Benign Childhood Epilepsy

Epilepsy is defined as 2 or more unprovoked seizures. The various types of epilepsy differ in many aspects, including (1) age of onset, (2) semiology, (3) EEG findings, and (4) outcome. In 1987, Freeman et al reported that most children with generalized tonic-clonic seizures have a benign developmental disorder that reduces their seizure threshold and will be outgrown. ^[1] This disorder has been termed benign childhood epilepsy and is thought to be secondary to central nervous system (CNS) immaturity.

In this article, the term benign epilepsy is used to refer to a group of pediatric epileptic disorders in which remission and lack of significant neurologic sequelae are expected in the vast majority of patients. These disorders are idiopathic, occur in otherwise healthy children, and have (with rare exceptions) a strong genetic component. They include generalized epilepsies and partial epilepsies. These epilepsies are presented according to the age of onset, starting from the neonatal period.

Benign epilepsies in the neonatal period

Although the prognosis of neonatal convulsions remains poor, benign neonatal convulsions are differentiated by their generally good prognosis. Two syndromes in which no metabolic, hypoxic-ischemic, or structural etiology is apparent are benign familial neonatal convulsions and benign idiopathic neonatal convulsions. (Regarding the former syndrome, some authors prefer to identify it by the term familial neonatal convulsions, dispensing with the adjective benign.)

Benign generalized epilepsies in childhood and adolescence

These include generalized, as well as partial, epilepsies. The generalized epilepsies discussed are limited to childhood absence epilepsy, which is also called pyknolepsy, and juvenile absence epilepsy, also known as epilepsy with nonpyknoleptic absences or epilepsy with spanioleptic absences.

The benign partial epilepsies include benign partial epilepsy of childhood with centrotemporal spikes, benign occipital epilepsy, and benign epilepsy with affective symptoms.

Go to Epilepsy and Seizures for a general overview, and see the following articles for information on these specific disorders:

• First Pediatric Seizure

• Benign Neonatal Convulsions

• Neonatal Seizures

• Pediatric Status Epilepticus

• Myoclonic Epilepsy Beginning in Infancy or Early Childhood

• Juvenile Myoclonic Epilepsy

• EEG in Common Epilepsy Syndromes

• Generalized Epilepsies on EEG

Epidemiology

In a study from Finland, the point prevalence of active epilepsy was found to be 3.93 per 1000 in children aged 0–15 years; almost 1% of the patients had benign familial neonatal convulsions. Based on reports of 77 cases, boys constituted the majority (43 boys and 34 girls).

Clinical characteristics

Seizures occur in otherwise healthy neonates. Onset is usually in the first week of life; in 80% of patients, onset is on day 2 or 3 of life. However, seizures can occur any time in the neonatal period until age 3 months. Seizures may occur during sleep or wakefulness, frequency is 3–6 per day, and duration is brief (commonly 2–60 s). Seizure types vary; however, seizures most often are multifocal clonic, followed in frequency by focal clonic. In most cases, seizures are associated with cyanosis due to apnea. Generalized tonic seizures occur less commonly. Seizures may be precipitated by feeding.

Electroencephalography

Benign familial neonatal convulsions have been proven to be epileptic by electroclinical correlation. The following variable patterns are reported in interictal encephalography: (1) normal, (2) discontinuous, (3) focal or multifocal sharp waves or epileptiform patterns, and (4) theta pointu alternant. ^[2]

The reported ictal electroencephalogram (EEG) may show either focal or generalized patterns. Recordings of focal ictal patterns have led some authors to question the appropriateness of the current international classification of benign familial neonatal convulsions as generalized seizures. The suggestion has been made that expression of a generalized seizure may be asymmetrical, probably because the immaturity of the corpus callosum or other related structures prevents synchronization. The electroclinical events occurring in benign familial neonatal convulsions can occur in other types of neonatal seizures.

Genetics

Benign familial neonatal convulsion was first linked to a gene locus on arm 20q. However, genetic heterogeneity was suggested (and later established) after identification of another gene locus on band 8q24. Approximately 80% of benign familial neonatal convulsion pedigrees are due to a genetic defect on 20q13.3. 

In 1998, the genes responsible for benign familial neonatal convulsions were identified as voltage-gated potassium-channel genes (KCNQ2 on chromosome arm 20q and KCNQ3 on arm 8q). Transmission is by autosomal dominant fashion with incomplete penetrance, although some cases arise de novo. 

No correlation between the type of mutations involving KCNQ2 and KCNQ3 and the severity of the phenotype has been found. 

Treatment

Phenobarbital is the most commonly used drug for treatment of benign familial neonatal convulsions; it is effective in about 75% of patients. Valproic acid and phenytoin also have been tried in some patients. Levetiracetam more recently is the drug of choice in many institutions.

Although prolonged therapy with antiepileptic drugs (AEDs) after the first few months of life probably is not warranted, patients (when of appropriate age) and their parents should be counseled regarding the increased risk of subsequent seizures.

Prognosis

Most authors report a favorable prognosis. In a study of 69 affected individuals, seizures stopped by 6 weeks in 68% of cases. The reported range of prevalence of subsequent epilepsy is 11–22%; however, incidence of subsequent seizures after the first year of life is reported to be as high as 40%. Risk of subsequent epilepsy is not restricted to benign familial neonatal convulsions linked to arm 20q.

Psychomotor development is usually normal. Ronen et al reported that 7% of patients had learning disabilities or mild cognitive impairments. ^[3]

Go to Benign Neonatal Convulsions for complete information on this topic.

Benign idiopathic neonatal convulsions represent about 4% of neonatal convulsions. However, the literature reports a significant discrepancy regarding the existence (ignored) and incidence (up to 38% of convulsions in neonates) of this syndrome.

In a study of epilepsy and epilepsy syndromes in children, benign idiopathic neonatal convulsions represented 1% of epilepsies in children younger than 16 years.

The following criteria must be present for diagnosis:

• Normal pregnancy and delivery

• Birth after 39 weeks’ gestation

• Birth Apgar score greater than 8

• Seizure-free interval between birth and seizure onset

• Seizure onset on days 4–6 of life (This is the onset in 80% of cases.)

• Normal neurologic state before and between seizures (at least at the beginning of seizures)

• Clonic and/or apneic seizures (never tonic)

• Normal findings on biological and radiological examinations

• Brief seizures lasting 1–3 minutes

• Interictal EEG with theta pointu alternant pattern

Regarding the last item above, the theta pointu alternant pattern occurs in 60% of cases. The EEG findings may be normal or moderately altered but never of paroxysmal, inactive, or low-voltage type.

Because of the timing of occurrence, these seizures were referred to initially as fifth-day fits. However, this term probably is a misnomer and should be avoided. The etiology is unknown; however, cerebrospinal fluid zinc concentration has been reported to be low in some cases. The diagnosis remains one of exclusion, and other etiologies (eg, metabolic, infectious, structural) must be sought.

Mutations in the genes responsible for benign familial neonatal convulsions could possibly be found in sporadic cases. This was suggested by Ishii et al when they reported a mutation in KCNQ2 gene in a girl with nonfamilial benign convulsions. ^[4] Mutations in the same gene were also reported in 4 other patients. ^[5]

Benign idiopathic neonatal convulsions carry a favorable outcome, with only a few patients reported to have transitory psychomotor retardation until the age of 1 year, febrile or afebrile convulsions, or EEG spikes with no clinical seizures. Risk of late epilepsy is 0.5%.

The following are differences between benign familial neonatal convulsions and benign idiopathic neonatal convulsions:

• Family history is common in benign familial neonatal convulsions but rare (about 2%) in benign idiopathic neonatal convulsions

• Benign familial neonatal convulsions occurs earlier (days 2–3) than benign idiopathic neonatal convulsions (days 4–5)

• Persistence of convulsions is longer in benign familial neonatal convulsions

• Occurrence of epilepsy is more frequent in benign familial neonatal convulsions

Go to Benign Neonatal Convulsions for complete information on this topic.

Benign myoclonic epilepsy of infancy

Of all the myoclonic epilepsies, benign myoclonic epilepsy of infancy (also known as benign infantile myoclonic epilepsy) is distinguished by its appearance early in life and its favorable prognosis. This belongs to the group of primary generalized epilepsies and is probably the equivalent of juvenile myoclonic epilepsy. Since its first description by Dravet and Bureau in 1981, many other cases have been described.

Go to Myoclonic Epilepsy Beginning in Infancy or Early Childhood and Juvenile Myoclonic Epilepsy for complete information on these topics.

Epidemiology

In a review of benign myoclonic epilepsy of infancy, ^[6] Dravet and Bureau found that the syndrome occurs in 7% of children with myoclonus and in 2% of epileptic children aged 1–36 months;  The male-to-female ratio is about 2:1. Age of onset is usually between 4 and 6 months and 3 years, ^[6]  although earlier or later onset has been reported. ^[7]

Genetics

The genetics is unknown. In 78 cases, family history of febrile seizures was present in 17% and history of epilepsy was noted in 27%.

Clinical symptoms

Generalized myoclonic seizures occur in otherwise healthy infants, some of whom (about 25%) have a history of isolated febrile convulsions.

Myoclonia involves the axis of the body and limbs, causing head drops, upward and/or outward movements of the upper limbs with flexing in the lower limbs, and possible rolling of the eyes. Seizures vary in intensity from severe forms (eg, causing the child to fall suddenly) to mild forms (eg, eye closure).

Episodes are brief, lasting 1–3 seconds. Less commonly, episodes may be repeated up to 10 seconds, especially in older children. They do not occur in clusters and are not favored by awakening, but rather by drowsiness. Alertness may be slightly reduced with repeated seizures. The seizures are not associated with other seizure types such as absence or tonic seizures.

Electroencephalography

Findings on interictal waking EEG usually are normal for age. Spontaneous spike-wave (SW) discharges are rare. Almost all SW and polyspike-wave (PSW) discharges have some form of clinical expression.

Drowsiness and early stages of sleep activate generalized SW. During light sleep, they almost always are accompanied by myoclonus. The discharges gradually disappear during slow-wave sleep, as does the myoclonus.

Clinical and EEG photosensitivity are present in one third of patients. Ictal EEG recordings show generalized fast SW or PSW accompanying the myoclonus.

In a study of 22 patients with benign myoclonic epilepsy of infancy, Darra et al reported that the ictal EEG discharges were often focal, being limited to the rolandic and vertex regions, and concluded that seizures are rarely truly generalized. ^[8]

Treatment

Seizures usually are controlled easily by sodium valproate monotherapy. If seizures are not controlled, other proposed medications include benzodiazepines (ie, clobazam, clonazepam) and ethosuximide. Phenobarbital has also been tried. POLG DNA sequencing should be strongly considered prior to initiating valproate due to the risk of fatal liver toxicity (Alpers syndrome).

Evolution and prognosis

The seizure outcome is favorable. The myoclonias have disappeared in all reported patients who were monitored. In most patients, they lasted less than a year, with the longest duration being up to 6 years and 4 months. On long-term follow-up, 18% of patients had other seizure types, with some having rare generalized tonic-clonic seizures.

The psychological evolution of the patients is less favorable than is the clinical evolution of seizures. In 1996, Dravet and Bureau noted that the psychological outcome was normal in 83% of 69 cases in whom the outcome was precisely known. However, this outcome is controversial.

Some authors have indicated that a high incidence of neuropsychological and intellectual disorders occur in patients with benign myoclonic epilepsy of infancy. ^{[9, 10]} In a report by Darra et al on 22 patients, 2 had significant cognitive impairment, and 3 had a significant learning impairment at follow-up. ^[8] The earlier age of onset may be one of the main factors associated with less favorable outcome. Other factors may involve delay in treatment or the efficacy of drugs.

Differential diagnosis in benign myoclonic epilepsy of infancy

Clinical features, as well as the associated EEG findings, help to differentiate benign myoclonic epilepsy of infancy from nonepileptic conditions and other epileptic syndromes.

The following are nonepileptic conditions that may be mistaken for benign myoclonic epilepsy of infancy:

• Physiologic myoclonus

• Benign nonepileptic myoclonus

• Hyperekplexia (startle disease)

• Shuddering attacks

Epileptic syndromes that may resemble benign myoclonic epilepsy of infancy include the following:

• West syndrome

• Severe myoclonic epilepsy in infancy

• Early onset Lennox-Gastaut syndrome

• Myoclonic-astatic epilepsy (Doose syndrome)

Reflex benign myoclonic epilepsy of infancy

In a subgroup of patients, myoclonic jerks may be triggered by tactile or sudden acoustic stimuli, referred to as reflex benign myoclonic epilepsy of infancy. These may or may not be associated with spontaneous jerking. Although some authors have tried to distinguish between reflex benign myoclonic epilepsy of infancy and the classic form, Dravet and Bureau did not think such a distinction was necessary in their 1996 article.

Benign partial epilepsy with complex partial seizures

Described by Watanabe et al, ^[11] complex partial seizures often occur in clusters and are manifested in the following ways:

• Arrested motion

• Staring spells

• Decreased responsiveness

• Automatisms with mild convulsive movements

Features of benign partial epilepsy with complex partial seizures include the following:

• Family history of benign seizures (often)

• Normal development prior to onset

• Onset usually at age 3–10 months (ranges to 20 mo)

• No underlying disorders

• Normal findings on interictal EEGs

• Good response to treatment

• Normal developmental outcome

Epidemiology

Annual incidence has been estimated at 1–8 per 100,000 in children aged 0–15 years, making up 8% of epilepsy cases in school-aged children (probable). Girls represent 60-76% of patients. Onset ranges from ages 3–13 years, with a peak at ages 6–7 years.

Also see Absence Seizures.

Genetics

A positive family history of epilepsy is present in about one third of patients. Febrile convulsions occur. Although an autosomal dominant pattern of inheritance with age-dependent penetrance has been suggested, a multifactorial pattern that involves a combination of genetic and environmental factors is more likely.

One form of childhood absence epilepsy, designated ECA1, has been linked to band 8q24. Fong et al reported this linkage in a patient with childhood absence epilepsy with tonic-clonic seizures. ^[12]

Another form, ECA2, in which patients have absence and febrile seizures, is caused by mutation in the GABRG2 gene on band 5q31.1. This was described by Wallace et al in a large family from Australia. ^[13] Maljevic et al reported a de novo mutation in GABRA1 in a patient with childhood absence epilepsy. ^[14]

A third form, ECA3, is caused by a mutation of the chloride-channel gene CLCN2 on band 3q26. Haug et al identified mutations in this gene associated with the most common types of idiopathic generalized epilepsies. ^[15]

Chen et al reported mutations in the T-type, voltage-gated calcium-channel gene CACNA1H, coding for the alpha-1 H calcium channel Cav3.2. Mutations were present in 14 of 118 patients but not in 230 controls. ^[16]

Other variants in the CACNA1H gene were identified in childhood absence epilepsy, suggesting that this gene is an important susceptibility gene in this epilepsy syndrome in the Chinese Han population, as reported by Liang et al. ^[17]

Cav3.2 mutations and their functional gating effects were also described by Khosravani et al ^{[18, 19]} and by Peloquin et al. ^[20]

Audenaert et al reported a mutation in the sodium-channel gene SCN1B in a family with febrile seizures plus early-onset absence epilepsy. ^[21]

Seizure characteristics

Absence seizures are the initial seizures that occur in developmentally normal children. Seizures are brief, most commonly lasting 5–10 seconds (or 5–30 s, depending on the study). Seizures start and end suddenly, frequently occurring 10–100 times a day. Seizures occur spontaneously but may be precipitated by multiple factors, including emotional, intellectual, or metabolic (eg, hypoglycemia, hyperventilation) ones. Absence status occurs in 10% of cases.

The main feature of absence seizures is loss of responsiveness with cessation of ongoing activity. Depending on the associated symptoms, 6 types of absence seizures can be identified, as follows:

• Simple absence, manifesting only as impaired consciousness (10%)

• Absence with mild clonic components, usually involving the eyelids (50%)

• Absence with atonic components, resulting in gradual lowering of the head or arms (20%)

• Absence with tonic components (rotating the eyes upwards)

• Absence with automatisms that are either perseverative (ie, the patient persists in what he is doing) or de novo, such as lip smacking or swallowing (60%)

• Absence with autonomic components (eg, pupillary dilatation, flushing, tachycardia)

Electroencephalography

The background is usually normal, although mild abnormalities may be accepted. Interictal single or brief bilateral SW discharges are frequent. These are more abundant during non–rapid eye movement (REM) sleep.

During the ictal period, absence seizures are associated with bilaterally synchronous and symmetrical SW discharges that begin abruptly and synchronously in both hemispheres but end less abruptly. The SW discharges occur at a frequency of 3 Hz, may slow to 2–2.5 Hz toward the end, and have the highest amplitude in the frontocentral regions.

Prognosis and evolution

Prognostic parameters need to include the seizure and the psychosocial prognosis. The reported percentage of patients who become seizure free varies widely, ranging from 33–79.3%.

The longer the follow-up, the smaller the percentage of patients whose seizures are controlled; many patients develop generalized tonic-clonic seizures later in the course of the epilepsy.

Absence seizures persist in about 6% of cases (although they become less frequent). Generalized tonic-clonic seizures develop in about 40% of patients. They are infrequent, easily controlled, and generally occur 5–10 years after the onset of absences.

Juvenile myoclonic epilepsy is reported to occur in 44% of patients who do not have remission of their seizures.

Problems with cognition, social adaptation, or behavior are not uncommon. Such difficulties may occur in one third of patients.

Caplan et al, reporting on 69 patients with childhood absence epilepsy and 103 age- and gender-matched children, found that in patients with childhood absence epilepsy, 25% had subtle cognitive deficits; 43% had linguistic difficulties; 61% had a psychiatric diagnosis, particularly attention deficit hyperactivity disorder (ADHD) and anxiety disorders; and 30% had clinically relevant child behavior checklist (CBCL) broad band scores. ^{[22, 2]}

Differential diagnosis

Childhood absence epilepsy must be differentiated from the following conditions:

• Absence seizures with late adolescent onset

• Symptomatic absence epilepsy (eg, Sturge-Weber syndrome, lipidosis, brain tumors, and moyamoya disease ^[23] )

• Epilepsy with other seizure types preceding absences (implying a worse prognosis)

• Myoclonic absences

• Absence seizures associated with an unusual EEG pattern

Treatment

Ethosuximide and valproate each suppress absence seizures in more than 80% of patients. Valproate has the advantage of also controlling generalized tonic-clonic seizures. For refractory seizures, both medications can be used in combination. Lamotrigine may also be effective as monotherapy. According to a Cochrane Database review of the use of ethosuximide, sodium valproate, and lamotrigine in absence seizures, ^[24] evidence was insufficient to recommend a specific medication as a best choice for clinical practice. Levetiracetam ^{[25, 26]} and zonisamide ^[27] may also be effective. Acetazolamide and benzodiazepines, especially clonazepam, are other options. These alternate medications areusefulfor absence status.

In a double-blind, randomized, controlled trial, Glauser et al compared the efficacy of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed absence seizures and found that ethosuximide and valproic acid were more effective than lamotrigine for the treatment of newly diagnosed absence seizures. ^[28]

Children in the study were randomly assigned to treatment with ethosuximide (n =156), lamotrigine (n =149), or valproic acid (n =148). After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%) and were higher than the rate for lamotrigine (29%), while ethosuximide had the lowest side effect profile and thus is the drug of choice for absence epilepsy without convulsive seizures.

Epidemiology

The epidemiology has not been well studied, but juvenile absence epilepsy is less common than childhood absence epilepsy. It is reported to represent 2.4% of epilepsies in children aged 0–15 years, compared with 12.1% for childhood absence epilepsy. Age of onset is 7–16 years with a peak age of 10–12 years. The sexes are affected with equal frequency.

Genetics

Incidence of epilepsy is increased in families of patients with juvenile absence epilepsy; the frequency appears to resemble that in childhood absence epilepsy. One study suggested that allelic variants of the kainate-selective glutamate receptor GluR5 gene (GRIK1) on chromosome subband 21q22.1 contribute a major genetic determinant to the pathogenesis of juvenile absence epilepsy–related phenotypes.

Clinical features

As in childhood absence epilepsy, children with juvenile absence epilepsy usually are neurologically normal. Absence seizures occur in all cases. Compared with childhood absence epilepsy, however, absence seizures in juvenile absence epilepsy have the following features:

• Relative infrequency, with only a few episodes daily

• Longer duration, with a mean of 16 ± 7 seconds

• Less impairment of consciousness

• Less retropulsive in movements

Absence status is relatively common. A tonic-clonic seizure can be the presenting feature, occurring shortly after awakening. This type of seizure occurs in 80% of patients. Myoclonic seizures occur in about 15% of patients.

Electroencephalography

Background is usually normal. Characteristic features are the ictal and interictal generalized symmetrical spike-and-wave discharges with frontal accentuation. The SW frequency usually is a fast SW at 3.5–4 Hz and can be precipitated easily by sleep withdrawal and by hyperventilation. Photosensitivity is unusual.

Treatment and prognosis

Valproate is the drug of choice, because it controls absences and the other associated seizure types in about 80% of cases. Levetiracetam may be effective. ^{[25, 26]} Treatment choices include (1) lamotrigine (either as monotherapy or in combination with valproate), (2) ethosuximide in combination with valproate (keep in mind that valproate inhibits lamotrigine metabolism and may incrase the risk for Stevens-Johnson syndrome) or (3) acetazolamide in combination with valproate. The long-term evolution has not been well established, but the prognosis is worse than that of childhood absence epilepsy.

A benign partial epilepsy of childhood, this condition, benign epilepsy of childhood with centrotemporal spikes (BECTS), is defined within the International League Against Epilepsy (ILAE) classification scheme as an idiopathic age- and localization-related epileptic syndrome with a combination of clinical and EEG characteristics used for diagnosis.

This epileptic syndrome is characterized by brief, simple partial and hemifacial motor seizures with associated somatosensory symptoms, which have a tendency to evolve into generalized tonic-clonic seizures. EEG shows high-voltage centrotemporal spikes often followed by a slow wave. BECTS is also known as lingual epilepsy, sylvian seizures, benign centrotemporal epilepsy, and benign rolandic epilepsy.

If the patient has the typical clinical history and EEG findings and has normal findings on neurologic examination, further workup is not indicated. However, in the presence of atypical features or abnormal examination findings, the use of magnetic resonance imaging (MRI) is indicated. ^[29]

Benign rolandic epilepsy has been reported to occur in the presence of CNS pathology. However, in most of these reported instances, the BECCT was probably coincidental.

Epidemiology

BECTS is the most common epilepsy syndrome in childhood. In Connecticut, USA, it represents 9.6% of all epilepsies in children aged 0–15 years. However, BECTS and its variants may represent 20–25% of epilepsy cases diagnosed in patients aged 5–15 years.

Studies from other countries show that BECTS accounts for 6.5–16% of all childhood epilepsy. In a study from India, however, it represented only 1.6% of epilepsies in children younger than age 16 years. In a study from Italy, epilepsies with rolandic foci accounted for up to 23.9% of epilepsies in children aged 4–15 years.

Reported incidence of seizures with central temporal spikes ranges from 10.7–21 per 100,000. Age of onset ranges from 2–13 years but usually is between 4 and 11 years, and frequency of onset peaks at 5–9 years. The disorder occurs more commonly in boys; the boy-to-girl ratio is 6:4. A study by Kramer et al found no gender difference in incidence. ^[30]

Clinical manifestations of seizures

The syndrome is termed rolandic epilepsy because of the characteristic features of partial seizures involving the region around the lower portion of the central gyrus of Rolando.

Common characteristic features include the following:

• Unilateral somatosensory involvement, mostly of the tongue (occasionally of the inner cheeks, lips, gums, or even a single tooth)

• Speech arrest

• Preservation of consciousness in most cases

• Pooling of saliva

• Tonic or tonic-clonic spread to face

Less often, sensory spread to the face or arms occurs; very rarely, a typical jacksonian march occurs. Other features include (1) absence of psychic symptoms, (2) rarity of complex automatisms, and (3) absence of amnesia and postictal confusion states.

BECTS is associated with the following 3 types of nocturnal seizures:

• Typical brief hemifacial seizures associated with speech arrest, drooling, and preservation of consciousness (identical to diurnal seizures)

• Seizures similar to those described above but with gurgling/grunting noises, loss of consciousness, and, at times, vomiting at the termination of the seizure

• Generalized convulsions (often secondarily generalized)

Although the somatosensory aura is common, it often is missed, because the child is young and the symptoms usually occur at night.

The expression of seizures appears to be age dependent. In older children, pure hemifacial seizures are more common, whereas in younger children hemispheric and generalized convulsions are more frequent.

Seizures can occur during the day or night, although in most children, seizures occur most often during sleep. Seizures occur only during sleep in 51–80% of cases, during both sleep and wakefulness in 5–40% of cases, and only during wakefulness in 0–32% of cases.

Frequency of seizures is usually low. Approximately 10–13% of patients have only a single seizure during the entire course, regardless of AED therapy; 66% have infrequent seizures; and 20% have frequent seizures (sometimes multiple seizures per day).

Occurrence of seizures in clusters is common. Duration of seizures is usually quite brief, ranging from 3–60 minutes; diurnal seizures tend to be shorter, especially the sensory ones. However, associated status epilepticus may be resistant to standard AEDs. One case manifested as an anterior operculum syndrome. Status epilepticus may occur in as many as 11% of patients. Postictal paralysis may occur in 7–21%.

Other clinical features

Headache and migraine occur commonly in patients with BECTS. In one series, recurrent headache was present in 67% of patients with BECTS upon presentation, and up to 80% had migraine reported on follow-up care.

A case-controlled study, however, found no significant difference in migraine incidence between cases and controls.

Febrile seizure history is not uncommon in BECTS.

Neuropsychological assessment

Children with BECTS usually show normal development and intelligence and have normal neurologic examination findings. Considering its prevalence, BECTS may be present in developmentally or neurologically abnormal children. The presence of developmental abnormality does not rule out the diagnosis of BECTS, nor does it necessarily worsen the prognosis. Behavioral and learning problems do occur. ^[31]

Children with BECTS may have problems with visuomotor skills, visuospatial memory and skills, language, and attention; neuropsychological abnormalities are usually transient.

A systematic review on attention impairment in rolandic epilepsy, in which Kavros et al evaluated 14 studies, found that the weight of evidence, defined as the majority of studies evaluated, indicated that attention systems are impaired in children with active centrotemporal spikes. The impairments resolve upon EEG remission. ^[32]

A study by Connolly et al found that the quality of life in children with BECTS may be compromised. ^[33] The compromise, which affects domains such as competence and psychosocial function, may be related to a cognitive variable and the emotional impact of the child's epilepsy on the parent.

No evidence exists to suggest that BECTS causes neurologic or behavioral abnormalities.

Genetics

BECTS is considered to be of genetic origin. Some patients have significant family history of epilepsy or centrotemporal spikes, although the exact frequencies vary, with a range of 9–59%.

Isolated EEG abnormalities (including rolandic spikes) are common in families of patients with BECTS. One study reported that at least 1 close relative had a temporal spike or SW discharge in up to 30% of the families. In another study, 15% of siblings of probands had seizures and rolandic discharges, whereas 19% had rolandic discharges alone.

Centrotemporal sharp and spike activity on EEG has been proposed to be an autosomal dominant trait with age-dependent penetrance. Only 12% of affected individuals have even had a seizure. Penetrance is low during the first 5 years of life, approximates 50% between ages 5 and 15 years, and then drops off to a low value after age 20 years. Whether a given child with the EEG trait develops epilepsy depends on a variety of inherited factors. Therefore, BECTS is inherited multifactorially rather than in an autosomal dominant fashion.

Some individuals with benign neonatal seizures have later developed BECTS. Linkage studies failed to establish a relationship between BECTS and benign familial neonatal convulsions. Two loci previously thought to be linked with BECTS, the human leukocyte antigen (HLA) region on arm 6p and the fragile X site, have been excluded.

In a study, Neubauer et al found evidence for linkage of BECTS to a region on band 15q14. ^[34]

In 1995, a new autosomal dominant syndrome was characterized by rolandic epilepsy, oral and speech dyspraxia, and cognitive dysfunction, with electroclinical features that resembled BECTS. Clinical anticipation was found in the family described in the study, suggesting that the genetic mechanism could be an expansion of an unstable triplet repeat.

Etiology

BECTS arises from the lower portion of the central gyrus of Rolando. Because BECTS is age dependent, has a strong genetic predisposition and an excellent prognosis, and occurs in structurally normal brains, it most likely represents hereditary brain maturation.

Many children with the EEG trait never develop seizures. Whether a child develops seizures depends on many factors, which may be hereditary. There may be an inhibitory factor that is capable of preventing seizures but can be broken through by external or internal elements.

Electroencephalography

EEG findings in BECTS are distinctive. The typical interictal EEG shows centrotemporal spikes or SW, which are either unifocal or bifocal. The spikes are usually slow, high voltage, and diphasic. Typical findings include a negative SW with a blunted peak preceded by a small positive wave and followed by a prominent positive wave with amplitude frequently up to 50% of the preceding negative SW.

When the SWs are unilateral, they are always synchronous in the central and midtemporal areas, although sometimes of different amplitudes. When bilaterally asynchronous, the spikes vary in frequency and amplitude from side to side. They can occur singly or in clusters. In about 40% of patients, the spikes are bilateral on initial or subsequent EEG records.

Sleep and drowsiness activate the spikes. Centrotemporal spikes are present only during sleep in as many as 30% of patients. Obtain a sleep recording if BECTS is suspected on clinical grounds when the awake EEG is not revealing. Spike discharges are not altered significantly by photic stimulation or hyperventilation.

Rolandic spikes usually occur on a normal background. When the spikes occur frequently, however, a focal pseudoslowing occurs that is secondary to the slow-wave component of the spikes.

Typically, the centrotemporal spikes have a horizontal dipole, with maximal electronegativity in the centrotemporal region and electropositivity in the frontal region. This suggests that the spikes are the result of a generator located in the lower rolandic region where the zero potential exists—between the frontal positivity and centrotemporal negativity.

Rolandic discharges having the same dipole field can be seen in children without clinical seizures and in children with epilepsy who do not have typical benign rolandic seizures. The spikes included with BECTS may be located in many areas other than the typical central-midtemporal areas.

The morphology of the spikes (rather than the location) is the distinctive factor in identifying the discharge in association with the benign rolandic epilepsy. Insistence on a centrotemporal location for the EEG may lead to a misclassification of the type of epilepsy. The term benign focal epilepsy of childhood also has been used, and when the discharge is located in the centrotemporal region, it is called benign focal epilepsy of childhood with a centrotemporal (or rolandic) location.

Differential diagnosis

Benign rolandic epilepsy must be differentiated from the following:

• Rolandic spikes and no seizures (often with behavior problems, headaches, or autonomic dysfunction)

• Rolandic spikes and a history of antecedent brain damage, cerebral palsy, or active local pathology

• Central spikes occurring commonly in Rett syndrome and fragile X syndrome

• Malignant rolandic epilepsy

• Psychomotor seizures and evolving temporal lobe epilepsy

• The aphasia-convulsion (Landau-Kleffner) syndrome and massive midtemporal spikes

Treatment

In view of the benign nature of the condition, intensive therapy is unnecessary. In the case of infrequent nocturnal partial seizures, withholding AEDs is reasonable if the child and family are comfortable with this approach. There is insufficient evidence about the medium to longer term effects on seizure control, the optimum antiepileptic drug treatment and the effects of AED treatment on cognition. ^[35]

One study found that in treated patients with BECTS, the frequency and duration seizures and the prevalence of active epilepsy were no different from those in untreated patients with the syndrome.

If treatment is indicated, carbamazepine or oxcarbazepine is often the first medication to be tried, and seizures usually are well controlled. Once-a-day administration may be the only regimen needed to control seizures. Other reportedly effective AEDs include phenobarbital, phenytoin, valproic acid, clonazepam, clobazam, levetiracetam, and gabapentin. ^[36]

Although most patients respond to a low dose of a single drug, a few have seizures that are highly drug resistant. No correlation is known between resistance to AEDs and outcome.

Duration of treatment may be shorter in some cases than epilepsy in general, and AEDs may be discontinued successfully in patients with normal EEG findings who have been seizure free for more than 2 years.

Prognosis

In general, the prognosis of BECTS is excellent, as almost all patients achieve remission by adolescence. This includes patients whose seizures have been drug resistant.

A meta-analysis study on the course of BECTS found that 50% of patients were in remission by age 6 years; by age 18 years, 99.8% of the patients were in remission. Rarely, BECTS can relapse in adulthood; about 2% of patients in BECTS remission experience other seizure types.

The understanding of the syndrome of benign partial epilepsy with occipital paroxysms (also called benign occipital epilepsy of childhood) has evolved significantly with time. The syndrome, as first described by Gastaut, was initially the only childhood occipital epilepsy syndrome recognized by ILAE. It is characterized by seizures that start with visual symptoms, which often are followed by hemiclonic seizures or automatisms and, in some cases, migrainous headaches. The EEG findings include paroxysms of rhythmic occipital and posterior temporal spikes when the eyes are closed.

However, this concept was challenged by Panayiotopoulos in 1989, when he described an early-onset syndrome characterized mainly by ictal vomiting, head and eye deviation, and, sometimes, prolonged periods of loss of awareness. The syndrome was later incorporated into the ILAE as early-onset childhood epilepsy with occipital spikes (Panayiotopoulos type). This is also called Panayiotopoulos syndrome. This was confirmed by many authors, including Panayiotopoulos, Caraballo et al, ^[37] and Lada et al. ^[38] This was found to be a much more common syndrome than the first recognized one, which is now known as late-onset childhood epilepsy with occipital spikes (Gastaut type).

According to a consensus conference, ^[39] Panayiotopoulos syndrome is defined as "a benign age-related focal seizure disorder occurring in early and mid childhood. It is characterized by seizures, often prolonged, with predominantly autonomic symptoms, and by an EEG that shows shifting and/or multiple foci, often with occipital predominance." The group of international researchers in the conference concluded that the syndrome should be classified as an autonomic epilepsy rather than as an occipital epilepsy.

Epidemiology

Benign occipital epilepsy of childhood is less common than BECTS. Prevalence depends on selection criteria. The Panayiotopoulos syndrome is much more common than the late-onset Gastaut-type.

As noted by Panayiotopoulos in 4 independent studies of 607 patients, the prevalence of Panayiotopoulos syndrome was found to be 2.4 times lower than that of rolandic epilepsy. This means that around 6% of children with seizures have Panayiotopoulos syndrome, with the assumption of 15% prevalence of rolandic epilepsy.

Age of onset is 3–6 years in 80% of patients, with a mean age of 5 years and a range of 1–12 years. The Gastaut type of childhood occipital epilepsy is estimated to make up 2–10% of benign childhood partial seizures. The mean age of onset is 8 years, with a range of 3–15 years. Both sexes seem to be affected with equal frequency in both syndromes, although this is not reported consistently.

Clinical features

In Panayiotopoulos syndrome, seizures make up an unusual constellation of autonomic, mainly emetic, symptoms, often with unilateral deviation of eyes and other, more conventional, symptoms. Seizures are nocturnal in about two thirds of patients. The full emetic triad (ie, nausea, retching, vomiting) culminates in vomiting in 74% of seizures.

Other autonomic symptoms may occur, including color change (especially pallor), but also flushing and cyanosis. Pupillary changes, particularly mydriasis, also may occur. Less often, miosis, hypersalivation, and bladder incontinence occur. Even less often, bowel incontinence, abnormal intestinal motility, and cardiorespiratory and thermoregulatory alterations are reported.

Brief apnea and irregular or heavy breathing is reported to occur in 7% of cases. Ictal cardiorespiratory arrest has also been reported. Headache and cephalic auras that may be autonomic manifestations may occur, particularly at onset.

More conventional symptoms may follow, including confusion or unresponsiveness, eye and head deviation to one side (60%), wide opening of the eyes without deviation, speech arrest, hemifacial spasms, and visual symptoms or hallucinations (6–9%). The seizures may end with hemiconvulsions, often with jacksonian march (19%) or generalized convulsions (21%). Ictal syncope or a syncopelike episode has been reported to occur in one fifth of cases. These manifest as the child becoming unresponsive and flaccid.

Typically, the seizures are infrequent but long; 44% have seizures lasting 30 minutes or more, consisting of autonomic status epilepticus. Hemiconvulsive or generalized convulsive status epilepticus is rare (2%). One third of patients have a single seizure only. About half have 2–5 seizures. Only 5% have more than 10 seizures.

In late-onset childhood epilepsy with occipital spikes (Gastaut type), clinical semiology is complex and is characterized by ictal and postictal symptoms. Visual symptoms include (1) transient, partial, or complete loss of vision, (2) elementary or complex visual hallucinations, and (3) visual illusions (eg, micropsia, metamorphosis). Elementary visual hallucinations are the commonest and most characteristic ictal symptoms. These consist of small, multicolored, circular patterns that often appear in the periphery of a visual field, becoming larger and multiplying in the course of the seizure. Nonvisual ictal symptoms include adversive (versive) seizure manifested as tonic deviation of head and eyes. These are the most common of the ictal motor phenomena.

Other motor seizures include (1) hemiclonic convulsions, (2) complex partial seizures with automatisms, and (3) generalized clonic seizures. Other ictal manifestations include dysphasia and dysesthesia. Seizures are commonly diurnal and usually frequent. They are typically short, lasting seconds to less than 3 minutes. Other symptoms include postictal, diffuse, throbbing headache in about half of the patients and vomiting in about 10%. Ictal headache, mainly orbital, is rare.

Typically, children with both syndromes have normal findings on neurologic examinations. However, as with BECTS, neurologic abnormalities or developmental disorders may be present in a small number of children. This was affected by the selection criteria of the authors.

Genetics

Reported numbers regarding family history are affected by selection criteria. A family history of seizures in approximately more than a third of cases and of migraines in about 20% of cases has been reported in patients with late-onset childhood epilepsy with occipital spikes (Gastaut type). In Panayiotopoulos syndrome, reported family history of epilepsy ranged from none to 30% of patients and febrile seizure from 17–25% of patients.

Electroencephalography

In the late-onset Gastaut type, the interictal EEG shows normal background and distinct paroxysms of spikes, spike-and-wave, or SW with high amplitude typically over the occipital and adjacent head regions. These could be unilateral or bilateral and synchronous or asynchronous. Discharges can occur singly or in trains of 1–3 Hz and usually are attenuated by eye opening and occur again with eye closure.

The occipital paroxysms are actually induced by elimination of visual fixation and central vision (fixation-off sensitivity) rather than by darkness. Response to hyperventilation or photic stimulation is variable. Generalized spike-and-wave discharges, multiple spike-and-wave discharges, or central temporal or frontal spikes have been reported. Ictal EEGs show sudden occipital discharges.

The interictal EEG in Panayiotopoulos syndrome commonly reveals functional, mainly multifocal, high-amplitude sharp- and slow-wave complexes, with great variability at various electrode locations. All brain regions are involved, although the posterior predominate. About one third of patients never show occipital spikes.

Some authors have argued not to equate Panayiotopoulos syndrome with occipital epilepsy. ^{[39, 40]} In a study of EEG changes involving 76 children with Panayiotopoulos syndrome, Ohtsu et al found that occipital EEG spike focus was most frequently seen in children aged 2–5 years. ^[41] Frontopolar and occipital spike pattern was seen in seizures of later age of onset.

Differential diagnosis

Occipital spikes, like other focal spikes, can exist without clinical epilepsy. They can also be noted in children with visual impairment.

Benign occipital epilepsy of childhood should be differentiated from other symptomatic forms of occipital lobe seizures due to underlying pathology (eg, atrophic, neoplastic, degenerative). Examples include the following:

• Sturge-Weber syndrome

• Epilepsy with bilateral occipital calcification

• Late infantile neuronal ceroid lipofuscinosis

• Subdural hematoma

• Tuberous sclerosis complex

• Cortical dysplastic tumors

• Inflammatory processes

• Mitochondrial encephalomyopathies

Careful neurologic examination, developmental history, and brain imaging are necessary to verify or rule out the existence of benign primary occipital epilepsy.

Benign occipital epilepsy of childhood should be differentiated from other forms of primary partial epilepsy (eg, BECTS).

Migraines and epileptic syndromes can be confused and often coexist.

Treatment

Carbamazepine or oxcarbazepine may be the drug of choice, although almost all of the classic anticonvulsants (eg, phenobarbital, valproate, benzodiazepines) are effective.

In Panayiotopoulos syndrome, education about the nature and prognosis of the syndrome is the cornerstone of correct management. Regular antiepileptic drug treatment is probably most appropriately reserved for those children in whom seizures are unusually frequent or distressing or are otherwise significantly interfering in the life of the child.

Prolonged seizures may be treated with rescue benzodiazepines. No evidence indicates that any particular antiepileptic drug is more efficacious than any other. ^[39] Although many authors recommend carbamazepine as drug of choice, on rare occasions this medication worsens seizures. ^[42]

Prognosis

Prognosis is generally good but is more favorable with Panayiotopoulos syndrome, which is considered as a remarkably benign condition despite high incidence of autonomic status epilepticus. Seizure frequency, as noted above, is very low. Seizure remission usually occurs within 1–2 years of seizure onset and occasionally up to 8 years, as reported in a series by Caraballo. ^[37] Some patients may develop other seizure types, mostly age-related seizures, such as benign rolandic seizures. In the late-onset childhood epilepsy with occipital spikes (Gastaut type), remission can occur in 50–60% of cases, often within 2–5 years of onset.

In 1995, Della Bernardina et al described a group of 26 children with complex partial seizures in whom affective symptoms (predominantly fear) were the major clinical features. The children were aged 7–17 years.

Epidemiology

Age of onset in the study ranged from 2 to 9 years, with no sexual predilection.

Clinical data

The predominant feature of the seizures in the Bernardina study was sudden terror or fright in the patient, manifested by screaming or yelling or by the patient calling for or clinging to his or her mother. The patient’s terrorized expression was associated sometimes with chewing, swallowing, distressed laughter, arrest of speech, salivation, moaning, or autonomic manifestations (eg, pallor, sweating, abdominal pain).

Associated changes in awareness occurred with no complete loss of consciousness. The mean duration of the events was 1–2 minutes. Postictal lethargy was associated with the events. No tonic, atonic, or tonic-clonic seizures were reported.

Genetics

Family history is positive in 38% of cases. Five of the 26 children in the Bernardina study had a history of febrile seizures.

Electroencephalography

In the Bernardina study, the background activity was normal. Seventy-three percent of the patients had slow spike or slow waves involving the frontotemporal and parietotemporal areas of 1 or both hemispheres. Other abnormalities included unilateral rhythmic frontotemporal or parietotemporal SW and brief bursts of generalized spike waves (alone or in association with the above-mentioned abnormalities).

Prognosis

In the study, the course of the syndrome appeared to be benign; 3 patients never received treatment. Twenty-one patients responded to antiepileptic medications (usually carbamazepine or phenobarbital). In 2 cases, infrequent seizures persisted for months or years despite treatment, but ultimately disappeared.