Cognitive and behavioral outcomes of epileptic syndromes: implications for education and clinical practice

The educational and social progress of a child with epilepsy depends not only on seizure control but also on cognitive and behavioral factors. The various epilepsy syndromes of childhood and adolescence differ greatly in terms of cognitive and behavioral outcome. A high proportion of babies who have West syndrome and children who have Dravet syndrome (severe myoclonic epilepsy in infancy) will have long-term cognitive and behavioral problems. The Lennox-Gastaut syndrome also often has a poor prognosis in this regard. Children with the Landau-Kleffner syndrome have a variable prognosis, some regain speech and others have permanent speech impairment. Benign childhood epilepsy with centrotemporal spikes is now recognised as lying on a spectrum with the Landau-Kleffner syndrome: mild cases have few if any cognitive or behavioral problems but others may have quite severe difficulties. People with juvenile myoclonic epilepsy may have characteristics suggesting frontal lobe impairment. The educational and social impairments associated with the epilepsy syndromes of childhood and adolescence are of major importance but they have been the subject of remarkably few well-performed studies. The impairments are not always necessarily permanent and it seems highly likely that the cognitive and behavioural outcome of at least some of these syndromes can be influenced greatly by early effective treatment with either antiepileptic medication or surgery.     

Cognitive and Behavioral Outcomes of Epileptic Syndromes: Implications for Education and Clinical Practice

Summary:  The educational and social progress of a child with epilepsy depends not only on seizure control but also on cognitive and behavioral factors. The various epilepsy syndromes of childhood and adolescence differ greatly in terms of cognitive and behavioral outcome. A high proportion of babies who have West syndrome and children who have Dravet syndrome (severe myoclonic epilepsy in infancy) will have long-term cognitive and behavioral problems. The Lennox-Gastaut syndrome also often has a poor prognosis in this regard. Children with the Landau-Kleffner syndrome have a variable prognosis, some regain speech and others have permanent speech impairment. Benign childhood epilepsy with centrotemporal spikes is now recognised as lying on a spectrum with the Landau-Kleffner syndrome: mild cases have few if any cognitive or behavioral problems but others may have quite severe difficulties. People with juvenile myoclonic epilepsy may have characteristics suggesting frontal lobe impairment. The educational and social impairments associated with the epilepsy syndromes of childhood and adolescence are of major importance but they have been the subject of remarkably few well-performed studies. The impairments are not always necessarily permanent and it seems highly likely that the cognitive and behavioural outcome of at least some of these syndromes can be influenced greatly by early effective treatment with either antiepileptic medication or surgery.     

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.     

Pediatric Epilepsy Syndromes: An Update and Critical Review

Summary: Epilepsy syndromes occupy an important position in the current nosology of the epilepsies, describing and classifying seizure disorders with shared clinical and EEG features. Increasingly, this schema is being refined as new information becomes available and our understanding of etiology and presentation of each syndrome widens. Advances in neuroimaging and neurogenetics have been particularly important and are likely to fundamentally change our concepts of syndrome classification. At present, the International League Against Epilepsy classification of epilepsy syndromes according to presumed localization (partial, generalized, undetermined) and etiology (idiopathic, cryptogenic, symptomatic). In clinical practice, it is often useful to conceptualize epilepsy syndromes according to their usual age at presentation, which greatly facilitates syndrome identification in new patients and recognizes the age-related expression of many childhood epilepsies. Definitional problems exist for many pediatric epilepsy syndromes, particularly the epileptic encephalopathies of early infancy, the benign epilepsies of infancy and childhood, the myoclonic epilepsies of infancy and early childhood, and the idiopathic generalized epilepsies of childhood and adolescence. It is likely that further input from the fields of molecular genetics and neuroimaging will enable the classification of epilepsies to become more etiologically oriented and disease specific.     

Benign partial epilepsy in infancy and early childhood with vertex spikes and waves during sleep: a new epileptic form

International epilepsy classification includes different epileptic syndromes with favourable outcomes in paediatric age, both partial and generalised. This is true in childhood while no partial benign forms are accepted in infancy. In 1987, Watanabe first described a new entity and he defined it as 'benign complex partial epilepsies in infancy'. In 1992, Vigevano referred similar but familial cases whose seizures had secondary generalisation. Both these forms had no interictal EEG abnormalities neither awake nor during sleep. This article presents a survey of 12 cases of partial epilepsy with favourable outcome differing from Watanabe and Vigevano's cases, both for the presence of interictal EEG abnormalities only during sleep and for seizure picture. All our patients are neurologically and neuroradiologically normal. Psychomotor development is unremarkable. Age onset range is 13-30 months. All cases present characteristic spikes and waves during slow-sleep in vertex cerebral areas. Awake EEG is always normal, at follow-up too. Our cases have such homogeneous electroclinical features as to hypothesise a new partial idiopathic epileptic syndrome with favourable outcome in infancy and early childhood. We propose to define it as 'benign partial epilepsy in infancy and early childhood with vertex spikes and waves' (BVSE).     

The epileptic encephalopathies of infancy and childhood

The epileptic encephalopathies comprise a group of devastating seizure syndromes which begin in infancy and early childhood and usually result in intractable epilepsy. While some syndromes are relatively easily diagnosed early in their course, others take time to evolve, hampering an early, confident diagnosis. Epileptic encephalopathies are associated with slowing of cognitive function and evolution of severe behavioral disorders, which are often more distressing to families than the epilepsy. While an underlying etiology may explain some of this co-morbidity, many children have no identifiable etiology found for their seizures. In these "idiopathic" cases, recurrent subtle seizures, frequent epileptiform discharge and non-convulsive status epilepticus probably all play a role in deterioration of cognitive function and evolution of behavior disorders. This paper will review the most common epileptic encephalopathy syndromes, discuss the cognitive and behavioral co-morbidities and review current therapeutic options.     

Early-onset acquired epileptic aphasia (Landau–Kleffner syndrome,LKS) and regressive autistic disorders with epileptic EEG abnormalities: The continuing debate

Early-onset acquired epileptic aphasia (Landau–Kleffner syndrome) may present as a developmental language disturbance and the affected child may also exhibit autistic features. Landau–Kleffner is now seen as the rare and severe end of a spectrum of cognitive-behavioural symptoms that can be seen in idiopathic (genetic) focal epilepsies of childhood, the benign end being the more frequent typical rolandic epilepsy. Several recent studies show that many children with rolandic epilepsy have minor developmental cognitive and behavioural problems and that some undergo a deterioration (usually temporary) in these domains, the so-called “atypical” forms of the syndrome. The severity and type of deterioration correlate with the site and spread of the epileptic spikes recorded on the electroencephalogram within the perisylvian region, and continuous spike-waves during sleep (CSWS) frequently occur during this period of the epileptic disorder. Some of these children have more severe preexisting communicative and language developmental disorders. If early stagnation or regression occurs in these domains, it presumably reflects epileptic activity in networks outside the perisylvian area, i.e. those involved in social cognition and emotions. Longitudinal studies will be necessary to find out if and how much the bioelectrical abnormalities play a causal role in these subgroup of children with both various degrees of language and autistic regression and features of idiopathic focal epilepsy. One has to remember that it took nearly 40 years to fully acknowledge the epileptic origin of aphasia in Landau–Kleffner syndrome and the milder acquired cognitive problems in rolandic epilepsies.     

Childhood epilepsy with occipital paroxysms: difficulties in distinct segregation into either the early-onset or late-onset epilepsy subtypes

The Commission on Classification and Terminology of the International League Against Epilepsy Childhood rigidly segregated epilepsy with occipital paroxysms into 2 separate syndromes with different predominant seizure types: early-onset seizure susceptibility type consisting of prolonged infrequent, nocturnal autonomic seizures and accompanied by eye deviation and ictal vomiting and late onset with short diurnal frequent seizures and visual ictal manifestations along with throbbing headaches. Epileptic clinical manifestations and electroencephalographic data were analyzed in 28 patients with suspected occipital lobe epilepsy in an attempt to segregate them into either the early or late forms according to the International League Against Epilepsy classification. Electroencephalography in 25 children demonstrated occipital epileptiform paroxysms compatible with the suspected epileptic syndrome. Only 14 (50%) children complied with the rigid criteria of either early-onset or late-onset presentations. The other 14 (50%) children presented with mixed diverse epileptic phenomena such as short-lived seizures in infancy or prolonged seizures during childhood, not complying with either rigid syndrome (ie, short-lived epileptic blindness at an early age or vomiting during later childhood). Despite present attempts to rigidly segregate childhood epilepsy with occipital paroxysms into 2 distinct epileptic syndromes, a high percentage of children still present with various mixed clinical phenomena. Therefore, clinicians should be aware of possible unique and unusual presentations of occipital lobe epilepsy at various ages.     

Long-Term Course of Childhood Epilepsy with Intractable Grand Mal Seizures

Abstract: Twenty-nine children with childhood epilepsy characterized by frequent grand mal (generalized tonic-clonic) seizures in spite of maximal doses of antiepileptic drugs and by an early onset of seizures (before 1 :year of age) were followed up for more than 5 :years. The children were divided into 3 :groups: severe myoclonic epilepsy in infancy (SME), no SME, and intractable childhood epilepsy with generalized tonic-clonic seizures (GTC). In all the 3 :groups, the grand mal seizures persisted, whereas the other types of seizures tended to disappear as the patients aged, and the prognosis for mental development was poor. In the majority of cases in all the 3 :groups, the waking grand mal seizures altered to sleep grand mal seizures with aging. Two pairs of monozygotic twins with SME suggested that genetic factors play a role in this epileptic syndrome. Intractable childhood epilepsy with GTC is distinguished by the absence of other types of generalized seizures. It cannot be regarded as an epileptic syndrome, but its pathogenesis and treatment require further studies.     

Atypical rolandic epilepsy

Typical benign rolandic epilepsy (BRE) is a frequent and well-delineated epileptic syndrome in childhood. Mild cognitive and behavioral difficulties are increasingly recognized in the course of BRE and should not be considered as atypical features. Atypical features are recognized on electroclinical grounds. These features, particularly early age at onset and frequent spikes or spike-wave discharges, seem to be risk factors for neuropsychological deficits but also for an atypical evolution of BRE. Atypical evolutions of BRE are defined by the appearance of severe neuropsychological impairments and continuous spike-and-waves during slow sleep (CSWSS). The clinical expressions of these situations correspond to the syndromes known as atypical benign focal epilepsy of childhood (ABFEC), status of BRE, Landau-Kleffner syndrome (LKS), and CSWSS syndrome, which may be part of a continuum related to BRE.     

Clinical and molecular genetics of myoclonic-astatic epilepsy and severe myoclonic epilepsy in infancy (Dravet syndrome).

The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEFS(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI.     

Atypical presentations of benign childhood epilepsy with centrotemporal spikes: a review

Benign childhood epilepsy with centrotemporal spikes is the most common epileptic syndrome in childhood. Atypical forms of benign childhood epilepsy with centrotemporal spikes are common. The different atypical forms of the condition are believed to represent a continuum of the same underlying genetic mechanism. The atypical forms of benign childhood epilepsy with centrotemporal spikes include electrical status epilepticus in slow waves sleep, Landau-Kleffner syndrome, status epilepticus of benign childhood epilepsy with centrotemporal spikes, "classic" atypical form, and others. This review delineates the different forms with emphasis on the cognitive hazards of the more malignant types.     

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.     

Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging

Detailed study of 4 patients and review of the literature allowed us to delineate further the epileptic syndrome associated with hypothalamic hamartomas, which characteristically begins in infancy with laughing seizures. Because early childhood psychomotor development is usually normal, the condition appears benign and may not even be recognized. The episodes of laughter are brief, frequent, and mechanical in nature. These features distinguish it from other forms of epileptic laughter, particularly that which occurs in temporal lobe epilepsy. Subsequently, the seizures become longer, other seizure types appear, and between the ages of 4 and 10 years, the clinical and electroencephalographic features of secondary generalized epilepsy develop. Cognitive deterioration occurs and severe behavior problems are frequent. Prognosis for seizure control and social adjustment is poor. Cortical abnormality occurs in association with the hypothalamic hamartoma. The lesions are best detected by magnetic resonance imaging but may be difficult to identify by computed tomographic scanning.     

Idiopathic West Syndrome followed by childhood absence epilepsy

West Syndrome (WS) is a severe epileptic encephalopathy occurring in the first year of life. According the ILAE classification of epileptic seizures and epilepsy the etiology could be symptomatic or cryptogenic. Some authors identified a small group of patients (5%) with a particular good outcome, a complete recovery from seizures and a normal cognitive development within the cryptogenic group that they suggested to be idiopathic. Between 1996 and 2007, at the Neurology Division of the Bambino Gesù Children's Hospital in Rome, we collected 241 patients with WS. Sixteen (6.6%) were considered with idiopathic aetiology. All clinical notes of these patients were reviewed in order to evaluate the prevalence of other epileptic syndrome after WS. Two of them had at the age of 8 and 3 months idiopathic WS, and at the age of 6 and 4 years respectively, they presented with childhood absence epilepsy (CAE) successfully treated with valproate.The favorable evolution of the WS and the later occurrence of an idiopathic form of epilepsy, such as CAE, confirm the possibility of an idiopathic aetiology for WS that, although rare, can represent one of the etiologies of otherwise severe syndrome. Even if a common physiophatogenetic role, probably related to a genetic predisposition, could be hypothesized and appears to be intriguing, no data are available and more studies are needed to confirm this hypothesis.     

Outcome at adulthood of the continuous spike-waves during slow sleep and Landau-Kleffner syndromes

PURPOSE: The aim of this study was to determine the clinical, social, and/or professional and cognitive outcomes in adulthood of the continuous spike-waves during slow sleep (CSWS) and Landau-Kleffner syndromes, which are two rare epileptic syndromes occurring in children. METHODS: We enrolled seven young adults, five who had a CSWS syndrome, and two, a Landau-Kleffner syndrome in childhood. We evaluated their intellectual level as well as their oral and written language and executive functions. RESULTS: This study confirmed that the epilepsy associated with these syndromes has a good prognosis. Only one patient still had active epilepsy. However, the neuropsychological disorders particular to each syndrome persisted. Only two patients had followed a normal pathway in school. Three of the five patients with a CSWS syndrome during childhood remained globally and nonselectively mentally deficient. We found no evidence of the persistence of a dysexecutive syndrome in this study group. The intellectual functions of the two patients with Landau-Kleffner syndrome were normal; however, their everyday lives were disrupted by severe, disabling language disturbances. We discuss the role of some prognostic factors such as the location of the interictal electric focus and the age at onset of CSWS. CONCLUSIONS: These two epileptic syndromes of childhood are very similar in many respects, but their clinical outcomes in adulthood are different.     

Epileptic encephalopathies with myoclonic seizures in infants and children (severe myoclonic epilepsy and myoclonic-astatic epilepsy).

Myoclonic attacks are not characteristic of a specific syndrome. In infancy and early childhood, they are often observed in the context of syndromes that are associated with other types of seizures and with cognitive impairment but no obvious brain lesion. Characterization of the associated seizures and age of expression allows inclusion of a number of cases in two main subgroups: severe myoclonic epilepsy (SME, or Dravet syndrome) and myoclonic-astatic epilepsy (MAE). Severe myoclonic epilepsy is an epileptic encephalopathy with invariably poor outcome in which myoclonic seizures, though frequently observed, may be absent altogether in some children. Prolonged and repeated febrile and afebrile convulsive seizures starting in infancy are the main feature and are probably causally related to cognitive decline. One third of children harbor mutation of the SCN1A gene, but the genetics of SME is probably more complex than expected with simple monogenic disorders. Treatment is usually disappointing. Myoclonic-astatic epilepsy is perhaps more a conceptual category of idiopathic myoclonic epilepsy than a discrete syndrome. Childhood-onset myoclonic-astatic attacks are the characteristic seizures associated in most with episodes of nonconvulsive status and generalized tonic-clonic seizures. Outcome is unpredictable. Either remission within a few years with normal cognition or long-lasting intractability with cognitive impairment is possible. Likewise, the effectiveness of antiepileptic drugs is variable. A number of cases of myoclonic epilepsies in infancy and early childhood, however, remain unclassified, and intermediate forms between the different syndromes exist. They must be distinguished from other syndromes with frequent brief attacks and repeated falls, especially the Lennox-Gastaut syndrome. This differentiation is often difficult and may require extensive neurophysiologic studies.     

Comorbidities and predictors of health-related quality of life in Dravet syndrome

Purpose: Health‐related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual’s physical, social, and mental well‐being. There is a paucity of data focusing on HRQOL in specific epilepsy syndromes and their associated needs. In this study our aim was to describe the comorbidities and disease‐related predictors for HRQOL in Dravet syndrome, an epileptic encephalopathy, with defined genetic etiology. We anticipate that this will help us to better recognize and understand the needs of children and families and aid treatment planning in this severe epilepsy syndrome. Methods: One hundred sixty‐three individuals with Dravet syndrome and their families participated in the study. Detailed clinical and demographic information was available for each case. HRQOL was evaluated with two epilepsy‐specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL); a generic HRQOL instrument; the Pediatric Quality of Life Inventory (PedsQL); and a behavioral screening tool, the Strength and Difficulties Questionnaire (SDQ). Key Findings: HRQOL was significantly lower for children with Dravet syndrome compared to normative data (p < 0.001). A cross‐sectional evaluation of measures across different age groups revealed that PedsQL generic core and cognitive function scales decreased in older age categories, indicating worse HRQOL (p < 0.001). Assessment of epilepsy severity demonstrated that symptoms were rated very severe in 10 (6%) of 162 cases, somewhat severe in 78 (48%) of 162, moderate in 51 (32%) of 162, and mild in 23 (14%) of 162 cases. The epilepsy severity correlated significantly with the IPES total impact score (r = 0.466, p < 0.001, n = 162). The IPES total impact scores in the Dravet group (n = 162) were significantly higher than scores measured in the original validation sample of epileptic children with and without learning difficulties (± SD) (21.0 ± 8.7 vs. 11.6 ± 5.4, t = 8.95, p < 0.001, n = 46). On the SDQ, 35% of children scored in the abnormal range for “conduct problems,” 66% for “hyperactivity/ inattention,” and 76% for “peer relationships.” Regression analysis revealed that young age at seizure onset (p = 0.019), presence of myoclonic seizures (p = 0.029), motor disorder (p = 0.048), learning difficulties (p = 0.002), epilepsy severity (p < 0.001), and behavioral difficulties (p < 0.001) each independently predicted poorer HRQOL. Behavioral problems such as hyperactivity/inattention were the strongest predictors of poorer HRQOL. Significance: This is the first comprehensive study of HRQOL in an etiologically well‐defined epilepsy syndrome. HRQOL in Dravet syndrome depends on a series of independent factors including seizure control, behavior, cognitive, and motor problems. Identification of specific comorbidities in Dravet syndrome will facilitate a distinct and multidisciplinary approach to management, addressing seizure control, behavior problems, cognitive difficulties, and motor impairment.