Clinical manifestations

Presentation and course

The benign infantile epilepsy syndromes share several clinical features. The typical age of onset is 3 to 12 months; however, onset has been reported in children as young as 6 weeks (03) and as old as 20 months in some cohorts (52). A female predominance has been reported with 2 to 1 ratio (55). At presentation, children experience the subacute onset of focal seizures occurring in clusters of 5 to 10 seizures per day, which may be frequent and successive but do not progress to status epilepticus.

Semiologically, the seizures often involve motor arrest, impairment in consciousness, staring, and some convulsive movements (35; 55). They have been described to occur during wakefulness or drowsiness. Watanabe and colleagues described temporal onset seizures characterized by limb and oral/facial automatisms in cases described as “benign partial epilepsy with complex partial seizures” (58). This group also described prompt generalization with tonic-clonic manifestations with more variable region of onset in cases described as “benign partial epilepsy with secondarily generalized seizures” (56). However, such a distinction in semiology does not seem to correlate with different etiologic factors, as patients with predominantly 1 or both of these seizure types can coexist within the same affected family (41). In addition, Vigevano and associates documented seizures characterized by slow deviation of head and eyes to 1 side, diffuse hypertonia, cyanosis, and unilateral limb jerking that is initially unilateral and progresses to involve the contralateral side in a synchronous, asynchronous, or alternating manner (54).

The interictal EEG recorded at a time remote from the seizure cluster is normal. Vigevano and colleagues described an interictal EEG performed during a seizure cluster that was notable for lateralized slow waves and spikes in the occipito-parietal areas in a familial case (54). In the presence of secondary generalization, ictal EEG reveals a focal discharge evolving in amplitude, spreading over the hemisphere, and ultimately involving the entire brain. Within the same patient, focal patterns may occur over alternating hemispheres, correlating with the alternating semiology described by Vigevano and associates (54; 55). Subsequently, several groups have failed to demonstrate significant differences in region of onset or EEG characteristics between patients with familial and nonfamilial benign infantile seizures (32; 07).

The gestational and medical histories of these patients are unremarkable. In familial cases first and second degree relatives endorse history of benign infantile seizures that resolved, often with an autosomal dominant inheritance pattern. Testing for etiologic factors, including metabolic and neuroimaging studies, are unrevealing. The seizures are classically quite responsive to pharmacologic treatment; however, if treatment is withheld they will persist often through the second year of life. Irrespective of pharmacologic treatment, all seizures will remit typically within 1 year of onset (by age 2). Preceding and subsequent to the epilepsy, psychomotor development is normal.

In the rarer subtypes, there is often an additional clinical feature or symptom that emerges after the resolution of the epilepsy and each syndrome is so named. For example, patients with benign familial infantile seizures with choreoathetosis will develop choreoathetotic movements in infancy or later in childhood. They occur at rest or during exertion/anxiety and are dystonic (48; 16). Patients with benign familial infantile seizures with familial hemiplegic migraine go on to develop hemiplegic migraine attacks (49; 51; 36).

Seizures are associated with gastroenteritis in benign infantile seizures with mild gastroenteritis (09) and there is an electrographic signature of midline or vertex spikes during sleep in benign infantile focal seizures with midline spikes and wave during sleep (17).

Prognosis and complications

Benign outcome is fundamental to the diagnosis. Children with benign infantile seizures have normal psychomotor development and do not manifest other forms of epilepsy later in life. In cases where pharmacologic treatment is withheld, seizures may recur within the first months or year after onset. However, seizures will remit nevertheless. The EEGs performed at follow-up remain normal.

Clinical vignette

The following is an example of a familial case reported by F Vigevano as well as by Giordano and colleagues (21).

A 3-months 21-days-old girl presented with a cluster of seizures characterized by fixed gaze, bilateral clonic jerks, and loss of consciousness that lasted 2 minutes.

On admission, a seizure was observed which was characterized by slow deviation of the head and eyes to the left and then to the right, loss of consciousness, oral automatisms, diffuse hypertonia, and bilateral clonic jerks. All laboratory testing (organic acids, lactate, pyruvate, ammonia in plasma, and urine) and neuroradiological examinations (CT head and MRI brain) were negative. EEG during wakefulness and sleep were normal.

At that time, neurologic examination and psychomotor development were normal, and no antiepileptic drug therapy was prescribed at the parent’s request. The patient continued to have 3 to 4 seizures per month from 5 to 7 months of age. Only a single seizure was reported from 7 to 11 months of age. At 1 year of age, the patient became seizure free. Neurologic examination and developmental trajectory remained normal.

There was a strong family history of benign convulsions during infancy, including 18 of 35 members of the mother’s family. In particular, the father and all but 1 of the mother’s siblings (4 sisters and 6 brothers) presented with similar seizures. In all 18 members of the affected family, the clinical characteristics of the seizures were similar to those described in the proband. In all 18 members, seizure onset was at 3 to 4 months of age and remission was achieved at 9 to 10 months of age. All affected members experienced seizure clusters at onset and subsequently isolated seizures, with frequency similar to that of the proband. The proband’s grandmother considered this type of convulsion to be a characteristic trait of the family and as such none of the 18 subjects received antiepileptic drug treatment.

All 18 affected family members had normal psychomotor development and attended high school. None of them experienced febrile convulsions, nor did they develop epilepsy.

Biological basis

Etiology and pathogenesis

The etiologies of the benign familial infantile epilepsy syndromes are genetic. The benign nonfamilial epilepsy syndromes are less well understood and their etiologies are likely multifactorial.

Benign familial infantile seizures. Autosomal dominant transmission is seen in benign familial infantile seizures. Early researchers suspected that the genes affected in these syndromes would be similar to those affected in benign familial neonatal convulsions; however, these theories were debunked (31; 38; 35).

The first pathogenic gene locus tied to these syndromes was identified in 1997 when a linkage analysis was carried out in 5 Italian families with benign familial infantile seizures and mapped the locus to chromosome 19q12-13.11 (23). Gennaro and colleagues later performed a linkage analysis on 7 different Italian families with benign familial infantile seizures and were not able to corroborate this, suggesting that this is not a major locus and that genetic heterogeneity may play an important role (20). Other groups had similar results (59; 45).

At approximately the same time, Malacarne and colleagues mapped a novel locus to chromosome 2q23-31 in 3 affected Italian families (34) but this was not corroborated in future linkage analyses (59).

In the past several years it has been discovered that a large percentage of patients affected by benign familial infantile seizures have a mutation in the proline-rich transmembrane protein 2 (PRRT2) gene located on chromosome 16p12-q12 (08; 59; 45; 42). In 2012, the largest study performed so far in families with “pure” benign familial infantile seizures showed the occurrence of a mutation of PRRT2 in 83% of them (41). Additionally, a large Italian collaborative study confirmed PRRT2 mutations in most of the families, but with a slightly lower incidence than in the previous study (70%) (61). This mutation is not seen in families with benign familial neonatal seizures (22).

Previously the PRRT2 gene was implicated in paroxysmal kinesigenic dyskinesia (11) and in fact paroxysmal kinesigenic dyskinesia is observed later in life in some benign familial infantile seizures patients with PRRT2 mutations (26; 37). This entity will be discussed below.

The product of the PRRT2 gene is a proline-rich protein whose precise function has not yet been elucidated. Its role seems related to synaptic function because it interacts, both in vitro and in vivo, with synaptosomal-associated protein 25 kDa (SNAP 25), a synaptic protein (43; 28; 50). SNAP 25 plays a relevant role in neurotransmitter exocytosis, vesicle docking, and fusion to the plasma membrane. Indeed, it has been shown in vitro that PRRT2 plays an important role in specific steps of neurotransmitter release (50). Further work must be done to elucidate (1) whether the mutations found so far are related to a loss of function and to what extent, and (2) why the epileptic syndromes associated with PRRT2 mutations have a limited time window of phenotypic expression, resolving without sequelae. It is worth noting here that the expression levels of CNS PRRT2 seem to vary during development, and apparently with a region-specific pattern (11; 26); this might be at least in part in line with the age-specific/self-limiting presentation of seizures, as well as with the phenotypic variability among patients. The mechanism by which this mutation is related to the occurrence of this brief, benign epilepsy syndrome is not well understood.

Interestingly, the PRRT2 sequence is highly preserved throughout phylogenesis (28), and this might help in understanding its precise role and function through experimental studies in rodents.

Other pathogenic mutations have been suggested. Zara and colleagues suspected involvement of KCNQ2, KCNQ3, and SCN2A and found that only approximately 10% of benign familial infantile seizures families had none of the 3 mutations (61). Subsequent linkage studies confirming these results have not yet been undertaken.

Benign familial infantile seizures and choreoathetosis. As discussed above, PRRT2 mutations are frequently found in patients with isolated benign familial infantile seizures; however, they also occur in benign familial infantile seizures patients who later develop choreoathetosis or paroxysmal kinesigenic dyskinesias.

In 1997 Szepetowski and colleagues demonstrated linkage to this pericentromeric region of chromosome 16 in 4 French families with the syndrome of benign familial infantile seizures and choreoathetosis (48). This finding was later replicated by several other groups studying families of varying ethnicities (30; 47; 08). The mutation is present in up to 80% of families with benign familial infantile seizures with choreoathetosis (Lee et al 2011; 26; 37) and seems to be inherited in an autosomal dominant manner.

Additionally, a mutation of the SCN8A gene has been described in families of patients affected by both paroxysmal dyskinesia and benign familial infantile seizures. Notably, these families did not have a coexisting PRRT2 mutation (19).

Benign familial neonatal-infantile seizures. In 2002 Heron and colleagues reported the presence of a mutation in the sodium channel subunit gene SCN2A in 2 families with seizure onset between 1 and 3 months of life which was intermediate between neonatal and infantile forms. One of the families also had mutations in KCNQ2 and KCNQ3 (25). Later, the same group found mutations in the sodium channel gene SCN2A in 6 other families (02). The authors coined the term “benign familial neonatal-infantile seizures,” referring to their patients whose epilepsy onset was between day 2 of life and 7 months of life. In 2006, Striano and colleagues reported a novel heterozygous mutation c3003 T → A in the SCN2A gene in a family with 3 affected individuals over 3 generations (44). All subjects in this series experienced clusters of focal seizures with or without secondary generalization, onset between 4 and 12 months of life, and had been diagnosed with benign familial infantile seizures. This report provided new evidence that suggested benign familial neonatal-infantile seizures and benign familial infantile seizures may have some overlapping clinical and genetic characteristics. However, it could not be excluded that the family described by Striano and colleagues (44) was affected by benign familial neonatal-infantile seizures, as suggested by Herlenius and colleagues (24).

Benign familial infantile seizures with familial hemiplegic migraine. There is a subset of benign familial infantile seizures patients who go on to experience hemiplegic migraine later in life, long after the resolution of the epilepsy. A mutation in ATP1A2 has been identified in some of these patients (49; 51). The loss of function mutation is hypothesized to lead to neuronal hyperexcitability and facilitate cortical spreading depression, which is a mechanism believed to be involved in both epilepsy and migraine.

Benign nonfamilial infantile seizures. The data on gene(s) involved in the sporadic cases are scarce. It has been observed that PRRT2 mutations do occur in some nonfamilial cases, as a de novo mutation (40; 42).

Benign infantile seizures with mild gastroenteritis. There are reports of sporadic cases of benign infantile convulsions associated with prolonged episodes of diarrhea caused by rotavirus infections (12). However, clear cause-effect relation is still to be demonstrated as other groups have found this entity to occur in infants with mild gastroenteritis that is rotavirus negative (09). Several large series of these patients have been described (13; 10). There has been some documentation of the lack of PRRT2 mutations in the few patients with convulsions with mild gastroenteritis assessed thus far (40; 27).

Benign focal epilepsy in infancy with midline spikes and waves during sleep. Capovilla and colleagues described a series of 12 patients who shared the clinical presentation of benign nonfamilial infantile seizures; however, they had interictal EEG abnormalities unlike the previously described cases. In all cases, characteristic spike and wave discharges were present over the vertex during sleep whereas the interictal EEG during wakefulness remained normal. On the basis of these uniform electroclinical features, the group proposed the creation of a new syndrome (04). The patients appear to have a benign outcome with normal psychomotor development and quick resolution of the epilepsy, and as such it has been suggested that they do not simply represent an early onset of other previously described epilepsy syndromes (05; 17).

Epidemiology

Due to the benign, self-limited and sometimes brief nature of these epilepsy syndromes, their incidence and prevalence are difficult to estimate. Many families who possess the condition consider it a “family trait” and may not seek care for affected infants.

There are worldwide reports of the familial and nonfamilial forms (29; 33; 14; 06; 03; Espeche et al 2010; 39; 41; 61); however, there is no reliable epidemiological study on this topic at the present time.

Differential diagnosis

In familial forms where the history is available, the diagnosis of benign familial infantile seizures can be made early. However, in many cases other etiologies such as infection, intracranial injury, metabolic disorder (including pyridoxine dependency/deficiency epilepsy), and electrolyte disturbance should be ruled out. Other more malignant epilepsy syndromes of infancy must also be considered at onset as neurodevelopmental outcome will be uncertain.

Diagnostic workup

In the setting of an appropriate family history, diagnostic testing may be minimal if benign familial infantile seizures is suspected.

In the absence of such a history, diagnostic workup will often be directed at ruling out malignant causes of the seizures. This evaluation will begin with collecting historical information on prenatal, perinatal, or postnatal etiologic factors, data on psychomotor development, clinical condition prior to seizure onset, and family history when available. Normal neurologic examination must be confirmed.

Diagnostic testing may include blood and urine tests to exclude infectious or metabolic disorders (complete blood count, comprehensive metabolic panel, organic acids, lactate, pyruvate, ammonia, cultures of blood/urine/CSF as indicated). Video EEG is advisable to characterize the suspected episodes as seizures and document the interictal record, which will be normal in most cases. Neuroimaging such as MRI brain should be performed, as normal findings are fundamental to the diagnosis. Genetic testing should be performed when indicated, specifically screening for KCNQ2, KCNQ3, SCNA2, PRRT2, and possibly SCN8A, as described above and others as indicated.

Management

In general, these patients’ seizures are successfully treated with medications such as carbamazepine, phenobarbital, valproate, or zonisamide, which may be efficacious even at low doses (60). Treatment in general is continued until the expected time of remission of the epilepsy, which is approximately 2 years.

Treatment is often withheld in benign familial infantile seizures cases, as many families are familiar with the benign outcome of the syndrome and as such may question the risk to benefit ratio of the antiseizure medications that are recommended.

Outcomes

The outcomes of these syndromes are universally benign. The epilepsy remits usually by the second year of life if not before, and neurodevelopmental outcome is normal.