Seizures in the neonatal period

Convulsões no período neonatal
Jaderson Costa da Costa, Magda Lahorgue Nunes, Renato Machado Fiori
J Pediatr (Rio J) 2001;77(Supl.1):s115-s22

Introduction

Seizures are among the most frequent neurological disorders of the neonatal period, with an incidence between 1.8-5/1,000 live birthsv(1-3). Newborns exposed to malnutrition in utero seem to be more commonly affected(1). In our study, approximately 14% of the newborns treated at the Neonatal Intensive Care Unit of the Hospital São Lucas (PUCRS) had at least one clinical episode compatible with seizure(4). Seizures in the neonatal period may be associated with several etiological factors, causing permanent or transient injuries to the central nervous system (CNS). Such condition may occur in utero, at the time of birth or in the immediate postnatal period. The prognosis for seizure-stricken newborns is extremely variable. In general, 50% of the patients die or have severe sequelae, and the other 50% are healthy or have minimal sequelae. This dichotomic prognosis has direct influence over the treatment of neonatal seizures, which is totally different from that in other age groups.

Classification

A clinical classification of neonatal seizures was proposed in the 1970s, and is still widely used today(5,6). This classification divides seizures into four groups: subtle, clonic, tonic, and myoclonic. A new classification was proposed later, based on the clinical findings associated with video-polysomnography, introducing two new concepts: clinical seizures without electroencephalographic manifestation and encephalographic seizures without clinical manifestation(7). These two new concepts caused a lot of controversy, and resulted in a thorough reevaluation of the criteria for the treatment of neonatal seizures Currently, there is a third classification based on a review of the previous one. This new classification, shown in Table 1, is still controversial since it groups seizures into neonatal epileptic seizures, and non-epileptic seizures that are characterized by primitive motor patterns of the cerebral and medullar trunk(8,9). This new classification does not include the so-called apnea of infancy. Ictal apnea, initially classified as a subtle seizure, is quite rare, requiring polysomnography for its adequate diagnosis(5,6,10).

Table 1 -
Clinical classification of neonatal seizures

Physiopathology

Most neonatal seizures are epiphenomena of insults to the CNS during the perinatal period or reflect transient disorders such as metabolic changes. Newborns are more susceptible to the development of seizures than older children or adults. This predisposition may be explained through several factors that are characteristic of the neonatal period:

1. The neonatal period is characterized by the fast growth and development of the central nervous system (CNS). The ontogenetic process of maturation of the CNS probably makes newborns more vulnerable to exogenous insults(9);

2. There is a predominance of excitatory systems over the inhibitory ones, thus facilitating convulsive manifestation, in addition to the extracellular accumulation of potassium, which results in hyperexcitability(11,12);

3. Neurotransmitters with inhibitory activity on the CNS have excitatory activity on the immature CNS(13);

4. The dissemination of the epileptogenic activity is more easily present in the immature brain due to the absence of restrictive inhibitory factors(14);

5. Subcortical structures such as the substantia nigra increase the epileptogenic activity of the immature CNS(15).

A question is still intriguing neurologists today: do seizures per se cause brain injury? The most widely discussed hypothesis today, which would explain brain injury after a prolonged seizure, is excitotoxicity. In this case, the excessive release of excitatory amino acids (glutamate, aspartate, quisqualate, and kainic acid), which stimulate their postsynaptic receptors, determine ionic alterations that result in the accumulation of intracellular calcium(16). Studies using nuclear magnetic resonance spectroscopy suggest that neonatal seizures do not determine metabolic changes and/or cerebral hypoperfusion unless significant hypoxemia or severe lactic acidosis is present(17). Experimental studies reinforce these clinical findings, showing there is no evidence that short seizures cause brain injury in immature animals(18,19), except if their CNS has been previously exposed to other types of insult (20).

Etiology

Differently from other age groups, most neonatal seizures are symptomatic, one fourth of them is cryptogenic, and just few are idiopathic. The etiology or associated disorders involve a wide series of neonatal diseases and metabolic disorders. Neonatal seizures are usually multifactorial, and their prognosis is strongly related to their etiology(4).

Perinatal care has helped to modify the etiological factors involved in neonatal seizures with the advent of nuclear magnetic resonance, which allows diagnosing neuronal migration disorders, through the advanced assessment of inborn errors of metabolism, and the reduction of seizures caused by metabolic disorders. However, even with these diagnostic breakthroughs, it is not possible to determine the apparent cause of seizures in a significant parcel of the newborn population(4).

In our environment, perinatal asphyxia is still the most frequently reported etiology of neonatal seizures(4,10,21).

Neonatal Epileptic Syndromes

Early myoclonic encephalopathy or neonatal myoclonic encephalopathy

Aicardi and Goutières(22), followed by other authors(23-25), were the first to report this syndrome, showing predominant myoclonic disorders, and electroencephalogram (EEG) with burst-suppression pattern. Several reports describing early myoclonic encephalopathy include cases with confirmed or suspected inborn errors of metabolism, while others show similarity of this syndrome to nonketotic hyperglycemia(26,27).

According to Aicardi, early myoclonic encephalopathy seems to involve several etiologies(28). Ictal events comprise partial or fragmentary erratic myoclonias, massive myoclonia, and tonic infantile spasms. The EEG shows a burst-suppression pattern characterized by spikes, sharp waves, and slow waves, with 1 to 5 seconds, alternated with periods of flat tracing during 3 to 10 seconds (Figure 1).

Figure 1 -
EEG tracing in newborn with refractory seizures, presenting a burst-suppression pattern

Early infantile epileptic encephalopathy

Early infantile epileptic encephalopathy, described by Ohtahara(29), includes tonic spasms (unilateral or bilateral, involving flexor or extensor muscles) that are hardly controlled with medication and are associated with the encephalographic burst-suppression pattern and marked neuropsychomotor development delay. The nosological position of early infantile epileptic encephalopathy and early myoclonic encephalopathy in this group of newborns is widely discussed(30). The main elements that allow distinguishing between them are(28,30,31): (1) the presence of tonic spasms in early infantile epileptic encephalopathy and absence of partial or massive myoclonias as observed in early myoclonic encephalopathy; (2) a high incidence of family cases and inborn errors of metabolism in early myoclonic encephalopathy, while in early infantile epileptic encephalopathy the major etiology is cerebral malformation; (3) on EEG, paroxysmal bursts seem to be longer in early infantile epileptic encephalopathy than in early myoclonic encephalopathy, and the suppression bursts are shorter(28); (4) early infantile epileptic encephalopathy tends to develop into the West syndrome and, later, into the Lennox-Gastaut syndrome(28).

Benign idiopathic neonatal convulsions

Benign idiopathic neonatal convulsions were initially described in the literature as "fifth day fits"(32). The seizures are clonic, mostly partial, and/or apneic seizures, but never tonic, occurring around the fifth day of life, with unknown etiology and favorable evolution. Approximately 60% of the cases present interictal EEG with Théta pointu alternant pattern(33). This pattern consists of a dominant, discontinued, alternant, non-reactive theta activity with sharp waves(33).

Benign familial neonatal convulsions

Benign familial neonatal convulsions (BFNC) are an idiopathic epileptic syndrome with autosomal dominant transmission, high penetrance, and favorable evolution(33). In BFNC, the seizures often occur on the 2nd and 3rd days of life. Two genetic loci, EBN1 and EBN2, were mapped in families with BFNC: the first, in 1989, on chromosome 20q(34) and, the other in 1993, on chromosome 8q(35). BFNC is associated with mutations in the voltage-gated potassium channel genes KCNQ2 and KCNQ3(36). There is no specific EEG pattern.

Treatment

The treatment of neonatal seizures should always follow the procedures established by the neonatology service. Figure 2 shows the proposed procedures, which were divided into three steps for teaching purposes.

Figure 2 -
Guidelines for the treatment of neonatal seizures

Initial measures

When faced with a seizure of unknown cause in a newborn, the major priority is checking for necessary airway aspiration, oxygenation or ventilation. At the same time, a venous access should be available, and a glucose solution at 10% should be instilled. A quick test (Haemoglukotest, Dextrostix, etc.) should be performed immediately in order to assess the sugar level. The blood sample for lab exams should initially include electrolytes, serum glucose, and hemogram. If these tests do not clarify the cause of the seizure, additional complementary exams should be carried out: creatinine level, ammonia level, blood culture, inborn error of metabolism screening, lumbar puncture with cerebrospinal fluid analysis, cranial ultrasound, and EEG, depending on the clinical status of the patient. Whenever possible, EEG should be carried out before implementing antiepileptic drug treatment.

Specific treatment of metabolism-related seizures

If the test result shows hypoglycemia (less than 40 mg%), 2 ml/kg of glucose at 10% (200 mg/kg) should be quickly infused (small volume bolus during one minute), followed by a slow infusion of glucose at 10% using 5 microdrops/kg/minute (8 mg/kg/minute). The sugar level normalizes within a few minutes in most cases(37,38).

If seizures are controlled, the sugar level should be regularly monitored until serum glucose levels stabilize. Newborns with persistent hypoglycemia may require increased infusion of glucose and, in some cases, use of corticosteroids (hydrocortisone - 2.5mg/kg every 12 hours)(39).

If the newborn presents with hypocalcemia, he/she should receive calcium gluconate intravenously at 5% at 4ml/kg (200mg/kg), slowly infused (longer than 10 minutes), with constant monitoring of his/her heart rate. Gradual or abrupt deceleration of the heart rate during infusion indicates that it should be discontinued or that infusion speed should be reduced. After seizures are controlled, the administration of calcium should continue at 75mg/kg/day until serum levels are stabilized(40). The administration of calcium should be carefully performed due to the risk of extravasation and consequent necrosis of the tissue. The rapid infusion of calcium gluconate may also cause hypercalcemia, reduction of serum phosphorus, and acidosis(41).

Hypomagnesemia (serum magnesium <1.5mg%) is treated with intramuscular magnesium sulphate at 50% (0.2ml/kg) or with an intravenous dose of magnesium sulphate at 3%, 2ml/kg, slowly infused (15 to 20 minutes). The rapid intravenous administration of magnesium may produce low blood pressure and block the sinoauricular or atrioventricular conduction system. Serum magnesium levels should be monitored and, if necessary, the dose should be repeated after 8 to 12 hours. Approximately 50% of newborns with seizures associated with late-onset hypocalcemia also present hypomagnesemia and, in these cases, if magnesium is not administered, the normalization of serum calcium levels may be hindered, and seizures will persist(42).

Reduced serum levels of sodium may cause seizures in the newborn. Hyponatremia is usually treated with concentrated solutions of sodium (3%). Fluid restriction may be necessary so that dilutional hyponatremia can be resolved.

In newborns with persistent seizures of unknown cause, a therapeutic test with pyridoxine is recommended. In this case, pyridoxine should be intravenously infused at 50 to 100mg and, if possible, there should be simultaneous monitoring through EEG(43). If the seizures are pyridoxine-dependent, they will be controlled a few minutes after infusion, and EEG should return to normal within some minutes or hours (Figure 3). If results are not clear after the first dose, the test should be repeated. Newborns with pyridoxine-dependent seizures may have apneas and hypotonia after drug infusion(44,45).

Figure 3 -
EEG in pyridoxine-dependent seizures. a) EEG before pyridoxine administration; b) EEG after the use of pyridoxine, without burst-suppression pattern

Antiepileptic drugs

The use of antiepileptic drugs is recommended if seizures persist after the resolution of metabolic disorders or when the etiological profile suggests that the seizures will not be controlled (e.g.: presence of infections, infarct, dysplasia or other malformations of the CNS)(4).

- The use of antiepileptic drugs should be avoided if the diagnostic profile and the physiopathology of the seizures are not well-defined.

- For the abstinence syndrome related to maternal drug use, chlorpromazine (3mg/kg/day) and phenobarbital (5mg/kg/day) are indicated(4).

- If seizures persist for longer than 24 hours or if the diagnostic profile suggests refractoriness, long-acting antiepileptic drugs should be administered. Phenobarbital is still the drug of choice, since an intravenous loading dose of 15-20mg/kg may be used, followed by an oral maintenance dose of 3.5-4.5mg/kg/day. If the intravenous form is not available, an oral loading dose should be used; the intramuscular route should be avoided due to its erratic absorption. The plasma level should be maintained at 20mg/ml. If the seizures are not controlled, intravenous phenytoin should be combined with a loading dose of 15-25mg/kg, followed by a maintenance dose of 4-8mg/kg/day, administered twice. The plasma level should be maintained between 10-20mg/ml. Oral phenytoin should not be used in the first week of life due to problems with gastrointestinal absorption(46). Other antiepileptic drugs that may also be used intravenously include clonazepam, midazolam, lidocaine and thiopental (Table 2)(4,8,46,47). Valproate may used in persistent myoclonic seizures at 25-30mg/kg/day together with liver function tests, and ammonia dosage. Other drugs that are widely used on adults such as carbamazepine and primidone, and new drugs such as vigabatrin, lamotrigine and topiramate are used non-systematically and sporadically during the neonatal period. However, their safety and pharmacokinetics are not well-known within this population(4,8).

Table 2 -
Other AEDs for IV administration (4,8,46,47)

- Although there is no general agreement in the literature, the use of short-acting antiepileptic drugs such as diazepam or lorazepam (whose intravenous formula is not yet available in Brazil)(4,48) is recommended when the etiological profile suggests transient seizures (related to the abstinence syndrome, sepsis, grade I and II intraventricular hemorrhage, hypoxia with no evidence of leukomalacia). Diazepam may be used intravenously at 0.25 to 0.5mg/kg or rectally at 0.5mg/kg; if necessary, the dose may be repeated every 4-6 hours(4,8). If available, lorazepam may be used intravenously at 0.05-0.10mg/kg, in an infusion of 2 to 5 minutes(46,47).

- The use of antiepileptic drugs should be suspended as soon as possible. The decision on when the drugs should be discontinued depends on the clinical status of each patient. The etiology of the seizures, the absence of clinical or encephalographic seizures, interictal EEG, and neuroimaging results should be considered(4,47,49).

Prognosis

The prognosis for seizure-stricken newborns consists of traditional methods such as the assessment of neuropsychomotor development, neurological examination, electroencephalogram, postepileptic development, and psychological or behavioral disorders(9).

Neonatal follow-up studies show that the prognosis seems to be associated with clinical aspects (type of seizure, interictal EEG), etiological factors, and electroencephalographic findings(2,9,10,21,47).

In our study population, the multifocal encephalographic pattern and suppression bursts are related to poor prognosis. Continuous EEG monitoring may also be useful; in this case, abnormal EEG recordings tend to be associated with poor prognosis(21).

In a cohort of newborns with seizures followed up at the Hospital São Lucas (PUCRS), we observed that 22% and 28.3% of the cases after respectively 12 months and 36 months of follow-up developed epilepsy. The need for anticonvulsants in the neonatal period, and congenital infections were significantly associated with the development of epilepsy. The normal results obtained through the interictal EEG were related to favorable neurological evolution(50).

Similar studies conducted elsewhere showed an incidence of postnatal epilepsy of approximately 20-28%(51,52). We observed a predominance of epilepsy in full-term newborns (30%) in comparison with preterm newborns (17%)(53).

Conclusions

1. The clinical pattern of neonatal seizures is different from that observed in other age groups since it shows anatomical, chemical and physiological immaturity of the developing brain. This means that an adequate classification for this age group is extremely necessary.

2. When we classify neonatal seizures according to their etiology, we observe that most of them are symptomatic, one fourth of them is cryptogenic, and just few are idiopathic. This finding is characteristic of the neonatal period since the etiological factors are more easily identifiable in this age group.

3. Neonatal seizures usually occur in a multifactorial scenario, in which the association between one or more factors potentially harmful to the CNS is present. Such factors include, for instance, asphyxia, hemorrhage, and hypoglycemia. It is crucial that these factors be promptly recognized and specifically treated.

4. The prognosis of neonatal seizures seems to be related to the etiological factor rather than to the severity, duration, or frequency of the seizures.

5. The electroencephalographic seizures without clinical manifestations should be treated with antiepileptic drugs. However, in some cases, polytherapy becomes necessary due to the refractory nature of these seizures.