Partial epilepsy in neurologically normal children: clinical syndromes and prognosis

A clinical and electroencephalographic study of 107 neurologically normal children with partial seizures was undertaken to verify the existence and determine the frequency of epileptic syndromes reported in selected populations. Sixty-three children had simple partial seizures, 39 had complex partial seizures, and 5 children were unclassifiable. The syndrome of benign partial epilepsy of children with rolandic spikes (BPEC, 38 cases) was clearly identified and its uniformly benign final prognosis was confirmed even if some of these children had at times severe or poorly controlled seizures. Among the children with simple partial seizures outside the BPEC (25 cases) and complex partial seizures (39 cases), no homogeneous clinical or electroclinical subgroup could be found. Two children with benign partial epilepsy and myoclonic-astatic seizures ("atypical benign partial epilepsy of childhood") and one child with "benign epilepsy with occipital spike-waves" were identified. 74% of children with epilepsy with complex partial seizures (ECP) had a 1-year seizure-free interval, and many children with epilepsy with simple partial seizures outside the BPEC group (ESP) had no more than two seizures. A benign course is thus not limited to the BPEC but is difficult to predict. Prospective studies are necessary to confirm the existence of well-defined benign syndromes among the idiopathic partial epilepsies of childhood, which appear quite rare outside the BPEC.     

Epileptic Syndromes in Infancy and Childhood: Recent Advances

Summary: Epileptic syndromes are more reliable than etiology in determining prognosis and optimal treatment in infants and children. Benign neonatal and infantile convulsions are either idiopathic or dominantly inherited, the latter being genetically nonallelic. Forms of idiopathic generalized epilepsy (IGE) include absence epilepsy, benign myoclonic epilepsy of infancy, and epilepsy with generalized myoclonic atonic seizures. Forms of idiopathic partial epilepsy include benign partial epilepsy with centrotemporal spikes (BECT), benign partial epilepsy with occipital paroxysms, idiopathic partial epilepsy with affective seizures, and benign partial epilepsies with extreme somatosensory evoked potentials (SEPS). These idiopathic epilepsies appear to result from a multifactorial genetic predisposition. The diagnosis is based on strict clinical and EEG criteria. In epileptogenic encephalopathies, cognitive disorders are the main feature and are linked to so–called interictal abnormalities. Some epileptic syndromes, particularly myoclonic epilepsies, remain unclassifiable because of poor understanding of nosology or heterogeneous outcome.     

Catastrophic Epilepsy in Childhood

Summary: Although for most children epilepsy is a relatively benign disorder, for some, epilepsy can be designated as "catastrophic" because the seizures are so difficult to control and because they are strongly associated with mental retardation. The catastrophic childhood epilepsies include uncommon disorders such as early infantile epileptic encephalopathy with suppression burst, severe myoclonic epilepsy of infancy, and epilepsy with myoclonic-astatic seizures. There are other syndromes that are relatively common such as infantile spasms, Lennox-Gastaut syndrome, and Sturge-Weber syndrome. Many children with catastrophic epilepsy have the seizures as a result of underlying brain abnormalities that will inevitably lead to mental retardation whether or not they have seizures. In some patients, however, the mental retardation appears to be caused by the seizures. Developmental plasticity provides children with an opportunity to recover from significant brain injuries. However, the plasticity may also be the cause of the mental retardation. In such patients, control of the seizures may lead to more normal intellectual development. Thus, every effort should be made to control seizures in children with catastrophic epilepsy.     

Video electroencephalographic diagnosis of epileptic and non-epileptic paroxysmal episodes in infants and children at the pre-school age

The main usefulness of video electroencephalographic (video-EEG) monitoring lies in the fact that it allows proper classification of the type of epileptic seizure and epileptic syndrome, identification of minor seizures, location of the epileptogenic zone and differentiation between epileptic seizures and non-epileptic paroxysmal manifestations (NEPM). In infants and pre-school age children, the clinical signs with which epileptic seizures are expressed differ to those of older children, seizures with bilateral motor signs such as epileptic spasms, tonic and myoclonic seizures predominate, and seizures with interruption of activity or hypomotor seizures, and no prominent automatisms are observed. In children with focal epilepsies, focal and generalised signs are often superposed, both clinically and in the EEG. NEPM may be benign transitory disorders or they can be episodic symptoms of different neurological or psychopathological disorders. NEPM are often observed in children with mental retardation, neurological compromise or autism spectrum disorders, who present epileptic seizures and epileptiform abnormalities in the baseline EEG. It then becomes necessary to determine which episodes correspond to epileptic seizures and which do not. The NEPM that are most frequently registered in the video-EEG in infants and pre-school age children are unexpected sudden motor contractions ('spasms'), introspective tendencies, motor stereotypic movements and paroxysmal sleep disorders.     

Epilepsy syndromes in infancy

An increasing number of infantile epilepsy syndromes have been recognized. However, a significant number of infants (children aged 1-24 months) do not fit in any of the currently used subcategories. This article reviews the clinical presentation, electroencephalographic findings, evolution, and management of the following entities: early infantile epileptic encephalopathy, early myoclonic epilepsy, infantile spasms/West syndrome, severe myoclonic epilepsy of infancy, myoclonic-astatic epilepsy, generalized epilepsy with febrile seizures plus, malignant migrating partial seizures of infancy, hemiconvulsions-hemiplegia-epilepsy, benign myoclonic epilepsy, and benign familial/nonfamilial infantile seizures. Issues related to their classification are addressed.     

Two epileptic syndromes, one brain: childhood absence epilepsy and benign childhood epilepsy with centrotemporal spikes

Childhood absence epilepsy (CAE) and benign childhood epilepsy with centrotemporal spikes (BCECTS), or benign rolandic epilepsy (BRE), are the most common forms of childhood epilepsy. CAE and BCECTS are well-known and clearly defined syndromes; although they are strongly dissimilar in terms of their pathophysiology, these functional epileptic disturbances share many features such as similar age at onset, overall good prognosis, and inheritance factors. Few reports are available on the concomitance of CAE and BCECTS in the same patients or the later occurrence of generalized epilepsy in patients with a history of partial epilepsy. In most cases described in the literature, absence seizures always started after the onset of benign focal epilepsy but the contrary has never occurred yet. We describe two patients affected by idiopathic generalized epileptic syndrome with typical absences, who experienced BCECTS after remission of seizures and normalization of EEG recordings. While the coexistence of different seizure types within an epileptic syndrome is not uncommon, the occurrence of childhood absence and BCECTS in the same child appears to be extremely rare, and this extraordinary event supports the hypothesis that CAE and BCECTS are two distinct epileptic conditions. However, recent interesting observations in animal models suggest that BCECTS and CAE could be pathophysiologically related and that genetic links could play a large role.     

Infantile epilepsy associated with mosaic 2q24 duplication including SCN2A and SCN3A

Epilepsies can be caused by specific genetic anomalies or by non-genetic factors, but in many cases the underlying cause is unknown. Mutations in the SCN1A and SCN2A genes are reported in childhood epilepsies; in particular SCN1A was found mutated in patients with Dravet syndrome and with generalized epilepsy with febrile seizures plus (GEFS+). In this paper we report a patient presenting with an atypical epileptic syndrome whose phenotype partially overlaps both Dravet syndrome and benign familial neonatal-infantile seizures (BFNIS). Array-CGH analysis suggested the presence of a mosaic duplication (about 12Mb) at the level of chromosome 2q23.3q24.3 involving SCN2A and SCN3A genes. Additional analyses (radiolabeled RFLP and quantitative PCR) confirmed the mosaicism of the duplication. We suggest that the array-CGH analysis is mandatory for children presenting with epilepsy and psycho-motor retardation even without dysmorphisms or other clinical features suggesting a specific genetic/epileptic syndrome. The analysis must nevertheless be performed taking into account the possibility of a mosaicism.     

Epileptic syndromes in infancy and childhood

PURPOSE OF REVIEW: The aim of this article is to review new epilepsy syndromes, acquire a new understanding of older ones and emphasize the impact of this concept on basic research regarding aetiology and treatment. RECENT FINDINGS: In addition to those included in the classification of the International League Against Epilepsy, new epilepsy syndromes comprise febrile seizures plus, benign familial neonatal-infantile seizures (BFNIS), benign infantile focal epilepsy with midline spikes and waves during sleep (BFIS), malignant migrating partial seizures in infancy, devastating epilepsy in school age children and late onset cryptogenic spasms. Genetics played a central role in identifying some new entities (BFNIS, BFIS with choreoathetosis), to delineate older syndromes (Dravet syndrome and myoclonic astatic epilepsy) and determine their mechanisms (infantile spasms, pyridoxine dependent seizures, neonatal encephalopathy with suppression bursts). SUMMARY: A significant number of children, mainly infants, do not fit in any of the described epilepsy syndromes. Still many patients with infantile epilepsy require the identification of cause or recognition of an epilepsy syndrome.     

Convulsions infantiles bénignes familiales et non familiales : une entité homogène ?

Among the epileptic syndromes occurring during infancy, which are mostly non-idiopathic and associated with a poor prognosis, benign infantile convulsions are characterized by a favourable evolution. This work aims to analyse and compare the clinical, EEG and outcome characteristics of familial benign infantile convulsions (FBIC) and non-familial benign infantile convulsions (NFBIC). This is a retrospective study, conducted between 1988 and 2008, in 40 infants who presented benign infantile seizures during the two first years of life. All of them had no personal history, normal psychomotor development, normal neurological examinations, no abnormalities on biological and radiological investigations and a favourable outcome. In 14 cases, there was a familial history of familial benign infantile convulsions. However, among the 26 cases with non-familial benign infantile convulsions, 11 children had a familial history of other epileptic syndrome. That may suggest a genetic familial susceptibility. In the two groups, the clinical features and the electroencephalography were similar. The seizures had short duration and occurred most often in clusters. Twenty-nine children had secondarily generalized partial seizures and 11 infants had generalized seizures but a focal onset cannot be excluded. The antiepileptic drugs allowed rapid resolution of seizures. One child necessitated a prolonged antiepileptic treatment. In the other cases, seizures cured in the first year without recurrence of seizures after treatment discontinuation. The evolution was characterised in five children by a later occurrence of dystonia. This subgroup was described as infantile convulsion and choreoathetosis syndrome (ICCA). Benign infantile convulsions are probably an underestimated epileptic syndrome. The diagnosis is relatively easy in the familial forms with dominant autosomal transmission. In contrast, in sporadic forms, the diagnosis can be confirmed only by the evolution. The good prognosis must be tempered by the subsequent onset of dystonia consisted in the ICCA syndrome and justifies a prolonged follow-up.     

Somatosensory evoked spikes and epileptic seizures: a study of 385 cases.

We examined 385 children whose EEG showed high voltage potentials evoked by taps applied to one or both feet or hands (SES). The relationship between characteristics of SES and the occurrence of epileptic seizures and the characterization of epileptic syndromes were studied. Ninety-one children (23.6%) had epilepsy, 42 (10.9%) had only febrile convulsions and 252 children had other complaints. Epilepsy occurred in a higher proportion of cases when: SES by foot tapping were multiphasic, with high amplitude or SES were obtained by hand stimulation and there was spontaneous epileptiform activity in the EEG. The following epileptic syndromes were diagnosed: benign childhood epilepsy with centrotemporal spikes in 21 cases, benign epilepsy of childhood with occipital paroxysms in 2, benign psychomotor epilepsy in 1, "partial idiopathic others" in 43, generalized idiopathic in 8, symptomatic epilepsies in 13 and undetermined in 3 cases. In most cases SES were observed in children without evidence of cerebral organic lesion, suggesting the existence of an age-related, functional mechanism. Some characteristics of SES and the occurrence of spontaneous epileptiform activity showed a positive association with epileptic seizures. SES occurred in different types of partial and generalized epilepsies of childhood but in nearly 50% of the cases with epilepsy, there was a benign condition involving mainly the parietal lobe with versive, unilateral and sleep-generalized seizures.     

Primary generalized epilepsy during infancy and early childhood

The present study delineates a benign generalized epileptic disorder during infancy and early childhood similar to the well-defined syndrome of primary generalized epilepsy in adolescence. The inclusion criteria for the study required infants under the age of 4 years mainly presenting with generalized nonfebrile seizures, requiring corroboration with generalized epileptic discharges on electroencephalograms (EEGs); an unremarkable pregnancy, labor, and perinatal course; a favorable response to antiepilepsy drugs, preferably monotherapy; and a normal cognitive outcome. The clinical features of seizures, EEG correlates, response to medications, developmental outcome, and family history were analyzed. Twenty-five infants fulfilled the inclusion criteria, presenting at ages 4 to 36 months (mean 17 months) with recurrent generalized clonic seizures, which were commonly short-lived, lasting up to 5 minutes; two infants also had status epilepticus. Fourteen infants (56%) had accompanying febrile seizures, which preceded the nonfebrile seizures in 10 of them. A positive family history of seizures was found in 8 (32%) patients. Analysis of the EEG showed generalized epileptiform discharges in the form of 3 to 4 Hz spike-wave and normal background activity in 21 patients (84%), with a photosensitive response induced in 3 children. A larger group of 18 infants promptly responded to therapy, mainly valproic acid, which was terminated after 2 years, along with EEG normalization and no recurrence of seizures. A smaller group of 7 patients require prolonged therapy that keeps them seizure free; the EEG remains paroxysmal, and the seizures could recur when treatment is discontinued. All patients are presently seizure free within a follow-up period of 1.5 to 14 years. Their cognition is normal, but 12 patients have short attention and concentration spans, impulsiveness, and learning difficulties. As such, the data presented here delineate an idiopathic generalized epileptic disorder during infancy with a benign course, a rapid response to therapy, and preservation of cognitive skills that may be added to the current classification of the epileptic syndromes.     

The spectrum of benign infantile seizures

Benign epilepsies during infancy are a wide topic, which needs both clinical and nosological clarifications. Already in 1963 Fukuyama reported patients with seizures during infancy with a benign outcome. In the late 80s and early 90s, Watanabe reported series of infants with complex partial seizures or partial seizures with secondary generalization, with a normal development before onset and a benign outcome. In the same years Vigevano focused on familial cases: he described several families with seizures with onset around the 6-month of age, and autosomal dominant mode of inheritance. To define this condition, he coined the term "benign familial infantile seizures" (BFIS). Afterwards, studying families with this phenotype, loci on chromosomes 19, 16 and 2 responsible for BFIS were detected. Similar loci were found in families affected by BFIS and subsequent choreoathetosis, and BFIS associated with familial hemiplegic migraine. In most recent years a new form of benign epilepsy has been proposed, with an intermediate onset between the neonatal and infantile age, which was defined with the term benign familial neonatal-infantile seizures (BFNIS). This condition could have some clinical and genetic features overlapping with BFIS. Seizures with a benign outcome have been reported also in infants during episode of mild gastroenteritis (BIS with MG) frequently with positive Rotavirus antigen. Lastly, sleep EEG abnormalities have been reported in children with a peculiar form of epilepsy by Capovilla, who defined this condition as benign infantile focal epilepsy with midline spikes and waves during sleep (BIMSE). Some of these entities have been included in the last classification proposed by the ILAE and have been differentiated in familial and non-familial forms. The aim of this review is to describe these entities, discuss their nosological aspects, pointing out the similarities and differences with benign neonatal seizures and benign focal epilepsies appearing later in life such as early-onset benign occipital seizure susceptibility syndrome (EBOSS), or benign epilepsy of childhood with centro-temporal spikes (BECTS).     

Epilepsy and brain tumours in children

Although epilepsy is one of the clinical manifestations of brain tumour in one out of three children, such tumours are only found in 1 to 2% of epileptic children explored. When epilepsy reveals the tumour, the latter is benign in 9 out of 10 cases: usually an astrocytoma, an oligodendroglioma or a mixed oligoastrocytic tumour. These tumours accounted for 84% of benign tumours of the cerebral hemispheres among children treated by surgery in our department at the Enfants Malades hospital, Paris; 76% of them had been revealed by epileptic seizures. Among other lesions responsible for epilepsy were 2 cavernous angiomas and 6 thrombotic angiomas. Brain tumours were located in the temporal lobe in almost one half of the cases. The type of epileptic attack was variable, but complex partial seizures were the majority (47%). Several types were associated in 30% of the cases. Surgery was the only treatment in view of the very low recurrence rate. In 80% of the case, removal of the tumour was sufficient to suppress epilepsy. 71% of the children operated upon have an IQ of more than 80; 77% have normal schooling.     

Overtreatment in children with epilepsy

Children with epilepsy are at risk for overtreatment, defined as the use of an excessive number or amount of antiepiletic drugs (AEDs). While the extent of overtreatment of epilepsy in children is not known, there is increasing awareness that overtreatment with AEDs contributes to the morbidity associated with childhood epilepsy. Reasons for overtreatment include using AEDs in a child with seizures who does not require therapy, choosing an inappropriate AED for the seizure type or syndrome; treating non-epileptic behaviors as seizures, use of polytherapy when monotherapy would suffice, and inadequate therapeutic options. Despite the introduction of eight new AEDs in the United States during the last decade, many children continue to be treated with the older generation sedative AEDs. Numerous investigators have now demonstrated that sedative AEDs can be safely removed from the drug regimen of children with epilepsy with resultant improvement in behavior, alertness, and improved seizure control. However, the biggest obstacle to overtreatment is the lack of effective therapies for many of the childhood epileptic syndromes. Until there are more effective therapies developed it is highly likely that children will continue to be over-medicated on ineffective and detrimental AEDs.     

Acquired epileptiform aphasia in children (Landau-Kleffner syndrome)

The association of a language disorder with epilepsy is frequent in children, but there is usually no causal relationship. In acquired epileptiform aphasia (AEA), the so-called Landau-Kleffner syndrome, there is increasing evidence that the language disorder is directly caused by epileptic discharges in critical language areas and must be viewed as a special kind of epileptic aphasia. This is based on a review of the published cases of AEA over the last 30 years and on the analogies that can be made between AEA and other epileptic syndromes, mainly benign partial epilepsy with centrotemporal spikes. AEA can start early in development and present as developmental dysphasia. It is only one among other cognitive or behavioral disturbances that can be epileptic manifestations of some particular epileptic syndromes, for example, epilepsy with continuous spike waves during slow sleep, which probably has the same pathophysiology as AEA. AEA must be seen, at least in some cases, as a particular form of resistant epilepsy. AEA is an important model because it suggests that isolated cognitive and behavioral disturbances can be epileptic manifestations in children.     

Atypical benign partial epilepsy: recognition can prevent pseudocatastrophe

To characterize and distinguish atypical benign partial epilepsy of childhood among various epileptic syndromes, we conducted a clinical and electroencephalogram study. Seventeen children with atypical benign partial epilepsy of childhood were followed at our hospital. They all underwent a video/polygraphic study of characteristic daily seizures, facilitating a diagnosis of atypical benign partial epilepsy of childhood. Their clinical and electroencephalogram features were retrospectively analyzed. A video/polygraphic study indicated negative motor seizures including epileptic negative myoclonus, atonic absence seizures, or atonic seizures corresponding to spike-and-wave complexes arising from centro-parieto-temporal regions. Early in the clinical course, these seizures appeared every 4 ± 2 months, and lasted 1-3 months. Interictal sleep electroencephalograms, initially localizing in the centro-parieto-temporal regions, became widespread and displayed continuous, diffuse, spike-and-wave complexes, although the spike-wave index did not exceed 85%. Negative motor seizures responded to ethosuximide, corticotropin, and high-dose steroid, whereas other antiepileptic drugs were much less effective. All patients ultimately entered remission before age 12 years. Patients with atypical benign partial epilepsy of childhood exhibited a characteristic clinical course, and responded favorably to anti-absence treatment. Atypical benign partial epilepsy of childhood should be recognized as a discrete epileptic syndrome. Its early diagnosis leads to the prevention of pseudocatastrophe.     

Familial benign nonprogressive myoclonic epilepsies

Work on the classification of epileptic syndromes is ongoing, and many syndromes are still under discussion. In particular, special difficulty still persists in correctly classifying epilepsies with myoclonic seizures. The existence of special familial epileptic syndromes primarily showing myoclonic features has been recently suggested on the basis of a clear pattern of inheritance or on the identification of new chromosomal genetic loci linked to the disease. These forms in development include familial infantile myoclonic epilepsy (FIME), benign adult familial myoclonic epilepsy (BAFME), or autosomal dominant cortical myoclonus and epilepsy (ADCME), and, maybe, adult-onset myoclonic epilepsy (AME). In the future, the identification of responsible genes and the protein products will contribute to our understanding of the molecular pathways of epileptogenesis and provide neurobiologic criteria for the classification of epilepsies, beyond the different phenotypic expression.     

The benign partial nonrolandic epilepsies

Although rolandic epilepsy is the only epileptic syndrome that, at present, fully meets all the criteria of benignity and is widely recognized as such, there are also other forms of partial epilepsy that are benign. These are also genetically determined and age-dependent, occurring in neurologically intact children older than 18 months of age. As a rule, the seizures are brief and infrequent, usually responding well to antiepileptic drugs and remitting spontaneously before adulthood. The EEG background is normal, the morphology of the spikes is typical, and they are activated by sleep; generalized spike-wave discharges may occur. During the past decade, there have been reports of a number of additional syndromes of benign partial epilepsy. These include benign occipital epilepsy (the most common in this group), benign frontal epilepsy, benign epilepsy with affective symptomatology (or benign psychomotor epilepsy), benign epilepsy with extreme somatosensory evoked potentials, benign partial epilepsy of adolescence, and benign epilepsy associated with multiple spike foci. The Landau-Kleffner syndrome is often included among the benign epilepsies. These nonrolandic benign epilepsies are described in detail, and the relevant literature is reviewed.     

Benign childhood epilepsy with centrotemporal spikes: is it always benign?

Most children with benign childhood epilepsy with centrotemporal spikes have few seizures, and some have only one. We describe two children with interictal and ictal findings consistent with this epileptic syndrome but with severe intractable seizures and cognitive decline that resulted in consideration for epilepsy surgery. Spontaneous remission occured in one child; the other is still young. Despite the high seizure burden and cognitive decline, surgical consideration should be withheld, as these seizures are likely to remit.     

Concepts of Epilepsy

Summary: The word “epilepsy” refers to a group of disorders characterized by recurrent epileptic seizures. Differential diagnosis first requires distinction between epileptic seizures and the many systemic, neurologic, and psychiatric disorders associated with paroxysmal behaviors that might be mistaken for epilepsy. By definition, isolated epileptic seizures that occur as a natural reaction to a noxious insult are not sufficient evidence for a diagnosis of epilepsy. Many factors contribute to the appearance of an epileptic condition, including nonspecific predisposing factors that alter the threshold for epilepsy and specific epileptogenic disturbances that cause chronic epilepsy to become manifest in susceptible individuals, both of which can be either genetic or acquired. Endogenous or exogenous precipitating factors determine when specific ictal events occur. The many clinical expressions of epileptic seizures reflect the location and extent of the cerebral disturbance, as well as diverse fundamental mechanisms that involve alterations of excitatory and inhibitory influences, resulting in hyperexcitability, hypersynchronization, or both. The various forms of epilepsy and epileptic syndromes are defined by a constellation of signs and symptoms that include characteristic seizure types, other clinical features, and family history. Whereas treatment is largely based on seizure type, identification of a specific epileptic syndrome often provides additional insights into management and prognosis. An example of the usefulness of syndromic classification is the existence of surgically remediable syndromes that have a known poor prognosis with pharmacotherapy, but an excellent prognosis with surgical intervention. Research on underlying basic mechanisms of the epilepsies, particularly molecular genetics designed to identify specific biological defects in idiopathic epilepsies and invasive investigations carried out in the epilepsy surgery setting to elucidate the pathophysiology of symptomatic epilepsies, may reveal definitive substrates that will ultimately permit epileptic syndromes to be reclassified as diseases.