Current understanding and neurobiology of epileptic encephalopathies

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Abstract

Epileptic encephalopathies are a group of diseases in which epileptic activity itself contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone. These impairments can worsen over time. This concept has been continually redefined since its introduction. A few syndromes are considered epileptic encephalopathies: early myoclonic encephalopathy and Ohtahara syndrome in the neonatal period, epilepsy of infancy with migrating focal seizures, West syndrome or infantile spasms, Dravet syndrome during infancy, Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spikes-and-waves during sleep, and Landau-Kleffner syndrome during childhood. The inappropriate use of this term to refer to all severe epilepsy syndromes with intractable seizures and severe cognitive dysfunction has led to confusion regarding the concept of epileptic encephalopathy. Here, we review our current understanding of those epilepsy syndromes considered to be epileptic encephalopathies. Genetic studies have provided a better knowledge of neonatal and infantile epilepsy syndromes, while neuroimaging studies have shed light on the underlying causes of childhood-onset epileptic encephalopathies such as Lennox-Gastaut syndrome. Apart from infantile spasm models, we lack animal models to explain the neurobiological mechanisms at work in these conditions. Experimental studies suggest that neuroinflammation may be a common neurobiological pathway that contributes to seizure refractoriness and cognitive involvement in the developing brain.

Section snippets

Neonatal epileptic encephalopathies

The recent report of the International League Against Epilepsy (ILAE) commission on classification and terminology (Berg et al., 2010) recognizes three neonatal electroclinical syndromes: Benign Familial Neonatal Epilepsy (BFNE), Early Myoclonic Encephalopathy (EME), and Ohtahara syndrome (OS). While BFNE is a self-limited form of epilepsy associated in most cases with normal development, EME and OS are characterized by a severe disruption of cerebral functions associated with seizures, often

West syndrome

West syndrome, or Infantile Spasms (IS), is one of the most common epilepsy syndromes in the first year of life, although the overall incidence is relatively low (1 in 2000). West syndrome is characterized by the association of epileptic spasms, psychomotor regression and a specific EEG pattern called hypsarrhythmia (Fig. 3). IS result from a whole range of causes comprising focal or multifocal, pre-, peri- or postnatal brain damage or malformation, or genetic predisposition, or can occur

Dravet syndrome

Dravet syndrome (DS) is a refractory epilepsy syndrome characterized by early-onset, febrile or afebrile, generalized or unilateral, clonic or tonic–clonic seizures. Usually, the first seizures are long-lasting episodes of status epilepticus (SE) occurring during the first year of life in an otherwise normal infant. Later, myoclonus, atypical absences and partial seizures are observed. Mutations in the voltage-gated sodium channel gene SCN1A are the main genetic cause of DS (60–80% of the

Lennox-Gastaut syndrome

Lennox-Gastaut syndrome (LGS) is a childhood EE. The main clinical hallmarks of the syndrome were identified and accurately described early on (Lennox and Davis, 1950, Gastaut et al., 1966). The diagnosis is not always easy since the electroclinical characteristics appear progressively. Moreover, the term LGS has often been loosely used to define all kinds of severe childhood epilepsy syndromes (Arzimanoglou et al., 2009). This is an important clinical issue since their treatment and outcomes

EE with continuous spike-and-wave during sleep/Landau-Kleffner syndrome

EE with continuous spike-and-wave during sleep (EE-CSWS) and Landau-Kleffner syndrome (LKS) are two distinctive EEs with different clinical phenotypes. These rare epilepsy syndromes typically start with seizures around 2–4 years of age in a child with normal or moderately abnormal baseline development. Seizures are not frequent. Around age 5–6 years, severe and global neuropsychological regression occurs and seizures including head drop become usually more frequent. Both syndromes are

Role of inflammation in the neurobiology of EE

Emerging evidence highlights a putative pathogenic role of neuroinflammation, both in sustaining the recurrence of seizures and in mediating the development of long-term morbidity (Nabbout et al., 2011, Vezzani et al., 2013) (Fig. 6). Neuroinflammation is defined as an “innate immunological response of the nervous system, involving its own immune cells (microglia, astrocytes), releasing cytokines and chemokines, thus activating down-stream inflammatory effector molecules, and related molecular

Conclusion

Among the epilepsy syndromes that are considered to be EEs (Table 1), there are in our opinion not many that truly fulfill the criteria defined by Berg et al. (2010). LGS, EE-CSWS and LKS can be regarded as the best examples of this definition. In case of neonatal-onset epilepsies, the complex links between gene dysfunction and seizure activity, between gene dysfunction and cognitive involvement, and between seizures in the developing brain and cognitive outcome make it difficult to determine

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