Seizures, syndromes, and etiologies in childhood epilepsy: The International League Against Epilepsy 1981, 1989, and 2017 classifications used in a population-based cohort.

OBJECTIVE: The study provides updated information about the distribution of seizures, epilepsies, and etiologies of epilepsy in the general child population, and compares the old and new classification systems from the International League Against Epilepsy (ILAE). METHODS: The study platform was the Norwegian Mother and Child Cohort Study. Cases of epilepsy were identified through registry linkages and sequential parental questionnaires. Epilepsy diagnoses were validated using a standardized protocol, and seizures, epilepsies, and etiologies were classified according to the old (ILAE 1981/1989) and new (ILAE 2017) classifications. Information was collected through medical record reviews and/or parental telephone interviews. RESULTS: The study population included 112,744 children aged 3-13 years at the end of follow-up on December 31, 2012. Of these, there were 606 children with epilepsy (CWE). Distribution of seizure types varied by age of onset. Multiple seizure types were common with early onset. Focal epilepsies were the most common, occurring in 317 per 100,000 children in the study population and in 59% of CWE. Generalized epilepsies were found in 190 per 100,000 (35% of CWE). CWE with onset during the first 2 years of life had an even distribution of focal and generalized epilepsies, whereas focal epilepsies became dominant at later ages of onset. A definite cause of epilepsy had been demonstrated in 33% of CWE. The ILAE 1989 classification allowed for a broad syndrome category in 93% of CWE and a defined epileptic syndrome in 37%. With the ILAE 2017 classification, 41% of CWE had a defined epileptic syndrome and 63% had either a defined syndrome or structural-metabolic etiology. SIGNIFICANCE: The distribution of seizures and epilepsies is strongly dependent on age of onset. Despite diagnostic advances, the causes of epilepsy are still unknown in two-thirds of CWE. The ILAE 2017 classifications allow for a higher precision of diagnoses, but at the expense of leaving more epilepsies classifiable only at the mode of onset level.

The classification and differential diagnosis of absence seizures with short-term video-EEG monitoring during childhood.

Absence seizures are idiopathic epilepsies characterized by impairment of consciousness and generalized 2.5-4 Hz spike and slow wave discharges. This prospective study was performed to classify and define properties of subgroups of absence epilepsies. We included 31 patients, of whom seven were in the differential diagnosis group. On admission, absence epilepsy provisional diagnosis was considered in 16 patients clinically and in the other 15 patients based on routine EEG findings. Ictal EEGs were recorded by video-EEG monitoring in 23 of the patients (totally 202 ictal recordings). Patients were diagnosed as childhood absence epilepsy (n=8), juvenile absence epilepsy (n=10), juvenile myoclonic epilepsy (n=3), eyelid myoclonia with absences (n=2), and perioral myoclonia with absences (n=1). Neuroimaging, video-EEG monitoring and especially ictal recordings are important for classification of epilepsies in addition to history, physical examination and routine EEG findings. Video-EEG monitoring is required to classify, to make differential diagnosis and to determine the treatment plan and prognosis.

Early-onset pure absence epilepsy: a distinct epileptic syndrome.

UNLABELLED: Early-onset pure absence epilepsy has not yet considered in the International League Against Epilepsy classification, but several reports have supported its existence as a distinct epileptic syndrome primarily manifesting with typical absences in early childhood. This review summarizes the current understanding on this epilepsy. CONCLUSIONS: Early-onset pure absence epilepsy is a distinct epilepsy characterized by absences starting from a few months to 4 years of age, normal early psychomotor development, good antiepileptic drug seizure control and normal intellectual outcome.

How to diagnose and classify idiopathic (genetic) generalized epilepsies.

Idiopathic or genetic generalized epilepsies (IGE) constitute an electroclinically well-defined group that accounts for almost one third of all people with epilepsy. They consist of four well-established syndromes and some other rarer phenotypes. The main four IGEs are juvenile myoclonic epilepsy, childhood absence epilepsy, juvenile absence epilepsy and IGE with generalized tonic-clonic seizures alone. There are three main seizure types in IGE, namely generalized tonic-clonic seizures, typical absences and myoclonic seizures, occurring either alone or in any combination. Diagnosing IGEs requires a multidimensional approach. The diagnostic process begins with a thorough medical history with a specific focus on seizure types, age at onset, timing and triggers. Comorbidities and family history should be questioned comprehensively. The EEG can provide valuable information for the diagnosis, including specific IGE syndromes, and therefore contribute to their optimal pharmacological treatment and management.

Absence seizures: a review of recent reports with new concepts.

Absence seizures with bilateral spike-wave (SW) complexes at 3Hz are divided into the childhood form, with onset at around 6 years of age, and the juvenile form, with onset usually at 12 years of age. These seizures typically last 9-12s and, at times, are activated by hyperventilation and occasionally by photic stimulation. Generalized tonic-clonic (GTC) seizures may also occur, especially in the juvenile form. There may be cognitive changes, in addition to linguistic and behavioral problems. Possible mechanisms for epileptogenesis may involve GABAergic systems, but especially T-calcium channels. The thalamus, especially the reticular nucleus, plays a major role, as does the frontal cortex, mainly the dorsolateral and orbital frontal areas, to the extent that some investigators have concluded that absence seizures are not truly generalized, but rather have selective cortical networks, mainly ventromesial frontal areas and the somatosensory cortex. The latter network is a departure from the more popular concept of a generalized epilepsy. Between the "centrencephalic" and "corticoreticular" theories, a "unified" theory is presented. Proposed genes include T-calcium channel gene CACNA1H, likely a susceptible gene in the Chinese Han population and a contributory gene in Caucasians. Electroencephalography has revealed an interictal increase in prefrontal activity, essential for the buildup of the ictal SW complexes maximal in that region. Infraslow activity can also be seen during ictal SW complexes. For treatment, counter to common belief, ethosuximide may not increase GTC seizures, as it reduces low-threshold T-calcium currents in thalamic neurons. Valproic acid and lamotrigine are also first-line medications. In addition, zonisamide and levetiracetam can be very helpful in absence epilepsy.

Frontal-onset absences in children: associated with worse outcome? A replication study.

We studied the clinical and electroencephalographic features in 30 children who were diagnosed with childhood absence epilepsy. According to their EEG pattern we divided the 30 children into two groups: group A: 11 children with classical absences whose ictal EEG showed primary generalized spikes and waves and group B: 19 children with frontal onset of the EEG epileptic abnormalities ('frontal group'). In the frontal group, more frequently complex absences were seen. Although the majority of children responded very well to valproate monotherapy, ethosuximide has to be added in 3 children of the frontal group to achieve seizure freedom. In the frontal group, also more learning and behavioural problems were encountered. This study largely confirms a previous study of Lagae et al. [Lagae L, Pauwels J, Monte B, Verhelle J, Vervisch J. Frontal absences in children. Eur J Pediatr Neurol 2001;5:243-251]. It seems that frontal onset absences constitute a specific subtype within the childhood absence epilepsies.

The evaluation of interictal focal EEG findings in adult patients with absence seizures.

PURPOSE: To investigate the focal interictal EEG abnormalities in adult patients with absence seizures (ASs) and to identify their clinical, EEG and semiological correlates. METHODS: Fifty patients older than 18 years, diagnosed as having IGE with AS documented with ictal recordings. Interictal focal sharp or spike-waves and strictly focal paroxysmal slow activity were considered as focal EEG features. The patients having focal EEG features were classified as "Group I", whereas the remaining of them was classified as "Group II". RESULTS: We observed focal findings in 34% of the patients, mainly in frontotemporal (41%), and frontal (29%) regions. There were no significant differences with respect to the clinical parameters such as sex, epilepsy duration, positive family history and the age of the onset between the groups. Psychiatric co-morbidities were significantly higher in Group I when compared to Group II (P=0.00). Accompanying automatisms were higher in Group I, whereas eye deviation during absences was higher in Group II. In Group I, the asymmetry of the ictal discharges was more frequently observed. Focal EEG features were more frequently seen in juvenile absence epilepsy syndrome, without reaching a significance level. CONCLUSION: The focal findings in adult absence epilepsy patients could have some unknown etio-pathogenetic and prognostic implications. We emphasize the cautious interpretation of isolated interictal focal EEG abnormalities to prevent a wrong diagnosis of focal epilepsy in patients who may indeed suffer from generalized epilepsy.

[Current clinical-neurophysiological findings in absence epilepsies]. / Aktuelle klinisch-neurophysiologische Befunde bei Absence-Epilepsien.

According to the international classification of epileptic seizures (1981) generalized seizures present ictal signs indicating seizure onset in both hemispheres whereas focal seizures present ictal signs pointing to one hemisphere at seizure onset. Recent neurophysiological studies using MEG, EEG, and fMRI suggest that in case of idiopathic generalized absence epilepsies, activity predominates in specific networks, which include frontoparietal cortical as well as subcortical areas of both hemispheres. In these network regions, epileptic activity can occur circumscribed and focal as spike or spike-wave activity but also widely distributed, bilateral, and homologous. As a consequence to the classification of "generalized" epileptic seizures and syndromes, it might be possible to distinguish a subgroup: regional bilateral homologous epilepsies. These must be distinguished from a pure culture of focal frontal lobe epilepsies, which can also be accompanied by the lead symptom of absences.

Absence epilepsy in childhood: electroencephalography (EEG) does not predict outcome.

Absence epilepsy is a form of generalized epilepsy commonly seen in children. The clinician is often presented with a patient whose electroencephalogram does not fit the typical absence pattern. The purpose of this study is to more closely examine both typical and atypical absence variants and their outcome. A retrospective chart review was performed on children diagnosed with absence epilepsy over the past 5 years at the University of Alberta. A total of 119 patients were reviewed. Patients were classified with typical or atypical absence seizures following International League Against Epilepsy criteria and electroencephalography (EEG) characteristics. Clinical seizure characteristics, magnetic resonance imaging (MRI), initial response to treatment, and outcome were examined. Seizure characteristics were similar in both the typical and atypical absence groups. Aura, complex automatisms, changes in tone, and incontinence were seen in both groups, although status epilepticus was found only in the atypical group. Associated comorbid conditions such as attention-deficit hyperactivity disorder (ADHD), learning disorders, and enuresis were found equally in both groups. Developmental delay was found more often in the atypical group. Of the typical group, 83% responded to an initial antiepileptic drug (either valproic acid or ethosuximide), whereas only 51% of the atypical group came under control. Remission at 2 years however, was similar between groups, with 76% of the typical group and 71% of the atypical group completely seizure free. Absence seizures in childhood, both typical and atypical, share similar clinical and electroencephalographic features and appear to be part of a continuum. Associated comorbid features such as ADHD, learning disorders, and developmental delay are also seen in both groups. The outcome for both types is excellent, although the atypical variants may be initially more difficult to control.

Are absences truly generalized seizures or partial seizures originating from or predominantly involving the pre-motor areas? Some clinical and theoretical observations and their implications for seizure classification.

In both the current (1981) ILAE Classification of Epileptic Seizures and the recently Proposed Diagnostic Scheme for People with Epilepsy and Epileptic Seizures, typical absence seizures are defined as generalized seizures, implying widespread subcortical and cortical neuronal involvement from onset with impairment of consciousness as the clinical hallmark. Clinical observations from three patients and clinical and experimental data from the literature suggest, however, that: (1) consciousness is retained in many typical absences; (2) the true hallmark of these seizures is arrest of motor initiation due to disturbance of pre-motor area frontal-lobe function; (3) typical absences and partial seizures from these areas may show similar clinical and EEG features and involve the same neuronal circuits. The neuronal system primarily involved in these seizures consists of a relatively limited cortico-thalamo-cortical circuit, including the reticular thalamic nucleus, the thalamocortical relay and the predominantly anterior and mesial frontal cerebral cortex, with the cortex probably acting as the primary driving site. Typical absences thus should not be classified or defined as generalized seizures, particularly since neuropathological and imaging studies increasingly argue for localized structural abnormalities, even in idiopathic or primary generalized epilepsy. These observations further highlight the intrinsic weaknesses of the current classification system for seizures and support further adaptations of the diagnostic system currently under development.

Idiopathic generalized epilepsy of adolescence: are the syndromes clinically distinct?

Juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures (GTCS) on awakening are the three syndromes of idiopathic generalized epilepsy of adolescent onset currently included in the classification of epilepsy syndromes of the International League Against Epilepsy (ILAE). Although they differ in their predominant seizure types, the syndromes share several clinical features, thus giving rise to questions of phenotypic overlap and purity. We studied the clinical features of 101 patients with idiopathic generalized epilepsy beginning in adolescence. A standardized interview was used to elucidate seizure phenomenology, precipitants, frequency, and response to treatment. Groups defined by seizure type were compared and their similarities examined. The group with myoclonic but not absence seizures (21 patients) corresponded to the ILAE syndrome of juvenile myoclonic epilepsy, whereas those with absences but not myoclonus (37 patients) resembled juvenile absence epilepsy. Twenty-six patients shared the features of juvenile myoclonic epilepsy and juvenile absence epilepsy. Epilepsy with GTCS on awakening was not a specific syndromic entity; 10 patients had this seizure type alone. Seven patients were without a syndromic diagnosis. In these patients only GTCS occurred, but neither on awakening nor in the evening period of relaxation. We conclude that whilst syndromes of idiopathic generalized epilepsy of adolescence can be recognized, the current classification does not include all patients. In addition, the boundaries between the syndromes are indistinct, suggesting underlying neurobiological, possibly genetic, relationships.

Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism.

Juvenile absence epilepsy (JAE) is a common subtype of idiopathic generalized epilepsy (IGE). Hereditary factors play a major role in its etiology. The important function of glutamate receptors (GluRs) in excitatory neurotransmission, synaptic plasticity, and neurodevelopment suggests their involvement in epileptogenesis. A tetranucleotide repeat polymorphism in the non-coding region of the kainate-selective GluR5 receptor gene (GRIK1) on chromosome 21q22.1 provides the tool to investigate this candidate gene. The present association and linkage study tested the hypothesis that allelic variants of GRIK1 confer genetic susceptibility to the pathogenesis of JAE. Our family-based association analysis using the haplotype-based haplotype relative risk statistic revealed an association of JAE with the nine-repeat containing allele of the GRIK1 tetranucleotide polymorphism (chi2 = 8.31, df = 1, P = 0.004). Supportive evidence for linkage to a JAE related IGE spectrum (Zmax = 1.67 at GRIK1) under an autosomal dominant mode of inheritance and significant allele sharing (P < 0.05) among the affected family members suggest that allelic variants of GRIK1 contribute a major genetic determinant to the pathogenesis of JAE-related phenotypes.

Long-term prognosis for childhood and juvenile absence epilepsy.

PURPOSE: To analyse prognostic factors for long term seizure remission in patients with childhood (CAE) and juvenile absence epilepsy (JAE). STUDY DESIGN: A retrospective analysis of a hospital based prevalence cohort. METHODS: The cohort consisted of 163 patients (104 females, 59 males) treated at the Universitatsklinik fur Neurologie, Innsbruck between 1970 and 1997. All had absences according to the ILAE classification. Follow up was in 1999 to 2000. We assessed multiple clinical and EEG factors as predictors of outcome and compared a classification according to the predominant pattern of seizure recurrence (pyknoleptic, PA or non pyknoleptic absence, NPA) with the ILAE classification with respect to prognosis. RESULTS: The mean age at seizure onset was 10.9 years (range, 3 to 27); age at follow up was 36.7 years (range, 13 to 81); duration of follow up was 25.8 years (range, 3 to 69). Sixty four patients (39 %) had CAE and 64 (39 %) JAE, while 35 (22%) had typical absences but could not be clearly defined as either CAE or JAE, and were therefore called "the overlap group". Patients with JAE or patients in the overlap group developed more often generalized tonic clonic seizures (GTCS) (p<0.001) and myoclonic attacks (p<0.05) during the course of the disease. At follow up 36 (56 %) of patients with CAE, 40 (62%) with JAE and 19 (54 %) of the overlap group were seizure free for at least two years (p=ns). When classified according to the predominant absence pattern at seizure onset 42 (51%) patients with PA and 53 (65%) with NPA were in remission (p=ns). In a stepwise binary logistic regression analysis the pattern of absence (PA or NPA) together with the later development of additional seizure types (myoclonias or GTCS), but not the CAE/JAE classification was predictive for long term lack of remission with a correct prediction of 66% of all patients. CONCLUSION: Only 58% of patients with absences were in remission after a long term follow up. CAE and JAE are closely related syndromes with large overlap of the age of onset. A classification according to the predominant seizure pattern at onset, together with later development of myoclonic attacks or GTCS is useful in predicting seizure remission in absence epilepsies.

Therapeutic response of absence seizures in patients of an epilepsy clinic for adolescents and adults.

Responses of seizures to therapy is one of the most important prognostic factors in epilepsy. Absences are among the seizure types with a good response to antiepileptic drug treatment and, usually, remission before adult age. Absence patients attending an epilepsy clinic for adults can be expected to represent a group with negative bias because they have not yet remitted. Furthermore, the majority have additional generalized tonic-clonic seizures, which is a recognized negative factor in prognosis. We studied 229 adolescents and adults who were under our care for at least 2 years, and divided them into three groups according to their becoming absence free for at least 1 year: (1) responders to simple therapy (one anti-absence drug in doses not exceeding 2 g/day); (2) responders to complex therapy (one anti-absence drug in higher dose or combination of anti-absence drugs); (3) non-responders. Groups 1 and 2 can be considered jointly as responders as opposed to the non-responder group. Similarly, groups 2 and 3 can be considered jointly as a group with poor as opposed to good therapeutic response. It was found that significant differences exist between good and poor responders, and 15 factors which had a negative effect on therapeutic response could be identified. No single factor or combination was responsible for non-response, but non-responders had the highest score of negative factors. Patients with complete absence control had a 93% chance of total seizure control, and, with constant medication, relapses after 1 year of control were very infrequent.(ABSTRACT TRUNCATED AT 250 WORDS)

Recognizing and classifying epileptic seizures and epileptic syndromes.

The appropriate diagnosis of the patient with epilepsy is first dependent on a determination of the type of seizure. When the type of seizure has been determined, consideration must be given to the nature of the epileptic syndrome, including concerns regarding the etiology of the attacks. The gradual evolution of the various classification schemes of epileptic seizures and epileptic syndromes complicates the task of the physician but also affords evidence of the dynamism extant in clinical epilepsy research. Intensive monitoring will assist not only in the diagnosis of the individual patient but also in the long-term re-evaluation and revision of the empirical classifications.

The epileptiform significance of intermittent rhythmic delta activity in childhood.

Intermittent rhythmic delta activity is reported in various disorders and is classified as a nonspecific abnormal electroencephalographic pattern. We have investigated its clinical and electroencephalographic features in childhood. Intermittent rhythmic delta activity was identified in 54 children over a period of 48 months. Epilepsy was present in 81%, 4% had only a single generalized tonic-clonic seizure, and 15% had no seizures. Generalized seizures were more common than partial seizures (83% versus 13%; 4% were mixed). The largest group of patients had idiopathic epilepsy. Epileptiform features were present in 70%. No patient identified prospectively has had a space-occupying lesion. Intermittent rhythmic delta activity should be considered an epileptiform pattern in children, most commonly occurring as an interictal pattern in primary generalized epilepsy.

Case summary: Benjamin.

Benjamin was diagnosed with Aspberger's syndrome on starting school. Prior to that, at the age of five years he presented with seizures involving deviation of the head and eyes to the right and jerking of the limbs. EEG was very abnormal with multifocal paroxysmal activity and occasional bursts of spike and slow wave activity. CT scan and MRI were normal and investigations failed to identify any underlying aetiology for the seizures. Carbamazepine was initially successful in controlling the seizures but improvement was not sustained despite maximal tolerated doses. A similar course of events was seen with sodium valproate, initially in combination with ethosuximide (for emergent tonic-clonic and absence seizures), then with vigabatrin (which unmasked myoclonic seizures), clonazepam and finally lamotrigine. The EEG remained abnormal even during periods of improved seizure control and there was no improvement in his Aspberger's syndrome. His epilepsy syndrome has not been classified. Subsequent treatment options include lamotrigine monotherapy.