ETIOLOGIC PROFILE AND NEURODEVELOPMENTAL OUTCOME OF SEIZURES INTERM NEWBORN INFANTS

ABSTRACT: 

The objectives of this study were to delineate the etiologic profile and neurodevelopmental outcome of neonatal seizures. The children with clinical seizures underwent neurologic examination, electroencephalography, neuroimaging and extensive diagnostic tests in the newborn period. After discharge, all infants underwent regular neurologic evaluation at 12 to 18 months. Seizure etiology remain powerful prognostic factor. Diagnostic advances have changed the etiologic distribution for neonatal seizures and improved accuracy of outcome prediction. Global cerebral hipoxi-ischemia, the most common etiology, is responsible for the large majority of infants with poor long-term outcome.

Seizures are the most common and distinctive clinical manifestation of neurologic dysfunction in the newborn infant. Despite increasingly sophisti-cated neonatal intensive care, clinicians managing seizures remain challenged by difficult prognostic and therapeutic questions. Among these are significant developments in obstetric and neonatal management that have changed the spectrum of insults to which the immature brain is exposed.

In addition, more accurate etiologic diagnosis has been facilitated by advances in neurodiagnostic technologyparticularly brain imaging. The mortal-ity of infants developing seizures during the neonatal period has shown a decreasing trend over time. In earlier studies, the mortality was as high as 40% but decreased in subsequent reports to 20°/o.As opposed to this increase in survival, the prevalence of long-term neurodevelopmental sequelae in survivors has remained unchanged at 30°/o.The most reliable early predictors of later neurologic outcome have been the underlying etiology of the seizures and specific elec-troencephalography (EEG) background patterns.

The aims of the current study were to describe the etiologic profile of neonatal seizures, the neurodevelopmental outcome.

Material and methods: Our study population in-cluded all newborn infants admitted to the Hospital of Mother and Child Health Care ,between 2007-2008. Eligibility criteria were a birth gestational age 37 weeks, clinical seizures in the neonatal period diagnosed by a child neurologist, EEG and neuroim-aging (computed tomography [CT] and/or magnetic resonance imaging [MRI]) studies in the neonatal period, and at least 12 months of follow-up . The diagnosis of neonatal seizures by the child neurologist is based either on direct observation of the clinical and/or EEG events in question or on the review of observations made by the neonatologists. During the clinical evaluation of suspected seizures, it is standard practice for the child neurologist to exclude phenom-ena that mimic seizures in the newborn using widely accepted criteria. We obtained prenatal, perinatal, and neonatal data by detailed review of the maternal and infants medical charts. At our center, neurologists with special expertise in neonatal neurologic condi-tions are involved from the outset in the diagnosis and acute management of all infants with seizures. Clinical seizures are classified according to Volpe as subtle, clonic, tonic, and myoclonic. Specifically, the first-line agent was Phenobarbital.

We made an etiologic diagnosis based on the clinical history and examination and a uniform protocol of special laboratory tests and imaging studies. All infants with neonatal seizures undergo early EEG and neuro-imaging studies . Laboratory studies included serum glucose and electrolyte levels, cerebrospinal fluid studies, and arterial blood gas and acid-base analysis etc.

Infants with thromboembolic or hemorrhagic le-sions were evaluated by a battery of coagulation studies, and if thromboembolic lesions remained unex-plained, these infants underwent echocardiography.
We assigned each infant to 1 of the following etiologic categories: cerebral hypoxia-ischemia (n=20), trauma/hemorrhage (n=12), cerebral dysgenesis (n=6), transient metabolic disturbances (n=5), infection/in-flammation (n=3), inborn errors of metabolism (n=5), familial/genetic syndromes and underlining causes (n=19).

In the cerebral intracerebral hemorrhage group, we included infants,with evidence for a diffuse cerebral intracerebral hemorrhage insult occurring in the neonatal, intrapartum, or antepartum periods.

The diagnosis of intrapartum cerebral intracerebral hemorrhage required that 4 specific criteria be met:
— severe metabolic acidemia (pH 7.0) on the umbilical cord or first neonatal blood sample, 5-min-ute Apgar score of 7, and neonatalseizures within the first 24 hours after delivery.

The intracranial hemorrhage group included infants with extra-axial (epidural, subdural, and sub-arachnoid) hemorrhage or intraparenchymal hemorrhage. We did not distinguish in this classification between the various causes of hemorrhage (eg, coagu-lopathic, parturitional, traumatic, or idiopathic).

We graded the interictal EEG background into 4 categories of abnormality using previously published criteria.

Normal studies had preserved sleep state modulation and transitions; voltage, synchrony, and symmetry appropriate for age; and age-appropriate patterns (eg, _ brushes and frontal sharp transients).

Mildly abnormal recordings had preserved sleep state modulation and transitions but excessive sharp wave activity and decrease or absence of normal patterns.

Moderately abnormal recordings had low voltage background activity; “dysmaturity” of more than 2 weeks for conceptional age; asymmetric voltage or frequency; excessive asynchrony for postconceptional age; and/or markedly excessive discontinuity for age. Severely abnormal recordings included those with low-voltage undifferentiated patterns; markedly dis-continuous and nonreactive tracings; burst-suppres-sion pattern, or electrocerebral inactivity.

If the seizure etiology was identified by standard CT scan, infants did not always undergo MRI studies. We categorized CT and/or MRI examinations as normal or abnormal, and if abnormal, into extra- and/ or intraparenchymal lesions.

At our center, all infants with a history of neonatal seizures are followed for at least the first year of life where they are evaluated by a multidisciplinary team of experienced child neurologists, developmental psy-chologists, and physical therapists. In this study, we evaluated outcomebyneurologicexamination,developmental progress, and the presence of seizures. All infants with neonatal seizures were evaluated on at least 3 occasions ( around 2 months, between 6 and 9 months, and between 12 and 18 months of age).

During each of the neurologic examinations, we measured the head circumference, cranial nerve function, motor function, auditory function, and visual function.

Motor function was assessed by testing muscle strength, tone, posture, coordination, and reflexes (deep tendon, primitive, and postural). Motor skills were com-pared with those expected for age. In cases of suspected visual dysfunction, formal ophthalmology consultation was obtained. Visual impairment was diagnosed only if confirmed by ophthalmologic consultation. Neurologic function was categorized as follows: normal, if no ab-normalities were identified; mild deficit, if abnormalities were present on examination but had little or no funcţional significance; moderate deficit, if abnormalities caused funcţional impairment; or severe deficit, if full-time special assistance was required. After the first year of life, all infants underwent formal testing by an expe-rienced developmental psychologist using the Bayley Scales of Infant Development II (BSIDII).The primary outcome variable for this study was overall outcome defined as “poor” if an infant had at least 1 of the following: moderate to severe motor deficit and/or visual impairment at the 12- to 18-month visit, significantiy delayed mental performance or postneonatal seizures. All other infants were considered to have a “favorable” outcome.

RESULTS

In 2007,69 infants developed neonatal seizures. Of these, we excluded 2 infants from the study based on our entry criteria. Two infants left Moldova and were lost to follow-up, precluding reliable long-term evalu-ation. The study therefore focused on the 65 surviving term infants (31 girls and 34 boys), ranging in gesta-tional age from 37 to 42 weeks (median: 40 weeks), with a history of clinical seizures in the newborn period, followed for at least 12 months. Birth weight in these infants ranged from 2050 to 4536 g (median: 3400 g).1he onset of seizures was the first day of life in 41 infants (63,l±5,9°/o), the second or third day in 14 infants (21,5±5,l°/o), and after 3 days in 10 copii (15,3±4,5°/o). Distribution of the predominant clinical seizure type was as follows: clonic 43 (66,2%), tonic 10 (15,3%), subtle 7 (10,7%),and myoclonic 5 (7,7%).The distribution of etiologies for the neonatal seizures in our 65 term infants is presented in Table 1.

Table 1. Etiologic Distribution of Clinical Neonatal Seizures (n 65)

The most common etiologies for neonatal seizures were global intracerebral hemorrhage, cerebral vaso-occlusive lesions, and intracranial hemorrhage. Of note, none of our infants had toxin exposure; drug withdrawal; or familial, genetic, or syndromic causes for their seizures. Among the 20 infants with intrapartum asphyxia, 4 had moderate and 16 had severe encephalopathy. By definition, no infant had mild encephalopathy because seizures placed infants in at least the moderate level of encephalopathy The median 5-minute Apgar score was 5 (range: 0-6). Infants with vaso-occlusive lesions or unexplained hemorrhage were evaluated for coagulopathy. Diagnoses of extraparenchymal hemorrhage included subdural (7), subarachnoid (3), and combined (2). Among infants with no identified etiology, 13 infants had seizures around the third day, whereas in the remaining 9 infants, seizures occurred after the fifth day of life.

OVERALL NEUROLOGIC OUTCOME

By definition, the overall outcome was considered poor at the 12-month follow-up evaluation if signifi-cant abnormalities were present on neurologic examination or cognitive testing, or if seizures recurred after discharge. Table 2 summarizes the neurologic outcome of our overall group. Among the infants with a favorable outcome, 46 copii (70,8±5,6°/o) infants were considered normal in all areas evaluated, whereas 19 copiii (29,2±6,7°/o) had neurologic abnormalities on examination without apparent funcţional impact. Among the infants with overall poor neurologic outcome, 20 had severe and 5 had moderate neurologic impairment. Details of the neurologic findings are shown in Table 2.

Table 2. Summary of Neurologic Outcome at 1 Year of Age (n-65)

DISCUSSION

Important diagnostic and therapeutic advances have entered the practice of neonatal intensive care in recent years.The principal aim of this study was to assess the impact of these advances on the etiology and outcome of neonatal seizures. We found certain striking differences between our population and those from previous studies, whereas in other respects, there was little if any change.The large majority of seizures in our population was symptomatic of an identifiable cause from a broad spectrum of etiologies. In fact, the number of infants without identified etiologies was significantly lower than in previous studies. Cerebral intracerebral hemorrhage has been the leading cause for neonatal seizures in most previous studies, although the incidence has varied, likely as a result of the inconsistent diagnostic criteria used. Although global cerebral intracerebral hemorrhage remains the most common etiology for seizures in our study, there are distinct differences from previous reports. In our study, acute transient metabolic disturbances and central nervous system infections were less com-monly implicated as the cause of neonatal seizures than in earlier studies. In fact, seizures caused by transient metabolic disturbances (eg, hypoglycemia and electrolyte disturbances) show a 10-fold decrease compared with other reports over the past 30 years. As in earlier reports, the strongest early predictors of long-term outcome in our study were the underlying seizure etiology and EEG background patterns.

Etiologies associated with poor outcome included cerebral dysgenesis, global cerebral intracerebral hemorrhage, and central nervous system infection. Con-versely, infants with focal cerebral intracerebral hemorrhage, transient metabolic disturbances, or idiopathic seizures had an almost universally favorable outcome. The more favorable outcome in our infants with post-hemorrhagic seizures may reflect the exclusion of premature infants from our study. We found no significant relationship between the predominant clinical seizure type and outcome. This finding differs from other reports in which generalized tonic and subtle seizures have been associated with a worse outcome.

BIBLIOGRAPHY

1. Volpe JJ. Neonatal seizures. In: Neurology of the Newborn. Philadelphia, PA: WB Saunders; 2001:178-214
2. Andre M, Matisse N, Vert P. Prognosis of neonatal seizures. In:
3. Wasterlain C, Vert P, eds. Neonatal Seizures. New York, NY: Raven Press; 1990:61-67
4. Scher MS, Aso K, Beggarly ME, Hamid MY, Steppe DA, Painter MJ. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequehe. Pediatrics. 1993;91:128-134
5. Bye AM, Cunningham CA, Chee KY, Flanagan D. Outcome of neonates with electrographically identified seizures, or at risk of seizures. Pediatr Neurol 1997;16:225-231
6. Legido A, Clancy RR, Berman PH. Neurologic outcome after electroencephalographically proven neonatal seizures. Pediatrics. 1991;88:583-596
7. Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. NEnglJ Med. 1999;341:485-489
8. Rose AL, Lombroso CT. A study of clinical, pathological, and electroencephalographic features in 137 full-term babies with a long-term follow-up. Pediatrics. 1970;45:404-425
9. Kellaway P, Hrachovy RA. Status epilepticus in newborns: a perspective on neonatal seizures. Adv Neurol 1983;34:93-99
10. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology. 1987;37:1837-1844
11. Mizrahi EM, Plouin P, Kellaway P. Neonatal seizures. In: Engel JJ, Pedley TA, eds. Epilepsy: A Comprehefisive Text-book. Philadelphia, PA: Lippincott-Raven; 1997:647-663
12. Mercuri E, Cowan F, Rutherford M, Acolet D, Pennock J, Dubowitz L. Ischaemic and haemorrhagic brain lesions in newborns with seizures and normal Apgar scores. Arch Dis CMldFetal Neonatal Ed. 1995;73:F67-F74
13. Barkovich AJ, Westmark KD, Bedi HS, Partridge JC, Ferriero DM, Vigneron DB. Proton spectroscopy and diffusion imag-ing on the first day of life after perinatal asphyxia: prelimi-narym report.AJNRA?nJNeuroradiol 2001;22:1786-1794
14. Barkovich AJ, Chuang SH, Norman D. MR of neuronal mi-gration Miomdizs.AJRAmJRoentgenol. 1988;150:179-187
15. Rowe JC, Holmes GL, Hafford J, et al. Prognostic value of the electroencephalogram in term and preterm infants following neonatal seizures. Electroencephalogr Clin Neuro-physiol 1985;60: 183-196