Clinical manifestations

Presentation and course

Seizures occur between the first and seventh day of life in otherwise normal, full-term infants born after an uncomplicated, normal pregnancy, labor, and delivery. There is no family history of neonatal seizures. In 80% of cases, the seizures occur between the fourth and sixth days (hence, "fifth-day fits"). The seizures are most often clonic, usually partial, and occur with or without apnea. They are often unilateral and may change sides. It is thought that tonic seizures do not occur (25), but an infant with tonic-clonic seizures has been reported (10). Individual seizures may last from 1 to 3 minutes and recur in clusters, leading to status epilepticus, which may persist from 2 hours to 3 days (the reported mean duration of the seizures is 20 hours). Affected infants may become postictally drowsy and hypotonic for several days; however, the drowsiness and hypotonia may result from concomitant antiepileptic drug administration (25). Even though infants may experience prolonged status epilepticus, complete recovery usually follows (27).

Prognosis and complications

Although long-term prospective follow-up of neonatal seizures is lacking, the general agreement is that the outcome is favorable (21). Plouin, however, reported mild psychomotor retardation in some cases (25). Seizure recurrences have been infrequent (16).

Clinical vignette

A 4-day-old girl presented with abnormal movements. Some witnessed episodes were described as bicycling movements of legs and arms with lip smacking. The movements were forceful and rhythmic, unable to be suppressed, and lasted between 2 and 5 minutes each. Initially lorazepam (0.3 mg) was given to stop the movements. Pyridoxine administration did not stop the seizures. On day 5 of life she developed status epilepticus; she was intubated and treated successfully with phenobarbital (20 mg/kg). She was the product of a full-term uncomplicated gestation, delivered by normal, spontaneous, vaginal delivery. There was no family history of neonatal seizures or any other neurologic disease. Physical examination was unremarkable. Serum electrolytes and glucose were normal. There was no evidence for sepsis and lumbar puncture was normal. Her EEG showed the classic theta pointu alternant pattern. She was discharged from the hospital on tapering doses of phenobarbital. At last follow up, 5 years later, she remained seizure free and had a normal development.

Biological basis

Etiology and pathogenesis

Acute zinc deficiency has been found in the cerebrospinal fluid of infants suffering from benign neonatal seizures (07). Whether zinc deficiency in the central nervous system is truly the etiologic factor or only the consequence of neonatal seizures remains unknown. A viral illness has also been suspected. Dehan and colleagues reported that 9 out of 20 patients had diarrhea prior to the onset of the seizures, and 18 of 20 patients had the seizures between October and March (04). Hermann and colleagues identified rotavirus in the feces of 18 of the 19 babies with benign neonatal seizures (95%), whereas only 40% of the sick neonates without seizures (p greater than 0.01) had positive findings (11).

The pathophysiology of benign neonatal seizures remains unknown. The syndrome provides clinical evidence that seizure-induced hippocampal damage is an age-specific event and that idiopathic recurrent seizures and status epilepticus early in life may not lead to hippocampal injury in the absence of other complicating factors (30; 28; 06). Central temporal (rolandic) EEG foci have been observed in a few individuals as well as in familial neonatal seizures, suggesting that these 2 disorders may share common genetic factors with benign rolandic epilepsy (08).

Epidemiology

Plouin suggested that the prevalence is 7% of neonatal seizures (22; 23). Few cases have been reported since 1980. Boys are affected more frequently than girls (62% vs. 38%).

Differential diagnosis

Benign nonfamilial neonatal seizures is a diagnosis of exclusion. Etiologies of neonatal seizures with relative favorable outcome include late hypocalcemia, subarachnoid hemorrhage, and certain meningitides (25). Benign nonfamilial seizures can be differentiated from benign-familial neonatal seizures based on the lack of family history and the occurrence of tonic seizures in the latter. Furthermore, benign-familial neonatal seizures do not tend to cluster during a narrow age window (4 to 6 postnatal days). Although the phenotypes between these 2 syndromes are similar, the seizure semiology and localization of seizure onset is sometimes different between the familial and the sporadic forms. Although the former onset is usually parieto-occipital, the latter has a more anterior onset (24). De novo mutations of KCNQ2, causing early life seizures, can sometimes appear similar in both benign neonatal seizures and in early onset epileptic encephalopathies. Those with more severe outcomes usually display multifocal spikes or a suppression-burst pattern (17). The EEG in patients with KCNQ2 encephalopathy shows lack of organization interictally with ictal low voltage fast activity and theta rhythms, and these features may be helpful in differentiating KCNQ2 encephalopathy from BFNS (20).

Diagnostic workup

The most common (60%) interictal EEG pattern of benign neonatal seizures is the "theta pointu alternant" pattern (25). It consists of nonreactive dominant theta wave activity in the 4 to 7 Hz range, which alternates with sharp waves. The pattern is present during wakefulness or sleep and may be discontinuous and alternate between hemispheres. It may persist for 12 days after the cessation of seizures. "Theta pointu alternant" is not specific for the idiopathic benign neonatal seizures syndrome. It can also occur with other neonatal seizures, such as hypocalcemia, meningitis, subarachnoid hemorrhage (19), a variety of encephalopathies including hypoxic-ischemic encephalopathy (31), and even benign familial neonatal seizures (01). Other EEG patterns that have been described in this syndrome include focal or multifocal, nonspecific abnormalities (25%), centrotemporal spikes, or a discontinuous pattern (5%). In 10% of the cases, the EEG may be normal (25). The paroxysmal EEG discharge may be unilateral, bilateral, or first localized and then bilateral (18). Thus, the ictal EEG shows rhythmic spikes or slow waves, which can be localized to any area but are most commonly seen in the rolandic regions. Seizures originating from the frontocentral area during active sleep have been reported (10). It has been shown that some patients with KCNQ2 mutations may develop epileptic encephalopathy leading to profound intellectual disability with motor impairment, although epilepsy appears to resolve by 3 years of age. The initial EEGs showed a burst suppression pattern or multifocal discharges. MRI of the brain showed characteristic hyperintensities in the basal ganglia and thalamus early on that later resolved (33). There is also a case report of a girl with a history of benign neonatal seizures who later developed benign childhood epilepsy with centrotemporal spikes and was found to have a KCNQ2 mutation (13). One report suggests that mutations on the S2 and S3 regions of KCNQ2 are usually associated with benign neonatal seizures whereas mutations in S6 and adjacent regions are more likely to be associated with the more severe KCNQ2 encephalopathy (09).

Management

In the past, antiepileptic drugs such as phenobarbital, phenytoin, diazepam, paraldehyde, chloral hydrate, and clonazepam have been used to treat these neonatal seizures. The seizures may be shortened with these medications, but the results are inconsistent.

In most cases, the seizures will cease spontaneously without medications (25). If medications are used, they are usually discontinued soon after the seizures subside. Medications that work on voltage-gated sodium channels have been used as well. Several studies have shown the efficacy and safety of low-dose carbamazepine (20; 29; 26). Medications that work on the potassium channel are potential treatments; however, retigabine has been discontinued and other medications, such as diclofenac have not yet reached clinical approval (15).