study was HIE which is the most common case of neonatal seizure as reported in the literature [19,20]. The incidence was higher in preterm than term neonates which is usually seen as a result of a lack of inhibitory neurons in preterm neonates and also they are more prone to IVH and metabolic complications leading to neonatal seizures. The incidences of seizures were more in extramural neonates as these neonates are usually delivered in places which lack competent health care personals, making them prone to have asphyxia and neonatal seizure. The majority of seizures in our study cohort were early onset in nature as the cause was HIE which have its seizure within 24 hours of life in the majority of cases. The most common seizure was multi-focal in nature, even though subtle seizures are noted to be most common. This dispute could be because sometimes it becomes difficult to identify subtle seizure of many others. EEG did show abnormality in 72% of cases with various features. These days there is a trend towards continuous EEG monitoring as majority [21] of the neonatal seizure are EEG seizure with no clinical manifestations, hence EEG monitoring is must [22]. The background activity of EEG has been used as a prognostication marker with isoelectric pattern and burst suppression pattern having worst outcome [23]. In our work, we did not experience in-house EEG monitoring hence we were not capable to perform the continuous EEG monitoring. Nowadays there is growing importance of amplitude-integrated EEG (aEEG), which is used more and more in all nurseries for EEG monitoring. aEEG has also been used nowadays in preterm neonates and help as a guide for neurological prognostication [24]. EEG has also been used for therapeutic hypothermia selection of neonates [25]. Kumar et al. performed study to evaluate clinico-etiological and EEG profile of neonatal seizures. They enrolled 90 babies with clinical seizures in the study. The most common case of neonatal seizures was HIE followed by metabolic causes. They performed an EEG in 60 neonates out of which abnormal EEG’s were found in one-third cases. A total of 26.7% of children with perinatal asphyxia had abnormal EEG’s (8/30). They reported incidence of neonatal seizures as 11.7/1000 live births, with more common in very low birth weight babies before 5 d of life [26]. In our study also, most common cause of neonatal seizure was asphyxia followed by metabolic abnormalities and there was a high incidence of seizure in preterm neonates. Scher et al. conducted study to see comparison of electrographically confirmed seizures in preterm and term neonates with respect to clinical correlates, incidence, associated brain lesions, and risk for neurologic sequelae. They enrolled 92 newborns in the study and reported more incidence of seizure in extramural neonates and preterm, which correlates with our findings [17]. The most common seizure reported by them was subtle whereas in our study it was multi-focal (51%) followed by subtle seizure (43%).
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The deviation in resolutions with our study can be attributed in difficulty in diagnosis of subtle seizures by health care personnel as subtle seizure has varied presentation. Another survey led by Khan et al. evaluated the relationship of sequential neonatal EEG and neurological outcome in neonates with seizures to identify polysomnographic features predictive of outcome. They enrolled 58 newborns in the subject field and compared with the historic cohort. Abnormal examination combined with abnormal EEG was associated with poor neurodevelopmental outcome. They too reported that abnormal background activity was too related to neurodevelopment delay and EEG sequences either abnormal–abnormal or normal–abnormal significantly correlated to the outcome epilepsy. The abnormal sequential background activity of EEG was associated with neurodevelopment delay and subsequent epilepsy. The burst suppression pattern when present in any EEG correlated with epilepsy and postnatal death [27]. In our study, we did not do the neurological follow-up but burst suppression pattern was associated with increased mortality in our cohort too. Although many studies has been conducted to correlate the EEG and long-term neurodevelopmental outcome [28–31]. Strength of the study
Large sample size of the newborn babies with both intramural and extramural EEG performed in all of the neonates with no missed cases, largest number till now as per our knowledge Ultrasound head and CT scan was done in the majority of the events
Limitations of study
Lack of follow-up of the neonates with EEG abnormalities Absence of sequential EEG in cases of abnormal EEG pattern MRI brain was not done as it is more sensitive, which was because our cohort was of patients who were not affordable to pay the charges.
Conclusion Clinical diagnosis of neonatal seizure is difficult and repeated seizures may be unrecognized because of various presentations of seizures. The incidence of seizures was found to be 0.77% to 0.7% among term newborns and 1.1% among preterm neonates. The most common case of neonatal seizure was HIE, with majority of seizures occurred within 24 h of life span. The EEG abnormality was present in the majority of cases with different pattern of abnormalities depending on the etiology of neonatal seizures.
Declaration of interest No external funding was secured for this study. The authors have no financial relationships relevant to this article to disclose. The authors have no conflicts of interest relevant to this article to disclose.
J Matern Fetal Neonatal Med, Early Online: 1–5
References 1. Neonatal seizures. Lancet 1989;2:135–7. 2. Sharma D, Pandita A, Murki S, Pratap OT. Neonatal seizures: an emergency condition commonly seen in neonatal intensive care unit. BMJ Case Rep 2014: pii: bcr2014206577. doi: 10.1136/bcr2014-206577. 3. Sankar MJ, Agarwal R, Aggarwal R, et al. Seizures in the newborn. Indian J Pediatr 2008;75:149–55. 4. Nardou R, Ferrari DC, Ben-Ari Y. Mechanisms and effects of seizures in the immature brain. Semin Fetal Neonatal Med 2013;18: 175–84. 5. Vasudevan C, Levene M. Epidemiology and aetiology of neonatal seizures. Semin Fetal Neonatal Med 2013;18:185–91. 6. Sharma D, Pandita A, Pratap OT, Murki S. Laryngospasm and neonatal seizure due to hypocalcaemia and vitamin D deficiency: an emergency condition in NICU and challenge to the neonatologist. BMJ Case Rep 2014: pii: bcr2014206795. doi: 10.1136/bcr-2014-206795. 7. Uria-Avellanal C, Marlow N, Rennie JM. Outcome following neonatal seizures. Semin Fetal Neonatal Med 2013;18: 224–32. 8. Ramelli GP, Sozzo AB, Vella S, Bianchetti MG. Benign neonatal sleep myoclonus: an under-recognized, non-epileptic condition. Acta Paediatr Oslo Nor 1992.2005;94:962–3. 9. Sharma D, Murki S, Pratap OT. Benign sleep myoclonus in neonate: a diagnostic dilemma for neonatologist. BMJ Case Rep 2014: pii: bcr2014206626. doi: 10.1136/bcr-2014-206626. 10. Cross JH. Differential diagnosis of epileptic seizures in infancy including the neonatal period. Semin Fetal Neonatal Med 2013;18: 192–5. 11. Scher MS. Seizures in the newborn infant. Diagnosis, treatment, and outcome. Clin Perinatol 1997;24:735–72. 12. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976;33:696–705. 13. Hallberg B, Blennow M. Investigations for neonatal seizures. Semin Fetal Neonatal Med 2013;18:196–201. 14. Van Rooij LGM, Hellstro¨m-Westas L, de Vries LS. Treatment of neonatal seizures. Semin Fetal Neonatal Med 2013;18: 209–15. 15. Loiacono G, Masci M, Zaccara G, Verrotti A. The treatment of neonatal seizures: focus on Levetiracetam. J Matern-Fetal Neonatal Med 2014;5:1–6. 16. American Electroencephalographic Society Guidelines in EEG, 1–7 (revised 1985). J Clin Neurophysiol Off Publ Am Electroencephalogr Soc 1986;3:131–68. 17. Scher MS, Aso K, Beggarly ME, et al. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993;91: 128–34. 18. Sheth RD. Electroencephalogram confirmatory rate in neonatal seizures. Pediatr Neurol 1999;20:27–30. 19. Glass HC. Neonatal seizures: advances in mechanisms and management. Clin Perinatol 2014;41:177–90. 20. Sabzehei MK, Basiri B, Bazmamoun H. The etiology, clinical type, and short outcome of seizures in newbornshospitalized in Besat Hospital/Hamadan/Iran. Iran J Child Neurol 2014;8:24–8. 21. Claassen J, Mayer SA, Kowalski RG, et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology 2004;62:1743–8. 22. Lamblin MD, Andre´ M, Auzoux M, et al. [Indications of electroencephalogram in the newborn]. Arch Pe´diatrie Organe Off Socie´te Fr Pe´diatrie 2004;11:829–33. 23. McCoy B, Hahn CD. Continuous EEG monitoring in the neonatal intensive care unit. J Clin Neurophysiol Off Publ Am Electroencephalogr Soc 2013;30:106–14. 24. Scoppa A, Casani A, Cocca F, et al. aEEG in preterm infants. J Matern-Fetal Neonatal Med 2012;25:139–40. 25. Filippi L, Catarzi S, Gozzini E, et al. Hypothermia for neonatal hypoxic-ischemic encephalopathy: may an early amplitude-integrated EEG improve the selection of candidates for cooling? J Matern-Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet 2012; 25:2171–6.
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26. Kumar A, Gupta A, Talukdar B. Clinico-etiological and EEG profile of neonatal seizures. Indian J Pediatr 2007;74:33–7. 27. Khan RL, Nunes ML, Garcias da Silva LF, da Costa JC. Predictive value of sequential electroencephalogram (EEG) in neonates with seizures and its relation to neurological outcome. J Child Neurol 2008;23:144–50. 28. Hellstro¨m-Westas L, Klette H, Thorngren-Jerneck K, Rose´n I. Early prediction of outcome with aEEG in preterm infants with large intraventricular hemorrhages. Neuropediatrics 2001;32:319–24.
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29. Wikstro¨m S, Pupp IH, Rose´n I, et al. Early single-channel aEEG/ EEG predicts outcome in very preterm infants. Acta Paediatr Oslo 2012;101:719–26. 30. Shah DK, Zempel J, Barton T, et al. Electrographic seizures in preterm infants during the first week of life are associated with cerebral injury. Pediatr Res 2010;67:102–6. 31. Vesoulis ZA, Inder TE, Woodward LJ, et al. Early electrographic seizures, brain injury, and neurodevelopmental risk in the very preterm infant. Pediatr Res 2014;75:564–9.
ORIGINAL ARTICLE
To study the incidence, etiology and EEG profile of neonatal seizures: a prospective observational study from India Padmani Ghanshyambhai1, Deepak Sharma2, Ankur Patel3, and Sweta Shastri4 J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
1
Bachpan Children Hospital, Surat, Gujrat, India, 2Department of Neonatology, Fernandez Hospital, Hyderabad, India, 3Department of Neonatology, King Edward Memorial (KEM) Hospital and Seth G.S. Medical College, Mumbai, India, and 4ACPM Medical College, Dhule, Maharashtra, India
Abstract
Keywords
Aim: To study the incidence, etiology and electroencephalography (EEG) profile of neonatal seizures and also to study the correlation between clinical picture and EEG appearance. Type of study: Prospective observational cohort study. Study duration: September 2011 to April 2013. Inclusion and exclusion: Seizures within first 28 d of life and seizures documented by doctors. Population: Neonates admitted in intensive care unit: intramural (4412) and extramural (1900) admissions (all together 6312). Materials and methods: One hundred and seventy-two neonates with seizures were enrolled. All the neonates were evaluated with necessary investigation, ultrasound head and CT scan. All the neonates underwent EEG as early as possible with neonatal stabilization. The etiology of neonatal seizures, CT scan and ultrasound head, characteristic of the EEG and neonatal mortality were noted. Results: The incidence of neonatal seizure was 0.77% in the intramural and 7.3% among the extramural neonates. The incidence of seizures in term newborn was 0.7% and in preterm was 1.1%. The most common cause of neonatal seizure was hypoxic ischemic encephalopathy (HIE) followed by hypocalcemia. The predominant seizure type was multifocal (51%) followed by subtle seizure (43%). There was an EEG abnormality in 72% of the total EEG with varied patterns. The mortality rate in the cohort was 15% with HIE being the most common cause. Conclusion: Most common cases of neonatal seizure were HIE and with the most common type being multifocal. EEG was abnormal in the majority of the neonates with various pattern of abnormality.
Electroencephalography, etiology, incidence, mortality, neonatal seizures
Introduction Clinical seizures are defined as a paroxysmal alteration in neurological function, i.e. Behavioral, motor, and/or autonomic dysfunction [1]. The occurrence of neonatal seizures may be the first and only neurological sign, of an underlying central nervous system (CNS) abnormality in a newborn infant, and are viewed as a medical emergency in nursery [2] but due to the different clinical manifestation of this age, it is frequently difficult to recognize [3]. The mortality secondary to neonatal seizures parse has decreased to approximately 15% in the recent few years, with mental retardation and motor deficits being seen as a common sequel in 15–20% of surviving infants [4]. Etiology of the seizure determines the prognosis and outcome and guides therapeutic strategies.
Address for correspondence: Dr. Ankur Patel, MD, DNB (Paediatrics), Department of Neonatology, King Edward Memorial (KEM) Hospital and Seth G.S. Medical College, Mumbai, India. E-mail: [email protected]
History Received 16 December 2014 Revised 30 December 2014 Accepted 18 January 2015 Published online 10 February 2015
Neonatal seizures can be due to various causes like hypoxic-ischemic encephalopathy (HIE), intracranial hemorrhage (IVH), meningitis, hypoglycemia, hypocalcemia, congenital malformations, and so on [5,6]. Patients with HIE, intraventricular hemorrhage (IVH) (Grade III IVH and IVH with Periventricular Hemorrhagic infarcts), and neuronal migration disorder have the worst outcome [7]. Neurological deficits also predict a poor effect. Neonatal seizure needs to be differentiated with other benign condition like benign sleep myoclonus, jitteriness, etc. [8–10]. The most usual design in many neonatal intensive care units is to rely on clinical behaviors to identify seizures, without confirmation by electroencephalography (EEG), this is commonly looked at low income states, while in most developed countries the neonatal seizures are confirmed with bed side EEG monitoring [11]. The clinical appearance should be correlated with EEG and both of them with etiology. Hence a study was carried out in the neonatal intensive care unit of Krishna Institute of Medical Science Ltd, Hyderabad, to evaluate the correlation
2
P. Ghanshyambhai et al.
of EEG with clinical and etiological profile of neonatal seizures.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
Materials and methods This prospective observational study was conducted at the tertiary care level, neonatal intensive care units of the Department of Pediatrics, Krishna Institute of Medical Science Ltd, and Hyderabad. The age group consisted of Neonates admitted in the nursery (intramural and extramural) from September 2011 to April 2013. The study had ethical clearance from the institutional research board. All neonates in the extramural or intramural intensive care unit were included in the study if they satisfied the following criteria: (1) Seizures within first 28 d of life (2) Seizures documented by doctor weather it may be intramural or extramural neonate. A total 172 newborn satisfying our inclusion criteria were enrolled in the study after receiving the written consent from parents on consent performs. A redesigned patient performs was charted out and filled up for each newborn enrolled in the subject. The complete name, sex, address, date of birth and time of birth was noted down. Antenatal history of any infection in the mother, maternal diabetes and history of fever before delivery, previous abortions and history suggestive of fetal distress, instrumental delivery, need for resuscitation in the project room, low APGAR scores of less than or equal to 3 at 1 and 5 min were obtained if available. In case of extramural deliveries, since APGAR was not operable, if in that respect was a history of delayed cry at birth or history of need of resuscitation and if these neonates had postnatal evidence of neurological abnormality in the form of hypotonia of axial musculature, shoulder tone hypotonia, head lag, differential hypotonia, multi-organ dysfunction, they were considered as HIE. A report of seizures associated with poor feeding, prolonged lethargy, recurrent vomiting, with a family history of consanguinity and/or neonatal seizure with early fetal and neonatal death were taken and base-line investigation like serum ammonia, serum lactate, arterial blood gas analysis and urinary ketone and reducing substance were also served to rule out inborn error of metabolism. Day of onset of seizures/ hours of life were accurately recorded along with the duration of each seizure and their frequency. A complete description of the seizure was observed with associated eye movement, restraint of episode by passive flexion limbs, any associated color change or autonomic phenomenon and state of consciousness at the time of the seizure, and the type of seizure was followed. A complete examination of all vital was also done. Neurological examination was done at the time of onset of seizures. Any congenital malformation, cutaneous markers were noted. Stage of consciousness of the patient, condition of anterior fontanel, tone, posture, deep tendon reflexes, neonatal reflexes and papillary reactions were noted. Sarnat and Sarnat score was considered for HIE grading [12]. A complete systemic examination, including the cardiovascular system, signs of respiratory distress, bleeding from the gastrointestinal tract or other sites was particularly noted as
J Matern Fetal Neonatal Med, Early Online: 1–5
signs of multi-system involvement due to asphyxia. All the necessary investigation for evaluation of neonatal seizures, which included complete Blood Counts, C-reactive protein, random blood sugar, serum calcium, magnesium and sodium, Blood urea, serum creatinine, serum bilirubin, blood C/S, CSF examination, ultrasound head, CT scan, MRI (wherever feasible and indicated) and EEG were done as per the neonatal requirement [13]. All the neonatal seizures were management as the standard protocol of the nursery [14,15]. Once the neonate was hemodynamically stable and off intravenous fluids, he/she was transported to the EEG recording at the earliest. EEG was obtained with the RMS EEG machine having 25 leads. The techniques applied were as per guidelines of the American EEG Society for recording EEG in neonates [16]. Neonatal montages were used and 16 leads were used as against the standard of 25 steers in the adult. Trichlorphos was used in the dose of 50 mg/kg/dose for inducing sleep when needed. Children were also subjected to photic stimulation to provoke any abnormalities in brain activity. Each EEG recording was made for 30–40 min in order to wreak the sleep wake cycles in each newborn. Data were recorded on a predesigned detailed proforma and entered on Microsoft Excel worksheet. SPSS version 16 for Windows was used for analysis of the data.
Results During the study period, there were a total of 6312 newborn admitted, of which 4412 were retained in the intramural NICU and 1900 in the extramural NICU. A total of 172 newborns satisfying the inclusion criteria were enrolled in the study. EEG was performed in all neonates of the survey group. The incidence of neonatal seizure was 0.77% in the intramural NICU and 7.3% among the extramural neonates. In the intramural neonates, the incidence of seizures in term newborn was found to be 29/3920 (0.7%) while that among preterm newborns was found to be 5/492 (1.1%). In the extramural neonates the incidence of seizures in term newborn was found to be 133/1180 (11.3%) while that among preterm newborns was found to be 5/720 (0.7%). A total of 121 males and 51 females were enrolled in the cogitation. Male: female ratio was observed to be 2.44:1. On the basis of weight, 87 (2.8%) of the total low birth weight newborns developed neonatal seizures. Early onset seizures (548 hour of life) were found to be the major part of the seizures amounting to 139 (81%) neonates. Away of the 139 patients in our study with early onset seizures, 98 of them had onset of seizures within the first 12 h of life, 88 (90%) of which were due to HIE. Fourteen of these had onset of seizures within the beginning hour of life, the cause being HIE in 10 out of them. A summation of 352 seizures was observed in the 172 babies with an average of 2.03 seizure episodes per child in the first 28 d of life. The median age of onset of the first seizure episode was 38.5 h (38.5 h in term babies and 19.5 h in preterm babies). Among the seizures recorded in our study group, the predominant seizure type was found to be multifocal 180 (51%) followed by subtle seizure 151 (43%). The most common cause of Multifocal seizure was found to be HIE (80%) and the most common cause of subtle seizures was
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DOI: 10.3109/14767058.2015.1010199
also HIE (77%). Tonic seizures were found in 8 (4.6%) of the patients. The most common etiology was found to be hypocalcemia 3 (37.5%) and ICH 2 (25%). Clonic seizures contributed to 0.60% of the total seizures. HIE was honored to be the most frequent etiology of neonatal seizures contributing to 274 (77.9%) of the total seizure episodes. Hypocalcemia 31 (8.7%) formed the next most common instances of neonatal seizures in our study. A sum of 172 EEGs was done out of which 124 (72%) were found to be unnatural. EEG done in 134 neonates with HIE showed abnormality in 110 (82%) of cases with various abnormalities including absent frontal sharp waves, invariant delta background activity suggestive of diffuse encephalopathy, multi-focal discharges with sharp waves from occipital area, burst suppression pattern, isoelectric pattern and also disorganized sleep patterns. At that space was no EEG abnormality noted in the neonates with hypoglycemic seizures. EEGs done in patients with intracranial hemorrhage, 3 (50%) neonates were found to cause an abnormal EEG with invariant delta background activity. The common EEG abnormalities reported with intracranial hemorrhage were inter-hemisphere asymmetries, positive sharp rolandic waves, occipital sharps and positive temporal sharp waves. In our workplace, we could get done ultrasonography of the brain as a function of neonatal seizure work up. Of the total, 103 (60%) experienced no obvious abnormalities. Of the remaining patients, 24 patients showed mild dilatation of the ventricles and 24 patients had IVH (Grade II–III), 8 patients had parenchymal hemorrhage, 12 patients had choroid plexus cysts and 1 patient had cephalhematoma. One hundred and twenty patients had CT scan, out of which 32 patients having a normal CT scan feature. Of the remaining abnormal CT scan, 12 patient had IVH, 4 patients had parenchymal hemorrhage, 3 patient had small cerebral infarcts, which were delivered outside with assisted vacuum delivery (this could be incidental finding as usually prenatal condition which was the indication to perform the vacuum is the cause of brain damage and not the vacuum delivery itself), one patient had hypoglycemic changes (hypo density of parietal and occipital region), one patient had meningitis like picture and rest patient had changes suggestive of hypoxic ischemic changes. On examining our cohort of 172 patients, the mortality rate was found to be 26 (15%). The most usual reason was found to be HIE contributing to 21 (81%) of the mortality.
Discussion Motor or autonomic behavior, may represent normal age and gestation specific behavior, or non-epileptic paroxysmal conditions. Medical personnel also differ significantly in their ability to pick out such behaviors, thus giving to over or under diagnosis [17]. Therefore, verification of suspicious clinical events as seizures using coincident EEG recordings is now strongly advocated. Though EEG provides a useful noninvasive test to diagnose neonatal seizures and evaluate the level of perinatal damage to the genii, as well as long-term prognosis, yet its interpretation is defined by variations in normal brain development process. EEG abnormalities, such as burst suppression, low electric voltage, or multi-focal
Incidence, etiology and EEG profile of neonatal seizures
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abnormal discharges are associated with abnormal neurological outcome [18]. Neonatal seizures are normally a mutual expression of multiple etiology and neonates need to be assessed for the cause of seizure as treatment and prognosis depend on the etiology of the chapter. The most common case of neonatal seizure noted in our study was HIE which is the most common case of neonatal seizure as reported in the literature [19,20]. The incidence was higher in preterm than term neonates which is usually seen as a result of a lack of inhibitory neurons in preterm neonates and also they are more prone to IVH and metabolic complications leading to neonatal seizures. The incidences of seizures were more in extramural neonates as these neonates are usually delivered in places which lack competent health care personals, making them prone to have asphyxia and neonatal seizure. The majority of seizures in our study cohort were early onset in nature as the cause was HIE which have its seizure within 24 hours of life in the majority of cases. The most common seizure was multi-focal in nature, even though subtle seizures are noted to be most common. This dispute could be because sometimes it becomes difficult to identify subtle seizure of many others. EEG did show abnormality in 72% of cases with various features. These days there is a trend towards continuous EEG monitoring as majority [21] of the neonatal seizure are EEG seizure with no clinical manifestations, hence EEG monitoring is must [22]. The background activity of EEG has been used as a prognostication marker with isoelectric pattern and burst suppression pattern having worst outcome [23]. In our work, we did not experience in-house EEG monitoring hence we were not capable to perform the continuous EEG monitoring. Nowadays there is growing importance of amplitude-integrated EEG (aEEG), which is used more and more in all nurseries for EEG monitoring. aEEG has also been used nowadays in preterm neonates and help as a guide for neurological prognostication [24]. EEG has also been used for therapeutic hypothermia selection of neonates [25]. Kumar et al. performed study to evaluate clinico-etiological and EEG profile of neonatal seizures. They enrolled 90 babies with clinical seizures in the study. The most common case of neonatal seizures was HIE followed by metabolic causes. They performed an EEG in 60 neonates out of which abnormal EEG’s were found in one-third cases. A total of 26.7% of children with perinatal asphyxia had abnormal EEG’s (8/30). They reported incidence of neonatal seizures as 11.7/1000 live births, with more common in very low birth weight babies before 5 d of life [26]. In our study also, most common cause of neonatal seizure was asphyxia followed by metabolic abnormalities and there was a high incidence of seizure in preterm neonates. Scher et al. conducted study to see comparison of electrographically confirmed seizures in preterm and term neonates with respect to clinical correlates, incidence, associated brain lesions, and risk for neurologic sequelae. They enrolled 92 newborns in the study and reported more incidence of seizure in extramural neonates and preterm, which correlates with our findings [17]. The most common seizure reported by them was subtle whereas in our study it was multi-focal (51%) followed by subtle seizure (43%).
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P. Ghanshyambhai et al.
The deviation in resolutions with our study can be attributed in difficulty in diagnosis of subtle seizures by health care personnel as subtle seizure has varied presentation. Another survey led by Khan et al. evaluated the relationship of sequential neonatal EEG and neurological outcome in neonates with seizures to identify polysomnographic features predictive of outcome. They enrolled 58 newborns in the subject field and compared with the historic cohort. Abnormal examination combined with abnormal EEG was associated with poor neurodevelopmental outcome. They too reported that abnormal background activity was too related to neurodevelopment delay and EEG sequences either abnormal–abnormal or normal–abnormal significantly correlated to the outcome epilepsy. The abnormal sequential background activity of EEG was associated with neurodevelopment delay and subsequent epilepsy. The burst suppression pattern when present in any EEG correlated with epilepsy and postnatal death [27]. In our study, we did not do the neurological follow-up but burst suppression pattern was associated with increased mortality in our cohort too. Although many studies has been conducted to correlate the EEG and long-term neurodevelopmental outcome [28–31]. Strength of the study
Large sample size of the newborn babies with both intramural and extramural EEG performed in all of the neonates with no missed cases, largest number till now as per our knowledge Ultrasound head and CT scan was done in the majority of the events
Limitations of study
Lack of follow-up of the neonates with EEG abnormalities Absence of sequential EEG in cases of abnormal EEG pattern MRI brain was not done as it is more sensitive, which was because our cohort was of patients who were not affordable to pay the charges.
Conclusion Clinical diagnosis of neonatal seizure is difficult and repeated seizures may be unrecognized because of various presentations of seizures. The incidence of seizures was found to be 0.77% to 0.7% among term newborns and 1.1% among preterm neonates. The most common case of neonatal seizure was HIE, with majority of seizures occurred within 24 h of life span. The EEG abnormality was present in the majority of cases with different pattern of abnormalities depending on the etiology of neonatal seizures.
Declaration of interest No external funding was secured for this study. The authors have no financial relationships relevant to this article to disclose. The authors have no conflicts of interest relevant to this article to disclose.
J Matern Fetal Neonatal Med, Early Online: 1–5
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