Patrick Van Bogaert and Xavier De Tiège
In 1957, Landau and Kleffner (1957) reported children with normal early language development who became aphasic after the onset of epileptic seizures and had bilateral temporal interictal epileptiform discharges (IEDs) on EEG (Landau and Kleffner 1957). The authors suspected that persistent convulsive discharges resulted in the functional ablation of brain areas concerned with linguistic communication. The language disturbance was further characterized as auditory verbal agnosia, that is, the inability to decode phonemes despite intact peripheral hearing mechanisms, leading to a severe expressive and receptive verbal deficit (Rapin et al. 1977). Observations of language regression without clinical seizures were further reported (Deonna 1991; Paquie et al. 1992; Soprano et al.1994; Tassinari et al. 2002). Longitudinal follow-up of these children showed that the seizures as well as the EEG abnormalities remit at adolescence (Paquie et al. 1992). The Landau–Kleffner syndrome (LKS) was recognized by the International League Against Epilepsy (ILAE) as synonymous with acquired epileptic aphasia to be classified among the epilepsies and syndromes of childhood undetermined whether focal or generalized.
Electrical status epilepticus during slow sleep (ESES) was proposed by Tassinari et al. in 1971 for a particular EEG pattern characterized by diffuse spike-waves occurring during at least 85% of slow sleep and persisting on three or more records over a period of at least 1 month (Patry et al. 1971). Most children with ESES had refractory seizures and global cognitive regression leading to severe intellectual disability. However, some of them had more selective language-related impairment identical to that observed in LKS. Moreover, the evolution of the epilepsy showed remission at adolescence even if most patients had persistent and sometimes severe neuropsychological sequels.
Despite the clear overlap between ESES and LKS, the ILAE proposed in a first step to classify ESES separately under the name “epilepsy with continuous spikes and waves during slow-wave sleep (CSWS),” but recognized these two syndromes as epileptic encephalopathies, that is, epilepsies in which the epileptiform abnormalities may contribute to progressive neurological dysfunction (Engel 2001).
Subsequently, observations of children with CSWS presenting other types of cognitive deterioration than aphasia or dementia were reported. These included autism and more selective cognitive impairments such as frontal lobe dysfunction, apraxia and hemineglect, pseudo-bulbar palsy, visual agnosia, and learning arrest (Roulet Perez et al. 1993; De Tiege et al. 2004).
The ILAE now consider that there is insufficient evidence for mechanistic differences between LKS and CSWS to warrant considering them separate syndromes, and proposed the term of “epileptic encephalopathy with CSWS including LKS” for this particular childhood epileptic syndrome (Engel 2006).
Definition of epileptic encephalopathy with CSWS
There is now a large consensus to consider epileptic encephalopathy with CSWS as a spectrum of epileptic conditions defined by (1) an onset in childhood (3y to 10y); (2) the occurrence of cognitive or behavioral impairments that appear or worsen after the epilepsy onset; and (3) the presence of abundant IEDs during sleep, which tend to be more frequent, with increased amplitude and diffusion over the whole scalp during non-rapid eye movement sleep than during the awake state. LKS is a particular presentation in which acquired aphasia is the core symptom. Seizures are not a mandatory feature. When they occur, seizures have variable semiology (focal seizures without consciousness impairment, secondary generalized tonic–clonic seizures, focal negative myoclonia, atypical absences) but, unlike in Lennox–Gastaut syndrome, tonic seizures are usually not encountered (Galanopoulou et al. 2000; Tassinari et al. 2000).
However, what is less consensual are the frontiers with classic benign epilepsy with centrotemporal spikes (BECTS), and particularly the minimal EEG and clinical criteria needed to pose the diagnosis of epileptic encephalopathy with CSWS, because these two conditions overlap. This overlap was already pointed out by Aicardi and Chevrie (1982) who reported children who had an epileptic syndrome resembling BECTS but with atypical features such as frequent brief seizures (atypical absences, focal myoclonia), cognitive impairment, and CSWS. Authors now speak about atypical BECTS when daily seizures, CSWS, and neuropsychological impairment occur in a child diagnosed with BECTS (Fejerman 2009; Fujii et al. 2010). Observations of classic BECTS cases evolving to an epileptic encephalopathy with CSWS, sometimes precipitated by the use of some antiepileptic drugs (AEDs) (Tassinari et al. 2000; Saltik et al. 2005), and of CSWS and BECTS cases coexisting within the same family (De Tiege 2006), further outline this overlap. It should be too simplistic to state that it is the presence of CSWS and cognitive deficits that will distinguish BECTS from epileptic encephalopathy with CSWS. Indeed, if a pattern of CSWS was found in the course of the disease in all patients with LKS reported in some series (Dulac et al. 1983; Hirsch et al. 1990; Paquier et al. 1992; Massa et al. 2000; Robinson et al. 2001), it was found only in a minority of patients in another series (McVicar et al. 2005). More recently, three patients with LKS with initial normal sleep EEG were reported, the diagnosis being made after several weeks or months based on the demonstration of IEDs during sleep, including CSWS in two of them (Van Bogaert et al. 2013). Also, some data suggest that it is not only the IED percentage but also their increased amplitude and diffusion during sleep that is detrimental to normal brain function (Aeby et al. 2005; De Tiege et al. 2008). This is evidence that the EEG criteria of CSWS criteria as proposed by the Tassinari’s group (Patry et al. 1971) are too restrictive to define the syndrome.
Also, the minimal cognitive impairment needed to make a diagnosis of epileptic encephalopathy with CSWS is a subject of controversy. Indeed, numerous studies have reported an unexpected high rate of cognitive difficulties in the language, attentional, and memory domains in children with classic BECTS, which were associated with IED severity at the acute phase of the disease and resolved with the normalization of the EEG (Deonna 2000; Baglietto et al. 2001; Verrotti et al. 2014).
In conclusion, it is widely accepted that BECTS and epileptic encephalopathy with CSWS are the edges of a spectrum in which the most frequent and diffused IEDs during sleep seem to result in the more severe behavioral and cognitive deficits (Stephani and Carlsson 2006; Kramer et al. 2009; Moeller et al. 2013). The nosological limits between these two conditions are thus somewhat arbitrary.
Epileptic encephalopathy with CSWS is one of the childhood focal epileptic syndromes. According to the terminology revised in 2010 (Berg et al. 2010), the underlying aetiology allows classifying patients within one of the following three subgroups: structural/metabolic, genetic, and unknown. The subgroup of unknown aetiology is the most important, representing more than half of the patients. Patients with structural brain lesions identified on magnetic resonance imaging (MRI) are in the structural/metabolic subgroup and represent approximately 20% of the cases. Lesions are usually antenatal cortical malformations (polymicrogyria) or ante/perinatal cortical destructive lesions, but may also be purely subcortical, the association between thalamic perinatal injury and CSWS being well recognized (Guerrini et al. 1998; Guzzetta et al. 2005). These cases have usually preexisting signs of cerebral palsy. Within this subgroup are also patients with preexisting motor and cognitive deficiencies related to chromosomal anomalies (15q deletion for instance) or genetic syndromes such as Rett syndrome (Van Bogaert et al. 2006). In the genetic subgroup are patients with a demonstrated genetic mutation, but those with mutations associated with structural brain lesions (tubulin genes for instances) and those with chromosomal deletions and preexisting psychomotor delay do not belong to this subgroup. Up to now, there is only one gene demonstrated as pathogenic in the genetic subgroup. This gene is called GRIN2A. Mutations of GRIN2A have been identified by three independent research groups (Carvill et al. 2013, Lesca et al. 2013, and Lemke et al. 2013). Patients with GRIN2A mutations represented about 10% to 20% of cohorts of patients with epileptic encephalopathy with CSWS and normal MRI. Phenotypes are LKS or atypical BECTS, but some patients have a typical BECTS phenotype, further underlying the overlap between these two epileptic syndromes. GRIN2A encodes the N-methyl-D-aspartate (NMDA) glutamate receptor a2 subunit, GluN2A. Patients have either inherited or de novo mutations, which affect NMDA receptor function.
Pathophysiology of cognitive regression
Epileptic encephalopathy with CSWS is one of the best illustrations of the concept of epileptic encephalopathy, that is, conditions in which epileptiform abnormalities may contribute to progressive cognitive dysfunction, so that early effective intervention may improve developmental outcome (Engel 2006; Berg et al. 2010). Indeed, clinical improvement is evident and sometimes impressive when treatment results in EEG normalization, even in lesion-related cases (Guerrini et al. 1998; Aeby et al. 2005; Guzzetta et al. 2005; Buzatu et al. 2009; Peltola et al. 2011).
It should be noted that complete normalization of the sleep EEG is not always mandatory to obtain clinical improvement. Indeed, besides the percentage of spike–wave complexes during non-rapid eye movement sleep, the diffusion of the epileptic activity over the whole scalp is also important to consider, as children with diffuse CSWS may show spectacular clinical improvement under treatment even if a focus of spikes persists during a high percentage of sleep time (Aeby et al. 2005; Buzatu et al. 2009).
The initial hypothesis of a “functional ablation” of eloquent cortical areas by the “persistent convulsive discharge” to explain the neuropsychological impairment, as proposed more than half a century ago by Landau and Kleffner (1957), remains the most largely accepted hypothesis. However, some observations are not fully explained by this theory. First, the temporal association between CSWS on EEG and neurological regression is not always strict (Rapin et al. 1977; Hirsch et al. 1990; Van Bogaert et al. 2013). This suggests that other factors, for example, autoimmune factors as suggested by the response to corticosteroids (see the Treatment section below), could impact on language and cognition in some patients. Second, if some authors found strict association between the pattern of neuropsychological impairment and the location of interictal focus, others did not. Indeed, patients showing clinical frontal dysfunction but a parietal epileptic focus have been reported (De Tiege et al. 2004). This discrepancy can be explained regarding the pathophysiological model that emerged from positron emission tomography with [18F]-fluorodeoxyglucose (FDG-PET) data obtained at the awake state in children at the active phase of the disease as well as at remission. Those studies demonstrated that the acute phase of CSWS is characterized by a metabolic pattern associating regional increase(s) and decrease(s) in glucose metabolism in distinct brain areas, with heterogeneous location of the abnormalities across patients (Fig 13.1) (De Tiege et al. 2004; De Tiege et al. 2008). The combination of magnetoencephalography and FDG-PET demonstrated that focal hypermetabolism was related to the onset or the propagation sites of spike–wave discharges, whereas hypometabolic areas were not involved in the epileptic network as such (De Tiege et al. 2013). At the group level, hypometabolism occurred in regions that belong to the default network (prefrontal and posterior cingulate cortices, parahippocampal gyrus and precuneus) (Ligot et al. 2014). The pathophysiological model proposed to explain these findings is based on the “surrounding and remote inhibition theory,” which suggests the existence of epilepsy-induced inhibition of neurons that surround or are remote from the hypermetabolic epileptic focus and connected with it via cortico-cortical or polysynaptic pathways (Bruehl and Witte1995; Schwartz and Bonhoeffer 2001). The validity of this model in epileptic encephalopathy with CSWS is supported by (1) the evidence of altered effective connectivity between hyper- and hypometabolic areas, suggesting that the level of metabolic activity in hypometabolic areas is related to the epilepsy-induced metabolic changes in the hypermetabolic ones (De Tiege et al. 2004; De Tiege et al. 2008; Ligot et al. 2014) and (2) the complete or almost complete parallel regression of hypermetabolic and hypometabolic abnormalities at recovery from CSWS (De Tiege et al. 2008).