Basic Science Behind the Catastrophic Epilepsies

Summary:  The major catastrophic epileptic syndromes of childhood include infantile spasms, Lennox-Gastaut syndrome, and the progressive myoclonus epilepsies (PMEs). Although each of these syndromes manifests in an age-specific manner and is defined by distinct electroclinical features, they are all refractory to medical therapy and are invariably associated with psychomotor deficits, and in the most severe cases, either epileptic encephalopathy or progressive neurodegeneration. While much has been written about the clinical features and natural history of the catastrophic epilepsies, very little is known about the underlying pathophysiology. Progress in our understanding and treatment of these conditions has been hampered by the lack of suitable animal models in which putative mechanisms and novel targets for intervention could be rigorously studied. Nevertheless, recent clinical and basic investigations have identified certain mechanisms that may be relevant to their pathogenesis. In this review, three major hypotheses regarding the pathophysiology of infantile spasms are highlighted: the corticotropin-releasing hormone (CRH) hypothesis, the N-methyl-D-aspartate (NMDA) hypothesis, and the serotonin-kynurenine hypothesis. One or more of these mechanisms may be relevant in part to later-onset catastrophic epilepsies since infantile spasms can persist into later childhood and, like Lennox-Gastaut syndrome, well into adulthood. There is a profound need to develop more relevant animal models of the developmental encephalopathic epilepsies to truly develop better therapeutic strategies for these catastrophic disorders.     

Towards early diagnosis and treatment to save children from catastrophic epilepsy – Focus on epilepsy surgery

Objective: To analyze and to discuss whether by paying attention to the many recent advancements in the field of pediatric epilepsy surgery catastrophic childhood epilepsies caused by definitive or suspected structural lesions can be prevented more often these days in comparison to the past. Methods: Based on data from the literature and supplemented by the authors own experience, risks for children suffering from structural focal epilepsies that the epilepsy becomes catastrophic and ways how such evolutions can possibly be prevented are discussed for the different lesion-types separately – in the order of their frequency as they are seen at pediatric epilepsy surgery centers. Special emphasis is put on data regarding attempts to prevent permanent severe mental retardations. Results: There are common factors predisposing to catastrophic courses in all structural focal epilepsies, such as early onset and a longer duration of epilepsy (with respect to cognitive outcome not with respect to seizure outcome), but there are also differences. Moreover the better perspectives now in comparison to the past for children with conditions like MRI-negative focal epilepsies, subtle focal cortical dysplasias, epilepsies post hypoxic–ischemic events, tuberous sclerosis etc. are not well recognized yet. While there is agreement that “early” (and successful) surgery is essential in many instances to prevent permanent mental retardations there is insufficient data regarding the issue that “early surgery “might not be early enough under certain circumstances and there is also only little data regarding variables which would allow to keep calm when a child is presenting with early onset difficult to control seizures. One of the biggest changes seen over the last decade is the fact that children with very severe epilepsies, who have unilateral lesions, but “generalized” seizures and/or “generalized” EEGs, are not excluded anymore from considerations for epilepsy surgery. Even children with bilateral lesions can be surgical candidates. Conclusion: The gradually widening spectrum of indications for epilepsy surgery in children is resulting in an increasing number of preventions of catastrophic epilepsies. Insufficient data regarding timing of surgery in order to prevent permanent mental retardations are calling for prospective multi-center studies.     

Diagnosis of Infantile Spasms, Lennox-Gastaut Syndrome, and Progressive Myoclonic Epilepsy

Summary:  The epilepsies of childhood are distinguished by an interesting dichotomy between the benign and catastrophic disorders. Approximately 50% of children outgrow childhood epilepsy as they mature; although the disorder is disruptive for children and families alike, it is not considered a medical disaster. The catastrophic epilepsies of childhood, in contrast, are associated with significant morbidity and mortality. Infantile spasms, Lennox-Gastaut syndrome, and the progressive myoclonic epilepsies are correlated with significant disability and a multiplicity of underlying etiologies. Accurate diagnosis of both the syndrome and the etiology is very important for treatment purposes, as well as for family education, since many of the disorders have a significant genetic component.     

Investigational Antiepileptic Drugs for the Treatment of Childhood Seizure Disorders: A Review of Efficacy and Safety

Summary: Pediatric epileptology is very different from adult epileptology. Although some epileptic disorders occur in both children and adults (e.g., localization-related epilepsy with complex partial seizures and primary generalized epilepsy with tonic-clonic seizures), other disorders can be called the catastrophic epilepsies of childhood (e.g., infantile spasms and the Lennox-Gastaut syndrome). They occur, or at least begin, exclusively in childhood and are often associated with mental retardation. Many of these pediatric disorders are notoriously unresponsive to currently available antiepileptic drugs (AEDs). Although there are undoubtedly many reasons for this, one possible explanation is that the methods used to screen potential AEDs use animal models of adult epilepsy. No screening program uses an animal model of seizures that begin during development and lead to functional decline.     

Focal epilepsies: Update on diagnosis and classification

Correctly diagnosing and classifying seizures and epilepsies is paramount to ensure the delivery of optimal care to patients with epilepsy. Focal seizures, defined as those that originate within networks limited to one hemisphere, are primarily subdivided into focal aware, focal impaired awareness, and focal to bilateral tonic–clonic seizures. Focal epilepsies account for most epilepsy cases both in children and adults. In children, focal epilepsies are typically subdivided in three groups: self-limited focal epilepsy syndromes (e.g., self-limited epilepsy with centrotemporal spikes), focal epilepsy of unknown cause but which do not meet criteria for a self-limited focal epilepsy syndrome, and focal epilepsy of known cause (e.g., structural lesions—developmental or acquired). In adults, focal epilepsies are often acquired and may be caused by a structural lesion such as stroke, infection and traumatic brain injury, or brain tumors, vascular malformations, metabolic disorders, autoimmune, and/or genetic causes. In addition to seizure semiology, neuroimaging, neurophysiology, and neuropathology constitute the cornerstones of a diagnostic evaluation. Patients with focal epilepsy who become drug-resistant should promptly undergo assessment in an epilepsy center. After excluding pseudo-resistance, these patients should be considered for presurgical evaluation as a means to identify the location and extent of the epileptogenic zone and assess their candidacy for a surgical procedure. The goal of this seminar in epileptology is to summarize clinically relevant information concerning focal epilepsies. This contributes to the ILAE's mission to ensure that worldwide healthcare professionals, patients, and caregivers continue to have access to high-quality educational resources concerning epilepsy.     

Intractable Epilepsy and Disturbed Visuomotor Performance

Abstract: The factors relevant to intractability, types of epilepsy and impairment of dexterity in patients with intractable epilepsy were studied independently in different groups of patients. The factors relevant to intractable epilepsy that were disclosed in 202 patients, who required hospitalization more than twice, were as follows: strong seizure propensity, neuropsychiatric disorders including mental deterioration of various degrees, ataxia, personality changes and psychotic episodes, intolerance to antiepileptic drugs due to acute or chronic side effects, idiosyncrasy and internal disorders, self-induced seizure, misdiagnosis and mistreatment, and breakdown of family care of patients. The types of epilepsy in 224 patients with intractable epilepsy whose seizures were not adequately controlled and recurred on a monthly basis in spite of hospitalization were classified as follows: 101 patients with localization-related epilepsies or syndromes, 106 with generalized epilepsies or syndromes, 16 with undetermined epilepsies or syndromes and one with specific syndrome. In regard to partial epilepsies, frontal lobe epilepsy and partial epilepsy with multiple foci were at least partially intractable as temporal lobe epilepsy. With respect to intractable generalized epilepsies, miscellaneous symptomatic generalized epilepsies like intractable grand mal epilepsy with progressive mental retardation in childhood were as important as Lennox-Gastaut or West syndrome though it defies classification into any established syndromes. The proposed International Classification of Epileptic Syndromes and Epilepsies¹ was found adequate for analysis of intractable epilepsy. The disturbance of fine motor performance found in 84 patients who participated in occupational therapy was investigated by test programs comprising nine subbatteries. Disturbance of manual dexterity was found in about 80% of the patients and that of the visuomotor performance in about 90%. These impairments seemed to be responsible for the patients failing to be properly employed. It is necessary that in addition to persisting seizures, neuropsychological impairment must be identified for better social care for patients with intractable epilepsy.     

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.     

The epileptic network and cognition: What functional connectivity is teaching us about the childhood epilepsies

Our objective was to summarize and evaluate the rapidly expanding body of literature studying functional connectivity in childhood epilepsy. In the self‐limited childhood epilepsies, awareness of cognitive comorbidities has been steadily increasing, and recent advances in our understanding of the network effects of these disorders promise insights into the underlying neurobiology. We reviewed publications addressing functional connectivity in children with epilepsy with an emphasis on studies of children with self‐limited childhood epilepsies. The majority of studies have been published in the past 10 years and predominantly examine childhood epilepsy with centrotemporal spikes and childhood absence epilepsy. Cognitive network alterations are commonly observed across the childhood epilepsies. Some of these effects appear to be nonspecific to epilepsy syndrome or even to category of neurological disorder. Other patterns, such as changes in the connectivity of cortical language areas in childhood epilepsy with centrotemporal spikes, provide clues to the underlying cognitive deficits seen in affected children. The literature to date is dominated by general observations of connectivity patterns without a priori hypotheses. These data‐driven studies build an important foundation for hypothesis generation and are already providing useful insights into the neuropathology of the childhood epilepsies. Future work should emphasize hypothesis‐driven approaches and rigorous clinical correlations to better understand how the knowledge of network alterations can be applied to guidance and treatment for the children in our clinics.     

Pharmacologic Treatment of the Catastrophic Epilepsies

Summary:  Treatment of the catastrophic epilepsies [infantile spasms (IS), Lennox-Gastaut syndrome (LGS), and progressive myoclonic epilepsy (PME)] remains a challenge to clinicians. For IS, adrenocorticotropic hormone has traditionally been the drug of choice in the United States but may be associated with serious side effects in some patients. Vigabatrin has shown promise in treating IS patients, particularly those with tuberous sclerosis. However, the drug is associated with visual field loss and is not commercially available in the United States. Newer antiepilepsy drugs (AEDs), such as zonisamide, topiramate (TPM), and lamotrigine (LTG), may be useful in patients with IS. Although LTG, TPM, and felbamate are approved in the United States for the treatment of LGS, the overall effectiveness of therapy in patients with LGS is poor. For PME, valproate is a first-line treatment. Zonisamide and levetiracetam also show promise. Supplementation with certain cofactors to correct deficiencies and increase mitochondrial function may be useful in some patients with PME, but response to such therapy is not well documented. Advances in our understanding of the etiologies, mechanisms, and genetics underlying the catastrophic epilepsies may facilitate more effective pharmacologic interventions.     

Absence epilepsy with onset before age three years: a heterogeneous and often severe condition

PURPOSE: The classification of epilepsies and epileptic syndromes recognizes three syndromes with typical absences [TA, i.e., childhood and juvenile absence epilepsies (CAE and JAE), and epilepsy with myoclonic absences (EMA), none of which is characterized by onset in early childhood]. Although several other forms of absence epilepsies have been described recently, none concerns infants and very young children, and little is known about the nosology and prognosis of early-onset absences. METHODS: We retrospectively selected all cases with onset of absences as the only or major seizure type before age 3 years and >/=2 years of follow-up among cases newly referred between 1986 and 2002. Neuropsychological assessments (generally IQ measure), behavior patterns, and schooling situations were reviewed for each child. RESULTS: We found 10 patients (7 F, 3 M). No child had sensory or motor deficits: neuroimaging was performed in nine and was normal in eight, with aspecific findings in one. Only two could be characterized as CAE and EMA, respectively, both with seizure control and a good cognitive outcome. Among the remaining eight cases, four had a fairly homogeneous presentation with predominantly brief absences and clearly asymmetric interictal EEGs. All eight had neuropsychological and/or behavioral difficulties. Three had full seizure control, and five, persisting absences, with a follow-up ranging between 2 years 8 months to 9 years 4 months; only one child was older than 12 years. CONCLUSIONS: Great heterogeneity exists among absence epilepsies of early onset, which are rare conditions. Only a few patients can be categorized into well-known syndromes. The overall prognosis is poor. Early onset of absences is uncommon, and multicenter studies should help clarify the nosology and prognosis.     

Factors That Preclude the Successful Use of Monopharmacy in the Medical Treatment of Patients with Epilepsy

Abstract: A neurologist conducted research efforts for more than 12 years as a step toward the establishment of monotherapy for epilepsy. Of 406 patients with epilepsy, seizures could be controlled for more than one year in 72% and for more than 3 years in 54%. Monotherapy was given to 57% of all the patients with a success rate of 54%. Factors that were found likely to interfere with a reduction in antiepileptic drug therapy to one drug modality included: symptomatic etiology, prolonged duration of illness, low age at onset and secondary generalized epilepsy with a large number of seizures in combination, for generalized epilepsies; symptomatic etiology, prolonged duration of illness, low age at onset, other than occipital lobe origin, complex partial seizure with secondary generalization, temporal lobe epilepsy with associated automatisms, elementary sensorimotor seizure and high frequency of seizures, for partial epilepsies. In addition to these factors relevant to the nature of epilepsies, other factors apparently unrelated to the disease process, e.g., liability of polypharmacy to produce side effects precluding dosage elevation, patient's rejection to reduce drug and the inability of a physician to treat the patient properly for want of information, were also recognized to exist.     

Hirntumoren und Epilepsien

Today’s improved tumor and epilepsy treatment possibilities have led to increased numbers of long-term care patients with symptomatic epilepsies caused by tumors. Pathophysiology, epidemiology, advancements in diagnosis, drug as well as surgical treatments are discussed with special emphasis being placed on seizure control, side effects, and quality of life. Because long-term care – often 10 to 20 years – is necessary, optimal individual treatment strategies have to be selected. New electrophysiological techniques, e.g., magnetic resonance imaging (MRI) and magnetic encephalography (MEG), as well as the interaction of anticonvulsive and chemo-therapeutic drugs should be taken into account.     

Rational Treatment of Refractory Epilepsy in Childhood

Abstract: A multifaceted study on childhood refractory epilepsy disclosed an insufficient classification of epilepsies and epileptic seizures, and inappropriate polypharmacy as the most important factors preventing appropriate therapy. By means of an adjustment of AEDs based on the accurate classification of epilepsies and epileptic seizures, the number of AEDs could be reduced in 37.5% and monotherapy was successful in 13.8% of refractory cases. Most of the latter were those of partial epilepsy and generalized epilepsy with the monoseizure type. The exacerbation of seizures due to AEDs was also mentioned as one of the important side effects of AEDs.     

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.     

Clobazam Has Equivalent Efficacy to Carbamazepine and Phenytoin as Monotherapy for Childhood Epilepsy

Summary: Purpose: To compare the effectiveness of mono-therapy clobazam (CLB) to carbamazepine (CBZ) and phenytoin (PHT) in children with epilepsy.
Methods: Children aged 2–16 years with newly diagnosed epilepsy or previous failure of one drug (for poor efficacy or side effects) were assigned to one of two study arms and then randomized–CLB versus CBZ or CLB versus PHT. Eligible children had partial epilepsies or only generalized tonic-clonic seizures. After a drug initiation protocol, monotherapy treatment mimicked the usual routines used by Canadian child neurologists. Blinding used a "double dummy" technique with blinded medication serum levels (6–point scale). Intention to treat analysis using survival curves assessed the primary end-point–length of retention on the initial medication during the year after randomization.
Results: Fifteen centers entered 235 patients: 159 randomized to CLB versus CBZ and 76 to CLB versus PHT. Altogether, in all study arms, 119 received CLB, 78 CBZ, and 38 PHT. Overall, 56% continued to receive the original medication for l year with no difference between CLB and standard therapy (CBZ and PHT). Seizure control was equivalent for all three medications, as were side effects. PHT and CBZ induced more biologic side effects, such as rash, while CLB induced slightly more behavioral effects. Tolerance developed in 7.5% of patients receiving CLB, 4.2% with CBZ and 6.7% with PHT.
Conclusions: CLB should be considered as "first line" monotherapy along with CBZ and PHT for all partial and selected generalized childhood epilepsies.     

Gene Mapping in the Idiopathic Generalized Epilepsies: Juvenile Myoclonic Epilepsy, Childhood Absence Epilepsy, Epilepsy with Grand Mai Seizures, and Early Childhood Myoclonic Epilepsy

Summary: Idiopathic generalized epilepsies, i.e., juvenile myoclonic epilepsy (JME), childhood absence epilepsy, and epilepsy with grand mal [generalized tonic-clonic seizures (GTCS)], are the most common genetic epilepsies. Linkage studies using Bf, HLA serologic, and DNA markers by three independent investigators, one from Los Angeles and two from Berlin, have localized the JME locus to the short arm of chromosome 6 (6p). Because members of the same JME family have the same JME phenotype of childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or early childhood myoclonic epilepsy (ECME), our observations give evidence for a single-locus etiology in 6p for JME and for at least some of the childhood absence seizures, epilepsy with grand mal (GTCS) seizures, and ECME. Studies should now address whether locus heterogeneity exists within childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or ECME. Markers linked to JME (Bf, HLA serologic, and DNA markers in the DQ region) can be used to resolve etiologic heterogeneity. Using such markers, both linked and unlinked forms of phenotypes that are clinically indistinguishable may be detected and provide evidence for etiologic heterogeneity. Studies should also concentrate on narrowing the JME locus to 2 to 3 cm by screening families with recombinant events using RFLPs, candidate genes, and new expressed sequences on chromosome 6.     

Treatment of benign focal epilepsies in children: when and how should be treated?

Benign focal epilepsies represent almost one-fourth of all childhood epilepsies and are a frequent occurrence in clinical practice. They include benign infantile seizures (BIS), Panayiotopoulos syndrome (PS), and benign childhood epilepsy with centrotemporal spikes (BCECTS) in this order of the onset age. Because the prognosis is always excellent in patients with benign focal epilepsies, we must consider the risks and benefits of chronic antiepileptic drug (AED) administration. AED treatment is usually not recommended for the patients with a first attack, but should be considered for those with a second or third attack. A choice of AED has been based on the expert opinion. Carbamazepine (CBZ) is recommended for both acute and chronic treatment of seizure clusters in patients with BIS. Valproic acid (VPA), CBZ or clobazam (CLB) appears to be a first option of AED for patients with PS. A common first choice for BCECTS is CBZ in the USA and Japan, and VPA in the EU. The treatment period should be as short as possible without waiting for EEG normalization, possibly within 2 years after the initiation of AED. We must remember that some patients with BCECTS may have an “atypical evolution”. In conclusion, when and how to treat this benign condition should be determined in an individual manner based on the length and frequency of seizures, circadian rhythm of the attacks, interictal EEG findings, cognitive and behavioral functions in daily life and the attitude of the parents toward seizure recurrences and AED side effects.     

Epilepsy in the elderly: facts and challenges

The incidence of epilepsy in the elderly has increased steadily over the last few decades. In some industrialized countries, one-third of the population is expected to be over the age of 65 in 2030. Therefore, we will face a dramatic increase in the number of elderly patients with epilepsy, many of whom will likely present comorbidities. This increase will put a heavy burden on health care and pension systems. This article focuses on epidemiology, diagnosis and treatment in epilepsies in the elderlies and outlines current research as well as future requirements for research. The diagnosis of epilepsy in the elderly can be difficult and may require long-term video-EEG monitoring. Stroke is the most frequent etiology in epilepsies in the elderlies. Status epilepticus in acute symptomatic epilepsies often results in fatality and may become an increasing health problem. The article also describes the current strategies in antiepileptic drug treatment and epilepsy surgery in the elderly. Novel antiepileptic drugs are necessary as current antiepileptics have strong interaction potentials and harmful side effects, making them ill-suboptimal for treating epilepsy in the elderly.     

Treatment issues for children with epilepsy transitioning to adult care

This is the third of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper focuses on treatment issues that arise during the course of childhood epilepsy and make the process of transition to adult care more complicated. Some AEDs used during childhood, such as stiripentol, vigabatrin, and cannabidiol, are unfamiliar to adult epilepsy specialists. In addition, new drugs are being developed for treatment of specific childhood onset epilepsy syndromes and have no indication yet for adults. The ketogenic diet may be effective during childhood but is difficult to continue in adult care. Regional adult epilepsy diet clinics could be helpful. Polytherapy is common for patients transitioning to adult care. Although these complex AED regimes are difficult, they are often possible to simplify. AEDs used in childhood may need to be reconsidered in adulthood. Rescue medications to stop prolonged seizures and clusters of seizures are in wide home use in children and can be continued in adulthood.Adherence/compliance is notoriously difficult for adolescents, but there are simple clinical approaches that should be helpful. Mental health issues including depression and anxiety are not always diagnosed and treated in children and young adults even though effective treatments are available. Attention deficit hyperactivity disorder and aggressive behavior disorders may interfere with transition and successful adulthood but these can be treated. For the majority, the adult social outcome of children with epilepsy is unsatisfactory with few proven interventions.The interface between pediatric and adult care for children with epilepsy is becoming increasingly complicated with a need for more comprehensive transition programs and adult epileptologists who are knowledgeable about special treatments that benefit this group of patients.     

Evidence-based Treatment of Idiopathic Generalized Epilepsies with Older Antiepileptic Drugs

Summary:  Older antiepileptic drugs continue to play a major role in the treatment of the idiopathic generalized epilepsies. Comparative studies of ethosuximide and valproate have demonstrated equivalence in the treatment of childhood absence epilepsy. Valproate can be regarded as the recommended first-line treatment for juvenile myoclonic epilepsy based on case series reports. Studies in patients with generalized tonic-clonic seizures have not separated out idiopathic from secondary generalized events. Treatment for the other idiopathic generalized epilepsy syndromes lacks evidence other than a few case reports and diverse expert opinion. Further randomized controlled trials of older antiepileptic drugs are recommended to solidify the evidence-based treatment of the idiopathic generalized epilepsies.