ReviewCognitive functioning in idiopathic generalised epilepsies: A systematic review and meta-analysis
Introduction
The idiopathic generalised epilepsies (IGE) are a cluster of syndromes presumed to be of genetic origin. IGE syndromes are characterised electroencephalographically by bilaterally, synchronous activity with symmetrical spike-and-waves or polyspike-and-waves originating at some point within, and rapidly engaging bilateral networks of the brain (Berg et al., 2010). As a group, IGE constitute approximately 15–20% of all epilepsies (Jallon and Latour, 2005). The four most common forms of IGE recognised by the current ILAE classification are childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) and IGE with generalised tonic–clonic seizures only (IGE-GTCS; Berg et al., 2010). Although classified as distinct syndromes by the ILAE (Berg et al., 2010), some authors suggest that these subtypes may represent a ‘neurobiologic continuum’ (e.g. Berkovic et al., 1987, Nordli, 2005). A recent revision of the ILAE classification in 2010 recommended that the term ‘idiopathic’ be replaced by ‘genetic’, however there remains disagreement about the need for this change (Shorvon, 2011). The core syndromes remain essentially unchanged with the exception of GTCS on awakening now encompassed by IGE with generalised tonic clonic seizures only. Therefore, the term ‘IGE’ will be retained here to reflect its continued use in clinical and research practice, and in the diagnostic and classification systems used within studies included in this review.
In contrast to focal syndromes such as temporal lobe epilepsy (TLE), relatively little is known about cognitive function in IGE or in the hypothesised sub-syndromes. IGE effects on cognition are often considered relatively benign, within normal range but lower than the general population is a common description (e.g. Cutting et al., 2001, Hommet et al., 2006, Jeong et al., 2011). Studies of cognition in patients with IGE have typically been limited by small sample sizes, and lack of control groups. Inconsistent neuropsychological test selection and inadequate description of factors such as use of anti-epileptic drugs (AED) and co-morbid mood disturbance complicate interpretation of many of the available studies. Methodological factors relating to cohort selection (i.e. incident versus prevalent cases) and recruitment setting (i.e. community versus tertiary or specialised epilepsy centres) also complicate interpretation of prognosis (Seneviratne et al., 2012). Investigation of cognitive impairment across IGE syndromes, to date, does not provide a clear picture of the nature or extent of cognitive impairment in people with these syndromes.
The most frequently studied of the IGE syndromes has been JME, the most common form of IGE (Hommet et al., 2006). Specific deficits have been reported in so-called ‘executive’ or ‘frontal lobe’ functions such as planning, abstract reasoning, concept formation and verbal fluency (Devinsky et al., 1997, Roebling et al., 2009) although, as is well known, deficits in these functions may arise from dysfunction in a wide variety brain regions (Goldstein and Scheerer, 1941, Dodrill, 1997). Findings of aberrant frontal lobe structure and function including an increase of grey matter in the mesiofrontal regions (Woermann and Woermann, 1999) and reduction in glucose metabolism in a variety of brain regions including the dorsolateral prefrontal cortex have been reported (Swartz et al., 1996). These findings have encouraged the investigations of Janz's original hypothesis of a dysexecutive syndrome in JME (Janz, 1985). If supported, this hypothesis has important implications for the educational, occupational and psychosocial prognosis of patients and for the types of interventions most likely to benefit patients with JME.
No systematic review or quantitative synthesis of the literature has been conducted to date. The primary aim of this review is to evaluate cognitive dysfunction in the four primary syndromes of IGE: CAE, JAE, JME and IGE-GTCS. Specifically we seek to answer the following questions: (a) Is there evidence of cognitive dysfunction in people with IGE? (b) Which cognitive abilities are affected and to what extent? (c) Are there differences in the nature and extent of cognitive impairment between the four IGE syndromes?
Section snippets
Protocol registration
The systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO: registration number CRD42013004177). The review was conducted according to PRISMA guidelines (Moher et al., 2009).
Search strategies
Medline and Scopus databases were used to identify eligible studies. A keyword (Medline and Scopus) and MeSh term (Medline only) search was conducted on 2nd April 2013 for IGE and cognition terms (see Appendix A for list of search terms used). To limit the
Study selection and characteristics
Twenty-six studies met selection criteria and were included (Fig. 1). Eleven studies reported patients with JME, four with CAE, two with IGE-GTCS, none with JAE and eight with mixed IGE syndrome diagnoses. One additional study (Levav et al., 2002) conducted separate analyses of JME and CAE patient samples. Table 2 displays characteristics of included studies.
Studies varied with respect to demographic and epilepsy variables. CAE groups had mean age from 8 to10 years; participants in JME samples
Summary of findings
To our knowledge, this is the first systematic review and meta-analysis of cognitive function in IGE. To date, studies have focussed on JME, with relatively few studies of CAE and IGE-GTCS and no studies of JAE meeting inclusion criteria. The paucity of research on IGE-GTCS and JAE may be due to the relatively recent reclassification of the IGE-GTCS syndrome (incorporating epilepsy with GTCS on awakening) and the likely under-diagnosis of JAE (Engel, 2001, Jallon and Latour, 2005).
Although the
Conclusions
Medium to large deficits in cognitive function (up to 0.88 standard deviation units) were observed in patients with IGE, with the greatest reduction in scores observed on measures of cognitive processing speed. These deficits were observed despite a large degree of heterogeneity across results of individual studies. The heterogeneity of results may be due to the inherent heterogeneity of the clinical expression of these conditions or due to the variable methodologies used to study IGE.
Acknowledgements
A. Loughman was supported by an Australian National Health and Medical Research Council Public Health Scholarship.
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