Neonatal Seizures Developing Countries Perspective
Surekha Rajadhyaksha and K.N. Shah
Seizures in the newborn period are a frequent clinical problem and represent the most distinctive signal of neurological disease. Neonatal seizures are usually related to specific illness requiring prompt therapy. Early diagnosis of underlying cause is important, as some of the risk factors are associated with high mortality or adverse neurological sequelae. Neonatal seizures show clearly differentiated characteristics from seizures in older children. Several unique characteristics of neonatal seizures warrant a separate classification from the classification of epilepsies and epileptic syndromes proposed by International League Against Epilepsy (ICE-1989).1
Incidence
Seizures manifesting in the first month of life is greater than at any time later in childhood.2 Studies from the developed world indicate that seizures occur in 1.8 to 8.6 per 1000 live births and these studies also show increasing trends in the incidence rates.3-6 The increase in the incidence rates has been attributed to increased survival of preterm and sick babies.4 Data from developing countries is limited. Any incidence studies in developing countries will have significant limitations, mainly because of methodological issues. Health care systems are poorly developed and there are hardly any neonatal intensive care units, particularly in the rural areas. Most often births take place at home and problems exist in the recognition and documentation of subtle neonatal seizures. In Nigeria, an incidence of 7.5 per 1000 live births has been reported. The incidence was high in preterm infants than full-term infants, 47.6 vs 8 per 1000 live births.7 Hospital based studies involve more high-risk newborn evaluation and are likely to report a higher incidence8,9 (Table 1).
Clinical Seizure Semiology
Seizures manifest differently in newborn and seizure semiology depends on the neuroanatomical and neurophysiological development. In the perinatal period cortical organization, dendritic ramification, synaptic connections, and myelination of efferent systems and inter-hemispheric commissures is less advanced, while cortical development of the limbic system and its connection to the diencephalon and brainstem are well developed.10
Newborns rarely have well-developed generalized tonic-clonic seizures and preterm babies have even less organized spells. Focal clonic activity, rapidly shifting from one part of the body to another could be misinterpreted as generalized tonic-clonic seizures. Essentially four clinical seizure types are usually recognized in the neonates: subtle, clonic, tonic and myoclonic. They further can be categorized into multifocal and generalized. Multifocal refers to seizure activity that is asynchronous, migratory
Table 1. Incidence of neonatal seizures
Incidence/1000 Live Births
Type of Study Total Full-Term Pre-Term
Nigeria7 Community 7.5 8.0 47.6
South Africa8 Hospital-based 140 - -
India (Kanpur)9 Hospital-based 100 - -
Our series Hospital-based 62.5 - -
and involves more than one area while generalized denotes activity which is synchronous, bilateral and non migratory.10 Subtle seizures are paroxysmal alteration in the neonate's behavior such as slight posturing of limbs, apnea, deviation of eyes with or without nystagmus, eyelid fluttering, abnormal cry or vasomotor changes. Aberrant behavior may manifest as oro-buccal lingual movements such as yawning, lip smacking, chewing and wincing of facial muscles or apparent as limb movements like pedaling, rowing, or rotating arm movements. These are considered as clinical seizures because of their repetitive, rhythmic and stereotype nature. Myoclonic seizures are distinguished from clonic seizures by the rapid speed of the jerks and their predilection to the flexor group of muscles. Focal myoclonic jerks involve flexor group of muscles of upper extremity while multifocal myoclonic jerks are asynchronous twitching of several parts of body. Most often seizure diagnosis in neonates is based on the clinical observations of the ictal events and interictal electroencephalogram (EEG). However, sometimes clinical observations alone are not sufficient, video-EEG improves the descriptive accuracy of the clinical event.
The reported frequency of various seizure types varied in different series (Table 2). In the series reported from India, multifocal seizures were the most common seizure type, whereas generalized tonic seizures were more frequently observed in the study in Nigeria.7 Focal clonic seizures were more common in the study from Brazil.11 These differences may be related to the characteristics of patient population studied and the study methodology.
Clinical Seizures versus EEG Diagnosis
Clinical observation alone may not be adequate to distinguish behavioral events as epileptic or nonepileptic activity. Understanding of neonatal seizures and descriptive accuracy has improved by video-EEG with polygraphic recording. The major EEG correlates of neonatal seizures include (a) focal or multifocal spikes or sharp waves or both; (b) focal monorhythmic discharges. Abnormal background activity is a determinant of outcome. Mild to moderate EEG abnormalities include voltage asymmetry and delayed maturation patterns. Severe EEG abnormalities include marked decrease in voltage, burst suppression patterns, and electro-cerebral silence.
Focal clonic, focal tonic and generalized myoclonic jerks are more often associated with synchronized abnormal electroencephalographic activity.12 By contrast the relationship between EEG discharges and generalized tonic, focal and multifocal myoclonic paroxysms and also subtle seizures is inconsistent. The frequency of subtle seizures having EEG correlates (epileptiform activity) is variable. Ocular phenomenon such as sustained eye opening, ocular fixation and tonic horizontal eye deviation are associated with EEG abnormalities.10 Apnea in a full term infant has EEG correlate and often associated with other subtle phenomenon such as staring, eye deviation or mouthing movements, but not bradycardia.13 Synchronized generalized myoclonic jerking with flexion of both limbs resembling infantile spasms
heralds West syndrome and is associated with EEG discharges. A recently proposed classification of neonatal seizures is based on clinical seizure characteristics and EEG abnormalities; (a) clinical seizures with epileptiform discharges in the EEG; (b) epileptiform discharges in the EEG with no clinical seizures; and (c) clinical seizures with no epileptiform discharges or abnormalities of uncertain nature in the EEG.14
In one study electrographically confirmed seizures were correlated to clinical events in 92 preterm and term neonates.15 Clinical criteria contemporaneous with electrographic seizures were noted in only 28 (45%) of 62 preterm neonates, and 16 (53%) of 30 full-term neonates. Subtle seizures coincident with electrographically confirmed seizures were the most predominant clinical type for both term and preterm neonates (71% and 68%, respectively). We studied clinical seizures and EEG correlates in 28 neonates born outside the hospital admitted to our neonatal intensive care unit. Fourteen neonates had clinical seizures with associate EEG correlates, 2 neonates had clinical seizures without any EEG correlates, and 3 had seizure mimics, hyperekplexia and sleep myoclonus. Epileptiform discharges were recorded in 2 neonates without coincident seizures and in 3 the background activity was grossly abnormal.
International Classification of Epilepsies and Epileptic Syndromes (ICE) 1989
Of the 2060 children with various epilepsies and epilepsy syndromes in our series, 988 (48%) had symptomatic epilepsies. Similar were the observations in the series from Italy (44%)16 and Finland (36%).17 Birth related trauma was the putative risk factor for 14.6% of the symptomatic epilepsies in our series and it was 18% and 15% in the series from Italy16 and Finland17 respectively. Birth related trauma is an important cause of symptomatic epilepsy in the later life. In our series, of the infants who sustained insult in the neonatal period 59% later developed localization-related epilepsy and 16% developed symptomatic West syndrome. In the study from Japan 41% of the infants with symptomatic neonatal seizures later developed West syndrome and 50% of them later evolved into localization-related epilepsies.18
Very few epilepsies and epilepsy syndromes recognized in the International Classification of Epilepsies and Epileptic Syndromes (ICE)1 occur in the neonatal period. In our series 94 neonates could be grouped into one of the categories proposed in the syndromic classification (Table 3).
Etiology
Neonatal seizures are often related to specific illness (Fig. 1). Prompt identification of a treatable cause and rapid institution of etiology-specific therapy may decrease the chance of long-term neurologic sequelae. Such an approach may effectively control the seizures and there may not be the need for antiepileptic drug (AED) medication. In developing countries prenatal and perinatal insults and postnatal acquired infections of central nervous system (CNS) account for a significant proportion of etiological factors (see the Chapters 8 and 9).
Hypoxic-Ischemic-Encephalopathy
It is estimated that 2-4 full-term neonates per 1000 sustain perinatal asphyxia and the associated mortality is ~ 30%. Of the survivors a quarter develop hypoxic-ischemic-encephalopathy (HIE).19 In developed countries due to effective antenatal care and improved obstetric monitoring there is a steady decline in the
|
Multifocal |
Generalized | |||||
|
Clonic (%) |
Focal Clonic (%) |
Tonic (%) |
Focal Tonic (%) |
Myoclonic (%) |
Subtle/Minimal (%) | |
|
Our series |
44 |
11.5 |
19 |
4 |
21 | |
|
India (Kanpur)9 |
40.8 |
45.6 |
5.6 |
- |
1.6 |
6.4 |
|
Nigeria7 |
- |
23 |
51 |
- |
11 |
16 |
|
NCPP data3 + |
75» |
33 |
25 |
2.5 |
10 |
- |
+ Infants manifested more than one seizure type. • generalized clonic
+ Infants manifested more than one seizure type. • generalized clonic
Table 3. Neonatal epileptic syndromes (ICE 1989 classification)'
ICE Classification
2.1 Generalized idiopathic
23.1 Generalized symptomatic of nonspecific etiology 2.3.2 Generalized symptomatic of specific etiology
2.2 Generalized symptomatic 3.1 Undetermined whether focal or generalized
Total
Name of Condition
Benign neonatal familial convulsions
Benign neonatal convulsions
Early myoclonic encephalopathy (Aicardi)
Early infantile epileptic encephalopathy (Ohtahara)
Diseases states in which seizures are predominant features;
a. Aicardi syndrome b. Holoprosencephaly c. Lissencephaly/pachygyria etc
Early presentation of West and/or cryptogenic Neonatal seizures of other etiology
Prognosis-No. of Cases
64 94
Prognosis Seizure
Controlled
Neurological
Normal
Uncontrolled Grossly abnormal Uncontrolled
Uncontrolled Abnormal
Variable Variable
Abnormal Abnormal
s gfintracrai ial liaem
in d)kennctefus ii fjslmdural matformalion ¡s lOiin known
Figure 1. Etiology of neonatal seizures.
incidence of severe birth asphyxia20 and HIE.21 Comparing two time periods, Gunn et al22 found little change in the overall incidence of neonatal seizures in term infants with birth asphyxia. However, there was a marked reduction in small for date infants with seizures between the two periods. This was attributed to the improved obstetric monitoring.
Birth asphyxia still remains a leading cause of perinatal mortality in developing countries. HIE following perinatal hypoxia is the leading cause of neonatal seizures in term and preterm newborn and accounted for 48% of etiological factors in our hospital-based series (Fig. 1). In a study in Nigeria the reported incidence of birth asphyxia was 26.5 per 1000 live births. In this study for every 1000 neonates with birth asphyxia 12.1 neonates had persistent seizures and coma.23 Two independent studies in Nigeria, conducted in the same decade showed no change in the incidence of perinatal asphyxia and hypoglycemia, 47% and 19% respectively.23,24 In Asian countries low birth weight is the most important independent risk factor for birth asphyxia25 and is associated with high perinatal mortality.26
Diagnosis of HIE is based on: (1) complications of pregnancy, labor, delivery with evidence of fetal hypoxia, abnormal fetal heart rate pattern, low cord pH, low Apgar scores; (2) neurological signs of encephalopathy; and (3) associated metabolic, electrophysiological and neuroimaging abnormalities.27 Seizures associated with HIE are frequently subtle, mixed or fragmentary and usually occur in the first 6 to 12 hours and are maximum over 24-36 hours. Response to antiepileptic drug therapy is poor. Early and prolonged seizures are associated with high mortality and neurological sequelae.28 Similarly for full-term newborn with HIE, abnormal neurological behavior at 7th day of birth is a predictor of adverse outcome.29
Infections of Central Nervous System
Intrauterine and postnatal acquired infections of the CNS are important causes of neonatal seizures in developing countries and in our series these two etiologies accounted for 13% of risk factors. Neonatal meningitis is common in developing countries. A hospital-based study in Ethiopia reported an incidence of 1.37 per 1000 live births, both preterm and term.30 The clinical presentation of neonatal meningitis is often subtle and indistinguishable from that of neonatal sepsis without meningitis. Seizures are more common with gram-negative meningitis and can be the presenting symptom in 20% to 50% of neonates with meningitis.31 Neonatal meningitis is associated with high mortality and morbidity. In the Ethiopian study, 40% of neonates with neonatal meningitis died and 21% developed neurological sequelae such as hydrocephalus, spastic paresis and seizures.30
Metabolic Disturbances
A variety of metabolic disturbances, including inherited metabolic disorders are associated with neonatal seizures. Hypoglycemia and hypocalcemia account for a significant proportion of metabolic disturbances. In the Nigerian study hypoglyce-mia accounted for 19% of provoking factors7 and in our series it accounted for 11%. In developing countries hypoglycemia is more commonly observed in small-for-gestation age (SGA) newborns. The condition occurs in later part of the first or second post-natal day. Duration and severity of hypoglycemia determine the neurological outcome.32 Of the SGA newborns with hypoglycemia, 80% exhibit neurological symptoms and 50% of symptomatic cases experience seizures. Symptomatic hypoglycemia is associated with ~ 50% chance of normal development.10 In developing countries the most effective management approach is prevention of hy-poglycemia. Of particular relevance is identification of high-risk infants, prevention of hypothermia, implementation of early oral feeding, surveillance for clinical symptoms, and serial blood glucose monitoring. Hypoglycemia can accompany with disorders such as trauma, HIE, intracerebral hemorrhage, and infection.
Hypocalcemia with or without hypomagnesemia is another common metabolic cause for neonatal seizures and accounted for 28% of provoking risk factors in a study in India.33 Hypocalcemia is more common in neonates with low birth weight, particularly in the first 2 to 3 days of life. Pyridoxine dependency can result in severe seizures in the neonatal period. Diagnosis can be suspected from the characteristic EEG findings, paroxysmal bilateral synchronous high voltage 1 to 4 Hz burst activity intermixed with spike and sharp wave activity and EEG normalization with intravenous administration of pyridoxine.34
In developing countries kernicterus is often related to blood group incompat-ibility.10 In our series kernicterus accounted for 5% of metabolic disturbances. In Saudi Arabia severe neonatal jaundice and kernicterus is related to high prevalence of G6PD deficiency in the general population.35 In China, brain damage and poor outcome was noted with the use of a herbal medicine used to treat neonatal jaun-
dice.36
Prognosis
In developed countries the outlook for infants with neonatal seizures has improved over the years. This is partly related to better antenatal care and improved obstetric monitoring and also to intensive monitoring of high-risk neonates. Neonatal seizures and intracranial hemorrhage are independent predictors of poor neurological outcome.37 Seizures occurring in the first few days of birth and prolonged and repetitive seizure activity are associated with high mortality and abnormal neurological sequel. Neurological outcome is better in full-term babies with neonatal seizures than in preterm babies. Apgar score of less than 7 at 5 minutes in newborn with neonatal seizures is associated with high mortality and neurological impair-ment.38-40
Do Wfe Need to Treat AH Neonatal Seizures with Antiepileptic Drugs?
The immediate goals of therapy are seizure control and identification and treatment of etiological factor or factors. When potentially treatable causes are identified, etiology-specific treatment should be initiated to limit ongoing CNS injury. Not all seizures warrant AED treatment because they may not be epileptic. Epileptic seizures should be treated as continued seizure activity as it can result in brain injury and also can have adverse effects on respiratory function, circulation and cerebral metabolism. A more controversial issue centers around criteria applied for adequacy of treatment. Is it clinical or electrophysiological? Since there is no conclusive data, treatment is aimed to abolish the clinical seizures. The AEDs typically used in the acute treatment of neonatal seizures are phenobarbital, phenytoin, or a benzodiaz-epine (diazepam or lorazepam). Phenobarbital still remains the drug of choice and is administered in dosages to attain adequate blood levels with minimal risk to cardiovascular and respiratory function.
Conclusion
Seizures in the newborn period are a frequent clinical problem and represent the most distinctive signal of neurological disease. Much of neonatal seizures in the developing world, result from preventable causes prenatal and perinatal insults and postnatal acquired infections of central nervous system (CNS). Hypoxic-ischemic-encephalopathy following perinatal hypoxia is the leading cause of neonatal seizures in term and preterm and still remains a leading cause of morbidity and perinatal mortality in developing countries. The other important cause of neonatal seizures in developing countries is hypoglycemia commonly observed in small-for-gestation age (SGA) newborns. With effective antenatal care and improved obstetric monitoring some of the burden of neonatal seizures can be reduced. Fortunately in developing countries the concept of perinatal health is receiving much attention and also the awareness of the value of statistical indicators of health. With better allocation of resources and rationalization of services for maternal and child health a better picture is likely to emerge in future.
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