For a long time, neonatal seizures and focal epilepsies in infancy have been viewed with suspicion for a probable association with brain lesions. Now, it is well known that seizures may manifest in newborns and infants with normal neurological, neuroradiological, and metabolic status (1–4). If a family history of the same seizure type is present, a diagnosis of a genetic form with benign course is more likely. Three epileptic conditions have been delineated so far, accounting for focal seizures with and without secondarily generalized phase, benign outcome, and autosomal dominant mode of inheritance. These conditions are differentiated mainly according to the age of onset: typically during the first days of life in benign familial neonatal seizures (BFNS), between two days and 6 months of age in benign familial neonatal-infantile seizures (BFNIS), and between 3 and 18 months of age in benign familial infantile seizures (BFIS). At the ictal level, these disorders show analogous, usually brief, focal motor manifestations, typically head and eye deviation, staring, and apnea, often followed by a secondary bilateralization with clonic movements of the four limbs. They do not differ so much from the nonfamilial benign forms. Seizures may occur sporadically or in clusters of many per day, with spontaneous remission within the first year of age (1–6). Although these three conditions show a significant clinical overlap, genetic studies show that they are associated with mutations in a set of at least four genes. In particular, mutations in the voltage-gated potassium channel genes KCNQ2 and KCNQ3 are typically found in BFNS (7–10), mutations in the voltage-gated sodium channel alpha2 subunit gene SCN2A in BFNIS (11,12), and mutations in PRRT2 in BFIS families (13,14). This chapter reviews the electroclinical features and genetics of these early-onset forms of age-dependent, familial benign epilepsies starting in the first year of life.

BENIGN FAMILIAL NEONATAL SEIZURES

BFNS are a rare, dominantly inherited disorder manifesting mostly on the second and third days of life. Boys and girls are equally affected. The incidence is 14.4 per 100,000 live births, but it may be under-recognized (2,3,15).

Etiology

This is a genetically determined channelopathy of an autosomal dominant pattern of inheritance and high (approximately 85%) penetrance. The disease is caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2 on chromosome 20q 13.3 and, more rarely, KCNQ3 on chromosome 8q.13.3 (5,7–8). Some mutation-negative families have been described (10). In particular, benign familial neonatal seizures are caused by a small loss of function of heteromeric voltage-gated potassium channels that decrease the potassium current. This impairs repolarization of the neuronal cell membrane, resulting in hyperexcitability of the brain that can produce seizures. It has also been postulated that a slight reduction in KCNQ channels alone cannot produce seizure activity, but can facilitate it under conditions of unbalanced neurotransmission, either by an increase in excitation or decrease in inhibition (9). Thus, this imbalance in excitation and inhibition could be one possible explanation as to why the neonatal period is a vulnerable time for the seizures to occur. Another possibility is the differential expression of potassium channels during different stages of maturation (15). However, it is now known that de novo KCNQ2 mutations are associated with a severe neonatal epileptic encephalopathy, being related to a dominant-negative reduction of the resulting potassium current at subthreshold membrane potentials (16,17).

Clinical Manifestations

Seizures mainly occur in full-term normal neonates after a normal pregnancy and delivery and without precipitating factors (2,3,15). Seizures are brief, of 1 to 2 minutes in duration, and may be as frequent as 20 to 30 per day. Most seizures start with tonic motor activity and posturing with apnea, followed by vocalizations, ocular symptoms, other autonomic features, motor automatisms, chewing, and focal or bilateral clonic movements. The clonic components of the later phase are often asymmetrical and unilateral, asynchronous on the two sides of the body.

The postictal state is brief and interictally the neonates are normal. Pure clonic or focal seizures are rare (2,3,10).

Investigations

Biochemical, hematological, and metabolic screenings and brain imaging are normal. Family history can orient the diagnosis, which is based on electroencephalography and video recordings. Interictal EEGs are usually normal and are of limited value, though EEG may exclude other causes of serious neonatal seizures. Conversely, ictal EEGs usually display focal discharges of low-voltage fast waves or rhythmic or repetitive sharp alpha or theta waves of increasing amplitude and decreasing frequency, which are followed by theta and delta waves mixed with spikes or sharp waves with gradual or rapid spread to other regions (2,3). Genetic testing confirms the diagnosis.

Prognosis

Seizures remit between 1 and 6 months from onset; in 68% of affected children, during the first 6 weeks. However, 10% to 14% may later develop other types of febrile (5%) or afebrile seizures, more commonly of the Rolandic type. The subsequent risk of a recurrent seizure disorder depends mostly on whether other affected relatives developed a seizure disorder later in life (2,3,10).

Management

In the active seizure period, drug treatment is usually effective. Complete seizure control is achieved in nearly all cases. Recurrences after 1 to 2 months may occur in one-third of the patients, but these are also easily controlled by drug dose adjustments. Antiepileptic treatment should be limited to the first months of life.

BENIGN FAMILIAL INFANTILE SEIZURES

BFIS is a distinctive clinical entity characterized by partial seizures with or without secondary generalization, mostly occurring in clusters, first described by Vigevano (4,18). In contrast to the nonfamilial cases (1), where the age at onset is 3 to 18 months (even if with a peak at 5–6 months), the familial form mostly starts between 4 and 7 months. Boys and girls are equally affected. Patients typically show a normal psychomotor development at the onset of a seizure and a favorable outcome (3,4).

Etiology

BFIS is a genetically heterogeneous disease. Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene located at 16p11.2 have been found in most families (14). PRRT2 encodes a membrane protein that interacts with the presynaptic protein SNAP-25.

PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability (19). However, mutations have also been found in the SCN2A gene at 2q24.3 encoding the brain sodium channel NaV1.2 (20). Additional chromosomal loci have been mapped at 19q12–13.11 (21) and 1p36.12–p25.1 (22) but never confirmed.

Notably, BFIS associated with mutations in PRRT2 is allelic to the infantile convulsions and paroxysmal choreoathetosis (ICCA) syndrome, characterized by infantile seizures and paroxysmal dyskinesia, which are coinherited as a single autosomal dominant trait (23). The clinical expression is variable, and affected individuals may display infantile seizures, paroxysmal dyskinesia, or both. The paroxysmal dyskinesia starts at age 5 to 28 years and occurs spontaneously at rest or is induced by sudden movements, anxiety, or prolonged exercise. Some patients exhibited recurrence of epileptic seizures at a much later age. PRRT2 mutations are found in the vast majority (>90%) of ICCA families of Asian, African American, and Caucasian ethnicity from different countries (13,19). Finally, infantile seizures can also occur in families with hemiplegic migraine associated with ATP1A2 mutations (24).

Clinical Manifestations

Seizures usually occur between 3 to 8 months of life, with clusters (8–10 a day) of repeated and brief episodes (2–5 min) over a few days. The clusters can spontaneously remit, but seizures can recur after 1 to 2 months. They are focal in origin but often present a secondary bilateralization. Seizures are usually brief (0.5–3 min), but may be longer (3–6 min) at the beginning of the clusters. The repertoire of ictal manifestation of epilepsy in infants is typically variable. The most ordinary sequence of the seizures consists mainly of motion arrest, decreased responsiveness, staring or blank eyes, eye deviation, and/or head rotation, and mild clonic movements involving face, eyelids, and one limb, with increased limb tone. If the focal seizure progresses, clonic movements spread initially to one side of the body and then to the contralateral side. These clonic movements are not as intense as those in purely generalized tonic–clonic seizures, and are often asymmetrical, asynchronous on the two sides of the body. If the first part of the seizure is not observed by the parents, an erroneous diagnosis of generalized tonic–clonic seizures can be made. Autonomic changes such as flushing, mydriasis, pallor, cyanosis, apnea, or tachypnea may be seen (1,2,4).

Investigations

If a positive familial history is present, the diagnosis is easily made. However, in some cases, these data are difficult to obtain and the infant must be routinely investigated to exclude prenatal, perinatal, or postnatal etiologic factors (4). Normal neurologic examination must be confirmed. Blood and urine tests must be performed to exclude infectious or metabolic disorders (complete blood test, VES, organic acids, lactate, pyruvate, ammonia, etc.). Examination of cerebrospinal fluid is justified only if encephalitis is suspected, or in the presence of fever or alterations in blood values. Because the seizures are repetitive, EEG or video-EEG monitoring is advisable, as this will facilitate the recording of a seizure (1,3,4). The interictal EEG is normal. The ictal EEG demonstrates focal discharges of fast activity intermixed with spikes that usually spread to neighboring areas or the whole brain. Onset may be frontal, temporal, parietal, or occipital, and may vary in location and side between seizures in the same patient (1). In secondarily generalized seizures, ictal EEGs show focal discharges of low-voltage fast waves or rhythmic or repetitive sharp waves or spikes of increasing amplitude and decreasing frequency, which characteristically have an onset on one hemisphere and end on the contralateral side (Figures 15.1 and 15.2).

Prognosis

By definition, seizures remit within few months from onset. Benign outcome is an integral part of diagnosis. Development is normal. In untreated cases there can be isolated or brief clusters within this infantile period of life (2,3). The EEG at follow-up is normal. In infantile convulsions and choreoathetosis syndrome, choreoathetotic manifestations appear, usually during late childhood or adolescence (23).

Management

Although benign partial epilepsies and other benign infantile seizures have a tendency to spontaneous remission, seizures often occur in clusters, and the benignity of the condition cannot usually be ascertained from the beginning (1,2,4). Therefore, an antiepileptic drug (AED) may be administered for a certain period. However, there is no consensus as to the choice of an AED and the period of administration. Various AEDs have been tried, but the efficacy of each drug is difficult to assess because of the tendency toward spontaneous remission. Breakthrough seizure rates while on AED treatment were 11% to 37%; the highest was in the population in which phenobarbital was mainly used. However, there are reports in the literature of equally effective treatment with carbamazepine, valproate, or zonisamide (1,4).

BENIGN FAMILIAL NEONATAL-INFANTILE SEIZURES

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