Neuropsychological approaches to epileptic encephalopathies
The International League Against Epilepsy (ILAE) Commission report on classification and terminology indicates that “diagnosing an individual as having an encephalopathic course requires demonstration of a failure to develop as expected relative to the same-aged peers or to regress in abilities.” In this chapter, basing our discussion on the theoretical framework of neuroconstructivism, on the latest results deriving from functional neuroimaging and on the concept of system epilepsy, we use continuous spike-waves during slow-wave sleep (CSWS) as an example of how non–rapid eye movement (NREM) sleep spikes interfere with the organization and consolidation of neuropsychological networks in the sensitive phase of development, affecting also interconnected systems. Indeed, recent discoveries show that the normal overnight downscaling of slow wave activity (SWA) from the first to the last hours of sleep is absent in electrical status epilepticus during sleep (ESES) patients, thus impairing the neural process and possibly the local plastic changes associated with learning and other cognitive functions. Moreover, specific patterns of spike-induced activation (especially in perisylvian and/or prefrontal areas) and deactivation of default mode network (DMN) have been shown in patients with CSWS. Consequently, to date, we may conceive that the possible mechanisms underlying neuropsychological disorders in encephalopathic epilepsy (EE) may be double, since NREM sleep interictal epileptic discharges (IEDs) induce both a pathologic activation in epileptogenic areas and a pathologic deactivation of DMN beyond the epileptogenic zone. The growing body of literature on the effects of ESES in CSWS provides us with increasing knowledge on the complexity of brain development and a better understanding of plasticity, enlightening the pathogenesis of damage on developing neuropsychological functions. Finally, the need for an individually tailored interpretation of the neuropsychological testing results, expected to integrate neurophysiology and functional neuroimaging data, is suggested.
The study of neuropsychological functions in infancy and childhood epilepsy implies some theoretical key points that have to be considered both for the evaluation of a patient with epilepsy and the interpretation of its eventual impact on neuropsychological development. Some of these basic principles are described by the modern neuropsychological theories on brain development, whereas some others are specific in studying epilepsies of developmental age.
Most principles derive in a consistent manner from results obtained by functional neuroimaging methods such as diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), and electroencephalography (EEG)–fMRI, which continue to contribute to the definition of both physiologic mechanisms underlying the neuropsychological normal processes and of the pathophysiologic substrates in neurodevelopmental disorders such as epilepsy.
Epileptic encephalopathies (EEs), defined as disorders in which the epileptic activity itself influences global development and evolution include a number of epilepsies and syndromes: early myoclonic encephalopathy; Ohtahara syndrome; West syndrome; Dravet syndrome; myoclonic status in nonprogressive encephalopathies; Lennox-Gastaut syndrome (LGS); Landau-Kleffner syndrome (LKS); and epilepsy with continuous spike–waves during slow-wave sleep (CSWS). A detailed discussion on neuropsychology issues related to the preceding is beyond the aim and scope of the present work. Currently available data can be found either within specific publications or in global reviews and dedicated publications (Helmstaedter et al., 2011; Bureau et al., 2012). In this chapter, we briefly discuss the impact of non–rapid eye movement (NREM) sleep interictal epileptic discharges (IEDs) on neuropsychological development, particularly considering the latest discoveries in EEs with electrical status epilepticus during sleep (ESES) and focusing on the syndrome of CSWS. Indeed, the growing body of literature on the effects of ESES in CSWS provides us with increasing knowledge on the complexity of brain development and a better understanding of plasticity, enlightening the pathogenesis of damage on developing neuropsychological functions.
General Framework of Neuropsychological Development
Starting with the general theoretical framework based on neuroconstructivism (Karmiloff-Smith, 1992), neuropsychological development is characterized by a progressive specialization of brain (i.e., relative modularization) in neuropsychological and behavioral functions. Modularization process is allowed by the neuronal plasticity, which denotes several capacities including the ability to adapt to changes in the environment, to store information in memory associated with learning, and to organize neuronal networks in response to internal and external stimuli (Johnston, 2004). Adaptive plasticity refers to functional and structural changes in the brain that are advantageous in that they help to improve function (Johnston, 2009).
The building blocks of brain growth and plasticity are dendrites, axons, and synapses of neurons. Plasticity modifies, over developmental time windows, some mechanisms available throughout lifetime (increase in synaptic strength, decrease in local inhibition, dendritic sprouting, formation of new synapses, formation of new neurons), whereas others are available only during the early phase of brain development (synaptic pruning, use of unspecified labile synapses including silent synapses, competition for synaptic sites, persistence of normally transient connections, myelination) (Huttenlocher, 1984). Development of the cerebral cortex in children is characterized by an early postnatal burst and overproduction in synaptogenesis followed by activity-dependent pruning of excessive synapses later in the postnatal period (Huttenlocher & Dabholkar, 1997). Changes in plasticity turn out to be region precise, suggesting that each area owns specific developmental trajectories: the posterior areas are the first to develop, whereas in frontal lobes synaptogenesis peaks at around early adolescence (Casey et al., 2000). Local overproduction and pruning of synapses coincides with the most sensitive periods (i.e., “critical time window”) and the highest plasticity, determining the best capacity for learning (Munno & Syed, 2003).
As confirmed by fMRI and DTI results, brain development has to be studied by considering not only local changes at the level of single areas but also regional intrahemispheric and interhemispheric connectivity modifications determined by an age-dependent and activity-dependent myelination process (Luna et al., 2001; Durston & Casey, 2006). Like synaptogenesis, white matter development shows temporal and spatial gradients, going from posterior sensorimotor to anterior associative regions: in fact, in the frontal lobes, white matter maturation continues into the second decade of life (Klingberg et al., 1999). Moreover, an increase of white matter has been demonstrated in basal ganglia and thalamus, which have extensive reciprocal connections with the frontal cortex: this increase is considered to reflect the maturation of pathways subserving cognitive ability and behavioral regulation (Barnea-Goraly et al., 2005). Taken together, these results show that the maturation of white matter allows the passing from short-range to long-range cortico-subcortical connections and the organization of dynamic, widely distributed neuropsychological networks (Fox et al., 2005). Changes in one system will necessarily influence other systems, at different levels, even if only subtly (D'Souza & Karmiloff-Smith, 2011).
Neural networks can be differentiated also depending on the function subserved: there are task-related circuitries activated during a specific activity and there is the “default-mode network” (DMN) (Buckner et al., 2008). Among task-related systems, language processing results being associated with an initial activation of the perisylvian area, especially the superior temporal cortex (STC), and with a later involvement of the inferior frontal cortex (IFC) (Brauer et al., 2011). A set of skills called executive functions (EFs), playing a central role in in planning and controlling thought and behavior, depends primarily on a network or system comprising prefrontal cortex (PC) and its major connections ( Miller, 2005).
The DMN is composed by bilateral posterior cingulated/precuneus, inferior parietal cortex, and ventromedial PC and is characterized by a consistent decrease in activity during the initiation of goal-directed tasks compared to baseline (Supekar et al., 2010). It is present in the resting brain, while the individual is engaged in internally focused tasks (Fair et al., 2008). The DMN that constitutes a necessary favorable neurometabolic environment for cognitive functions represents a psychological baseline for processes of attention and working memory and supports dynamic integration of cognitive and emotional processes (Raichle & Mintun, 2006). DMN is considered as reflecting neural functions that consolidate the past, stabilize brain ensembles, and prepare for the future (Buckner & Vincent, 2007). Abnormal activity in the DMN and disturbed connectivity between the involved structures is shown to influence task-related performances and to contribute to the pathogenesis of neuropsychiatric disorders such as attention-deficit/hyperactivity disorder (Sun et al., 2012). A prominent pattern of activity in the DMN has been observed during slow wave activity (SWA) of NREM sleep (Dang-Vu et al., 2008; Horovitz et al., 2009). SWA is fundamentally associated with the processes of functional and anatomic connectivity underlying memory consolidation, synaptic homeostasis, and information processing, determining the local plastic changes and remodeling necessary to the learning process (Stickgold & Walker, 2005; Tononi & Cirelli, 2006; Esser et al., 2007).
Considering all of the preceding, it is clear that each function and its correspondent system needs to be studied on the bases of a dynamic and longitudinal approach, tracing developmental trajectories across time and functions, assessing progressive changes from infancy onward at the neural, cognitive, and behavioral level, and pinpointing how parts of the developing system may interact with other parts differently and at varying epochs across ontogenesis. Within this approach, the contribution of NREM sleep SWA to development and learning acquires a special importance.
Implications on Neuropsychological Development in Epileptic Encephalopathies
The relationship between the developmental trajectories of neuropsychological circuitry and the external and internal factors affecting plastic changes are among the most important factors that must be taken into account when trying to understand the impact of pathologic processes on neurodevelopmental disorders such as epilepsy.
Focusing specifically on epilepsies during infancy and childhood, the neuropsychological profile should be analyzed taking a multifactorial approach, including the assessment of the type of electroclinical syndrome and its etiology, the age at onset, the electroencephalographic pattern (frequency of ictal and interictal epileptic discharges, lateralization and localization both when awake and during sleep, presence or absence of spreading abnormalities), the seizure type(s) and their frequency, the antiepileptic treatment, and the psychosocial factors (including family, school, social and cultural contexts).
Different variations of neuropsychological impairments can be found in EEs, and it is important to define them correctly: there may be fluctuations within a normal range, stagnation (raw scores of tests do not increase according to age), regression (drop in raw scores), delay (mental age not increasing as expected by chronologic age), aberrant development, or nonemergence of specific skills. These variable evolutions can concern different skills, depending on the maturational stage of the functions involved at disease onset.
The concept of EE was recognized in 2001 (Engel, 2001) as embodying the notion that “the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g. cortical malformation), as well as the fact that those impairments can worsen over time.” The last International League Against Epilepsy (ILAE) Commission report on classification and terminology (Berg et al., 2010) added the notion that “diagnosing an individual as having an encephalopathic course requires demonstration of a failure to develop as expected relative to same-aged peers or to regress in abilities.” Moreover, it is underscored that “it is not necessary for an individual to have a syndrome identified as being one of the epileptic encephalopathies, like West Syndrome for example, in order to have an encephalopathic course.” Authors generally agree that the cognitive consequences are more global and profound when epilepsy occurs early in infancy, whereas a later onset is associated with more selective neuropsychological dysfunctions.
Within the EEs, different syndromes have been recently considered as examples of system epilepsies (Avanzini et al., 2012), depending on the dysfunction of complex cortical-subcortical interconnected systems. The pathophysiologic explanation of the negative impact of epileptic activity is strictly associated with the brain organization processes of synaptic pruning and, consequently, of corticosubcortical network building up. Epileptiform abnormalities, including interictal epileptic discharges, can affect this process by either maintaining those that are no longer useful, considering the child's chronological age and the environmental requests, or impeding the consolidation of new synaptic connections among regions (Maquet et al., 1995). Moreover, if synaptic pruning occurs too early in ontogenesis, that is, with EE occurring in the first years of life, the brain may specialize before the circuitry has been appropriately shaped by the relevant internal/external inputs. This could lead to a system that processes too few input types or loses previously acquired abilities: from a neuropsychological perspective, the most severe consequences may be global delay and/or regression. At later ages (for example, in EE with school-age onset), if pruning is impeded to take place or occurs in an aberrant way during critical epochs of neuropsychological development (i.e., since IEDs keep on beating against developing connections) then the brain may fail to specialize, and this could affect the system's ability to multitask and to integrate basic abilities into higher functions (Karmiloff-Smith, 2012). Consequently, the neuropsychological functioning may be characterized by a normal intelligence but with specific disorders, such as language, executive functions, memory, and learning (reading, writing, and arithmetic).
The Example of EE with Electrical Status Epilepticus during Sleep
The syndrome of continuous spike-waves during slow sleep (CSWS) is considered as a prototype of EE (Holmes & Lenck-Santini, 2006). It belongs to a large spectrum of age-related epileptic conditions characterized by the EEG pattern of electrical status epilepticus during sleep (ESES), consisting of sleep-related activation and diffusion of spike-wave discharges that usually can occupy ≥85% of NREM sleep; in addition, the significantly increasing abnormalities during each NREM phase of sleep are observed until morning awakening (Patry et al., 1971; Tassinari et al., 2005; Van Bogaert et al., 2006). From a broader perspective, ESES may be responsible for atypical evolutions of benign epilepsy with centrotemporal spikes (BECTS) and for LKS (Landau & Kleffner, 1957).
CSWS represents the most severe syndrome within the spectrum of EEs with ESES: it is characterized by acquired neuropsychological impairment and epilepsy with heterogeneous seizure types (Tassinari et al., 2009). Onset lies between 2 years and 10 years of age, although the precise onset is often difficult to determine as it depends on the time that a sleep EEG has been requested and performed. Neuropsychological impairments represent the hallmark of the CSWS electroclinical syndrome, despite a previous history of normal or mildly delayed development. There are different possible clinical pictures (Jambaquè et al., 2001), and the spectrum of severity is variable, including auditory or visual agnosia (Eriksson et al., 2003), acquired aphasia, apraxia and hemineglect (De Tiège et al., 2004), impaired spatial orientation, attention deficit and hyperactivity, global mental deterioration (Tassinari et al., 2000), psychotic state, and autistic features (Nickels & Wirrell, 2008). In CSWS, ESES and/or seizure resolution by antiepileptic drugs (AEDs) is usually associated with behavior and neuropsychological improvement, albeit cognitive and behavioral functions can remain mildly to severely impaired during follow-up (Tassinari et al., 2000).
The variability both in quality and severity of CSWS neuropsychological impairments depends on epileptogenic focus localization and on age at onset. Indeed, the range of impairments goes from the language deficits caused by ESES in the perisylvian areas to dysexecutive patterns when frontal regions are involved (sometimes behavioral problems are the first to appear preceding onset of the epilepsy) (Tassinari et al., 2005). An acquired epileptic frontal syndrome (AEFS) has also been described, characterized by a severe neuropsychological regression (either rapid or insidious) and loss of abilities that appear between 3,5, and 8 years of age, mainly in association with a frontal focus, clinical seizures of mild to moderate severity, and ESES (Roulet Perez et al., 1993). The cognitive regression is accompanied and sometimes preceded by behavioral changes (hyperactivity, aggressiveness, impulsivity, disinhibition, loss of sense of danger, and autistic-like features). Language expressive and pragmatic abilities can be disrupted, abstract reasoning is impaired both with verbal and nonverbal material, echolalia and inappropriate association of ideas can be present.
The physiopathologic mechanisms between CSWS and the peculiar pattern of neuropsychological, motor, behavioral derangement described in different conditions call in question of the role of SWA during NREM sleep in the neuroplastic remodeling of the neural networks. SWA during sleep is of interest in the context of ESES because the generation of both slow-wave and spike-wave complexes share common mechanisms. Indeed, authors have shown that the degree of synchrony among cortical neurons increases progressively from a preseizure sleep pattern to spike-wave seizures (Bölsterli et al., 2011; Urbain et al., 2013). The slope of slow waves during sleep is an EEG parameter related directly to the degree of synchrony of cortical neurons firing and constitutes an indirect but reliable electrophysiologic marker of synaptic strength (Tononi & Cirelli, 2006). The normal overnight downscaling of SWA from the first to the last hours of sleep is absent in ESES patients, thus the interference of prolonged focal spike waves with the activity of sleep's slow waves may explain the cognitive deterioration of these patients, impairing the neural process, and possibly the local plastic changes associated with learning and other cognitive functions (Tassinari & Rubboli, 2006; Urbain et al., 2013).
Moreover, in patients with CSWS, EEG-fMRI results during drug-induced sleep show a complex pattern of activation involving the perisylvian/prefrontal cortex, the thalamus, and a deactivation of DMN (Siniatchkin et al., 2010).
A dysfunction of these networks contributes to an explanation of the observed neuropsychological disorders. As already described, these networks are implicated in behavioral regulation, attention, language, and EFs, and are characterized by critical epochs of development at the time that CSWS appears. These EEG-fMRI results suggest that pathophysiologic effects associated with ESES activity are not restricted to the epileptic focus, but spread to connected areas due to remote functional consequences, so that the spike-associated deactivation of DMN is a further consequence of the individual focus of epileptic activity. This phenomenon has been defined as the “network inhibition hypothesis,” by which increased cortical activity in one region inhibits subcortical arousal systems, leading to widespread decreased cortical activity including the DMN (De Tiège et al., 2007).
Beyond the language and EF disruption due to NREM-sleep abnormal activity in the perisylvian/prefrontal areas, the pathologic spike-induced interruption of resting state activity represented by DMN during sleep may alter awareness and consciousness (Boly et al., 2008). Such alteration does not really affect specific functions, but seems more likely to globally influence the capability of the child to elaborate a coherent internal-external world representation and to prepare the internal milieu for task-dependent activities. To date, we may conceive that the possible mechanisms underlying neuropsychological disorders in EEs may be double, since IEDs induce both a pathologic activation in epileptogenic areas (with consequences depending on IEDs localization and age of onset) and a pathologic deactivation of DMN beyond the epileptogenic zone.
Consequently, the study of NREM sleep abnormalities in CSWS puts in evidence the double meaning of plasticity in developmental age: on the one hand, a more plastic child's brain allows an early compensation and overwhelming of a structural damage; on the other hand, when there is a functional and continuous abnormal process, short-range and long-range processes of plastic network changes can be permanently affected, leading to the consolidation of permanently diseased circuits. Specifically, considering the different types of plasticity (Johnston, 2004), EEs with ESES represent forms of “excessive plasticity,” consisting of a disability induced by the reorganization of new, maladaptive neuronal circuits.
Based on the theoretical framework of neuroconstructivism, considering ILAE definitions and the concept of system epilepsy, EEs represent a model of how an internal pathologic process may hinder the modularization of networks subserving specific functions, thereby affecting age-dependent plastic processes and determining cognitive and behavioral consequences. An impairment of basic cognitive processes, induced by early onset epilepsy, may have a variable and sometimes cascading impact on connected functions, over developmental time, affecting interconnected systems, some of them strongly and others more subtly.
The ESES pattern, characterizing some EEs (CSWS, LKS, atypical BECTS) raises questions about the complexity of the interactions between the specific developmental epoch of neuropsychological networks and the age of onset of ESES, since NREM-sleep spikes interfere with the organization and consolidation of neuropsychological networks in the sensitive phase of development. The spectrum of neuropsychological disorders depends on the location of the epileptic focus and its duration, but also on the connected cortical and subcortical areas, where specific patterns of spike-induced activation (especially in perisylvian and/or prefrontal areas) and DMN deactivation underlie the dysfunction of neuropsychological circuitries. More prospective studies using functional neuroimaging are needed to better understand the interaction of DMN deactivation with the other systems and its developmental milestones.
Age at onset also plays a role: The earlier the epileptic disturbance occurs, the greater the functional deficit. Moreover, the ESES pattern in childhood EE shows that despite EEG and seizure control the neuropsychological disorders can ameliorate but persist: the pathophysiologic basis may be represented by basic disrupted networks, which become unable to subserve higher-function organization or subserve them in an abnormal way. Hence, the disorder evolves from transient to persistent, since NREM-sleep IEDs impede the consolidation of synaptic connections otherwise favored by daily learning.
There are some limitations, which have to be considered at the time of elaborating pathophysiologic hypotheses, concerning the impact of sleep abnormalities on neuropsychological development. In fact, strict correlations between EEG and clinical data are complex: Interictal spikes on wakefulness, topography, and amplitude of paroxysmal activity (either during wakefulness or sleep) demonstrate considerable variability during their evolution, even in the same child. Prognosis cannot be inferred by the EEG data only. In addition, fMRI studies based on correlation analyses cannot shed light on the causal relationship between EEG and BOLD patterns. The “network inhibition hypothesis” has been shown in other electroclinical syndromes such as childhood absence epilepsy (Moeller et al., 2008) and idiopathic generalized epilepsy (McGill et al., 2012). Consequently, the preceding interpretation of results may be nonspecific to CSWS. More studies with EEG-fMRI and DTI in CSWS, LKS, and atypical BECTS are necessary to provide evidence of specific network organizations in the different electroclinical syndromes. Moreover, the hypothesis of a common underlying genetic basis of both ESES and neuropsychological impairment remains of crucial value (Doose et al., 2000).
Overall, some basic principles concerning the neuropsychological approach of EE can be applied. First, the effects of NREM-sleep abnormalities have to be monitored longitudinally through electrophysiologic and neuroimaging techniques to obtain an accurate picture of the impact of epilepsy on the developmental trajectories of functions beyond the acute phase and to determine its long-term consequences. Second, the pathologic involvement of one or more systems in epilepsy onset, propagation, and maintenance will affect other highly interconnected systems, determining a functional damage of complex interconnections.
From our point of view it appears of primary importance to interpret the results of a neuropsychological evaluation using a multidimensional approach. In other words, to specifically depict the unique pattern of development of a child with epilepsy, low scores in one or more neuropsychological tests can only be interpreted correctly following the integration of the EEG data, both ictal and interictal, as well as a consideration of the structural and functional neuroimaging information. Consequently, both neuropsychological testing and suggested care measures should be viewed in patients submitted to a presurgical evaluation as investigation of the areas to be spared or removed to establish an individually tailored postsurgical rehabilitation program.
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.