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Current thumbnail: This syndrome is characterized by clonic seizures that begin around the fifth day of life and may recur during the following 2 to 3 days). It is a benign syndrome but its diagnosis requires a work up to eliminate other potentially more serious epileptic syndromes during this period. The lack of familial history separates this syndrome from benign familial neonatal seizures.

Historical Note and Nomenclature
This syndrome was first described by Dehan and colleagues in 1977. They reported a neonatal convulsive disorder of unknown etiology that occurs around the fifth day of life and is associated with a favorable outcome (Dehan et aI 1977). In 1989 the Commission on Classification and Terminology of the International League Against Epilepsy proposed the term "benign neonatal seizures" (Anonymous 1989). Currently, it is classified under the idiopathic generalized epilepsies although partial seizures are common. Indeed, Watanabe and colleagues reported only partial seizures in 16 infants with the syndrome (Watanabe et al 1999), raising questions about the accuracy of the inclusion of benign neonatal seizures under the rubric of idiopathic generalized epilepsies.

Clinical Manifestations
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 (Plouin 2002) but recently, an infant with tonic-clonic seizures was reported (Guerra et al 2002). 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 (Plouin 2002). Even though infants may experience prolonged status epilepticus, complete recovery usually follows (Pryor et al 1981).

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 is 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 alterant pattern. She was discharged from the hospital on tapering doses of phenobarbital. At last follow up, five years later, she remains seizure free and has a normal development.

Etiology
Acute zinc deficiency has been found in the cerebrospinal fluid of infants suffering from benign neonatal seizures (Goldberg and Sheehy 1983). 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 (Dehan et al 1977). 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 (Herrmann et al 1993).

Pathogenesis and Pathophysiology
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 (Sperber et al 1991; Raynes and Moshe 1999; Galanopoulou et al 2002). Central temporal (rolandic) EEG foci have been observed in a few individuals, as well as in familial neonatal seizures, suggesting that these two disorders may share common genetic factors with benign rolandic epilepsy (Gonzalez Ipina et al 1996). Recently, three de novo mutations in KCNQ2 were found in four patients with benign neonatal seizures (Claes et al 2004) without a family history. As mutations in KCNQ2 have been described in patients with benign familial neonatal seizures, these data suggest of an overlap between the two syndromes.

Epidemiology
Plouin suggested that the prevalence is 7% of neonatal seizures (Plouin 1985; 1990). Few cases have been reported since 1980. Boys are affected more frequently than girls (62% versus 38%).

Prevention
No information is available.

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 (Plouin 2002). 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).

Diagnostic Workup
The most common (60%) interictal EEG pattern of benign neonatal seizures is the "theta pointu alternant" pattern (Plouin 2002). It consists of nonreactive dominant theta wave activity in the 4 Hz 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 (Navelet et al 1981), in a variety of encephalopathies including hypoxic-ischemic encephalopathy (Tharp 2002) and even in benign familial neonatal seizures (Alvarez et al 1986). 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 (10%) (Plouin 2002). The paroxysmal EEG discharge may be unilateral, generalized, or first localized and then generalized (Mizrah 2001). 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 frontocentral area during active sleep have been reported (Guerra et al 2002).

Prognosis and Complications
Although long-term prospective follow-up of neonatal seizures is lacking, the general agreement is that the outcome is favorable (Pellock 1990). Plouin, however, reported mild psychomotor retardation in some cases (Plouin 2002). Seizure recurrences have been infrequent (Miles and Holmes 1990).

Management
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 (Plouin 2002). If medications are used they are usually discontinued soon after the seizures subside.

Pregnancy
Not applicable.

Anesthesia
There are no special considerations.

References Cited
Alvarez LA, Lipton R, Spiro A, Moshe SL. Theta pointu altemant in benign familial neonatal convulsions. Neurology 1986;36(SuppI 1):90.

Anonymous. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30(4):389-99.

Claes LR, Ceulemans B, Audenaert D, et al. De novo KCNQ2 mutations in patients with benign neonatal seizures. Neurology 2004;63(11):2155-8.

Dehan M, Quilleron 0, Navelet Y, et al. Les convulsions du 5e jour de vie: un nouveau syndrome? Arch Fr Pediatr 1977;34:730-42.

Galanopoulou AS, Vidaurre J, Moshe SL. Under what circumstances can seizures produce hippocampal injury: evidence for age-specific effects Dev Neurosci 2002;24(5):355-63.

Goldberg HJ, Sheehy EM. Fifth day fits: an acute zinc deficiency syndrome? Arch Dis Child 1983;57:633-5.

Gonzalez Ipina M, Roche Herrero MC, Lopez Martin V, et al. Benign neonatal convulsions. Review of 23 cases. Neurologia 1996;11(2):51-5.

Guerra MP, Wilson GA, Boylan GB, Rennie JM. An unusual presentation of fifth-day fits in the newborn. Pediatr Neurol 2002;26(5):398-401.

Herrmann B, Lawrenz-Wolf B, Seewald C, Selb B, Wehinger H. 5- Tages-Krampfe des neugeborenen bei rotavirusinfektionen. Monatss-chr Kinderheilkd 1993;141:120-3.

Miles DK, Holmes GL. Benign neonatal seizures. J Clin NeurophysioI 1990;7(3):369-79.

Mizrah EM. Neonatal seizures and neonatal epileptic syndromes. Neurol Clin 2001;19(2):427-63.

Navelet Y, D'Allest AM, Dehan M, Gabilan JC. A propos du syndrome des convulsions neonatales du cinquieme jour. Rev Electroencephalogr Neurophysiol Clin 1981;32:529-44.

Pellock JM. The classification of childhood seizures and epilepsy syndromes. Neurol Clin 1990;8(3):619-32.

Plouin P. Benign neonatal convulsions (familial and nonfamilial). In: Roger J, Dravet C, Bureau M, Dreifus FE, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey, 1985:2-11.

Plouin P. Benign neonatal convulsions. In: Wasterlain CG, Pert P, editors. Neonatal seizures. New York: Raven, 1990:51-9.

Plouin P, Anderson VE. Benign familial and nonfamilial neonatal seizures. In: RogerJ, Bureau M, Dravet Ch, Dreifuss F E, Berret A, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence, 3rd ed. John Libbey & Company Ltd 2002:3-13.

Pryor OS, Don N, Macourt DC. Fifth day fits: a syndrome of neonatal convulsions. Arch Dis Child 1981;56:753-8.

Raynes HR, Moshe SL. Case report: benign idiopathic neonatal convulsions. Suppl to Resident & Staff Physician December 1999:21-3.

Sperber EF, Haas KZ, Stanton P, Moshe SL. Resistance of the immature hippocampus to seizure-induced synaptic reorganization. Dev Brain Res 1991;60:88-93.

Tharp BR. Neonatal seizures and syndromes. Epilepsia 2002;43:2-10.

Watanabe K, Miura K, Natsume J, Hayakawa F, Furune S, Okumura A. Epilepsies of neonatal onset: seizure type and evolution. Dev Med Child Neurol 1999;41:318-22.

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Abbreviations
EEG:electroencephalogram

ICD code
345.9

Synonyms
Benign neonatal convulsions
Benign neonatal seizures
Fifth-day fits

Associated Disorders
Neonatal seizures
Benign-familial neonatal seizures or convulsions

Major Keyword Descriptors
acute zinc deficiency
apnea
clonic seizures
epilepticus
fifth-day fits
idiopathic generalized seizures
neonate
partial seizures
seizures
theta pointu alternant
zinc deficiency

Minor Keyword Descriptors
benign
convulsions
diarrhea
epilepsy

Age of Presentation
0-01 month

Age of Typical Presentation
0-01 month

Population group(s) preferentially affected
none selectively affected

Occupation group(s) preferentially affected
none selectively affected

Sex
male>female, >2:1
male>female, >1:1

Family History
none

Heredity
none

Permuted topic, synonyms, subtopics
Benign neonatal seizures (nonfamilial)
neonatal seizures (nonfamilial), Benign
seizures (nonfamilial), Benign neonatal
nonfamilial, Benign neonatal seizures
neonatal convulsions, Benign
convulsions, Benign neonatal
idiopathic neonatal seizures, Benign
neonatal seizures, Benign idiopathic
seizures, Benign idiopathic neonatal
neonatal seizures, Benign
seizures, Benign neonatal
fits, Fifth-day
seizures, Neonatal

Related topics
Benign-familial neonatal seizures
Benign familial and nonfamilial infantile seizures
Epilepsy
Neonatal seizures

Differential Diagnosis
late hypocalcemia
subarachnoid hemorrhage
certain meningitides
benign-familial neonatal convulsions

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