Bettina Schmitz

15q13.3 microdeletions increase risk of idiopathic generalized epilepsy

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 × 10−8). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.

International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy

In order to address the major impact on quality of life and epilepsy management caused by associated neuropsychiatric conditions, an international consensus group of epileptologists met with the aim of developing clear evidence‐based and practice‐based statements to provide guidance on the management of these conditions. Using a Delphi process, this group prioritized a list of key management areas. These included: depression, anxiety, psychotic disorders, nonepileptic seizures, cognitive dysfunction, antiepileptic drug (AED)–related neurobehavioral disorders, suicidality, disorders in children and adolescents, disorders in children with intellectual disability, and epilepsy surgery. Clinical practice statements were developed for each area and consensus reached among members of the group. The assessment and management of these conditions needs to combine knowledge of psychiatric disorders, knowledge of the impact of epilepsy and its treatment on psychopathology, and an ability to deliver care within epilepsy services. The aim of these statements is to provide guidance on quality care for people with epilepsy that have a range of neuropsychiatric disorders.

Depression and Mania in Patients with Epilepsy

Summary:  Depression has a major impact on quality of life in patients with epilepsy and is also the main risk factor for the increased suicide rate in epilepsy. The frequency of depressive disorders depends on the severity of epilepsy and the localization of the epileptogenic focus, with a prevalence of ≤50% in patients with intractable temporal lobe epilepsy. The diagnosis of depression in epilepsy may be difficult because symptoms of depression may be fluctuating, and some symptoms, such as memory complaints, may be misinterpreted as being a consequence of drug treatment or the epilepsy per se. Affective disorders in epilepsy may differ from those seen in patients without epilepsy. A possibility exists that patients with epilepsy will develop a specific interictal dysphoric syndrome related to limbic system dysfunction. Recent epidemiologic studies suggest a bidirectional relation between depression and epilepsy. Depression does not necessarily occur after the onset of epilepsy; the sequence may as well be the other way round, suggesting a common underlying mechanism for both disorders. Classic bipolar disorder type I is rarely seen in epilepsy, and manic episodes occur almost exclusively in the setting of postictal psychosis or after epilepsy surgery. This article explores the clinical manifestations of depressive and manic disorders in epilepsy and the differences from bipolar disorder.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Clinical and psychopathological definition of the interictal dysphoric disorder of epilepsy.

Purpose: Different authors suggested the occurrence of a pleomorphic affective syndrome in patients with epilepsy named interictal dysphoric disorder (IDD). We sought to investigate whether IDD occurs only in patients with epilepsy and to validate IDD features against DSM‐IV criteria.

Genetic dissection of photosensitivity and its relation to idiopathic generalized epilepsy

Photosensitivity or photoparoxysmal response (PPR) is a common and highly heritable electroencephalographic trait characterized by an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. PPR occurs frequently associated with idiopathic generalized epilepsies (IGEs). The present genomewide linkage scan was designed to map susceptibility loci for PPR and to explore their genetic relationship with IGE. The study included 60 families with at least two siblings displaying PPR. To dissect PPR‐specific and IGE‐related susceptibility loci, we defined two distinct family subgroups, comprising 19 families with predominantly pure PPR and photosensitive seizures (PPR‐families) and 25 families, in which PPR was strongly associated with IGE (PPR/IGE‐families). MOD score analyses provided significant evidence for linkage to the region 6p21.2 in the PPR‐families (empirical p = 0.00004) and suggestive evidence for linkage to the region 13q31.3 in the PPR/IGE families (p = 0.00015), both with a best‐fitting recessive mode of inheritance. In the PPR/IGE‐families, linkage evidence was even stronger (p = 0.00003) when the trait definition was broadened by IGE traits. Our study shows two PPR‐related susceptibility loci, depending on the familial background of IGE. The locus on 6p21.2 seems to predispose to PPR itself, whereas the locus on 13q31.3 also confers susceptibility to IGE. Ann Neurol 2005;57:866–873

Psychiatric Syndromes Related to Antiepileptic Drugs

All antiepileptic drugs may provoke positive or negative psychiatric reactions in individual patients. These psy‐chotropic effects are not simply idiosyncratic but depend on the drugs anticonvulsive strength and the persons genetic and biographic psychiatric predisposition. Mechanisms related to psychiatric adverse events are polytherapy and folate deficiency, forced normalization, drug toxicity, and withdrawal. Our knowledge on dose independent, idiosyncratic psycho‐tropic side effects is still limited. With respect to the older antiepileptic drugs there are almost no systematic data, and knowledge is largely empirical and based on anecdotal reports. With respect to the new generation of anticonvulsants there are data on psychiatric side effects from drug trials. However, these data are not always entirely transparent to the interested epileptologist. Moreover, drug trials are designed to test anticonvulsive efficacy and psychiatric adverse events are not systematically reported, thus severity psychopathologic nature of behavioral problems remain obscure. Differences in patients included in trials do not allow comparisons of psychiatric risks of specific drugs, particularly since following the vigabatrin experience, patients with a psychiatric history were often excluded from trials. In this chapter, methodological issues related to data on psychiatric adverse events of AED are discussed followed by an overview on the current knowledge on psychiatric side effect profiles of old and new antiepileptic drugs.

Effects of Antiepileptic Drugs on Mood and Behavior

Summary:  Psychiatric disorders in epilepsy have a multifactorial etiology, pharmacotherapy being only one of many risk factors, which can be both biological and psychosocial. Two important mechanisms of drug‐induced psychiatric changes are seizure control/forced normalization in psychosis and GABA‐ergic effects in depression. Among the psychiatric adverse events of antiepileptic drugs (AEDs), behavioral problems are the most commonly reported, followed by affective disorders. Psychosis is a relatively rare, although severe, complication. Psychotropic effects of AEDs warrant further research because many relevant parameters related to pathological mechanisms, frequency, psychopathology, and prognosis are not well understood. Behavioral side‐effect profiles of AEDs, both negative and positive psychotropic effects, should be considered in the choice of the optimal drug for an individual patient.

Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period

PURPOSE To prospectively analyse the pharmacokinetics of lamotrigine (LTG) during pregnancy and lactation in a consecutive series of epileptic pregnant women. METHODS Nine women on LTG-monotherapy were studied during pregnancy, delivery and lactation, until a mean of 3 weeks postpartum. Maternal blood samples were available from all trimesters as well as umbilical cord blood samples of the newborn 24 and/or 48 h postpartum. In 4 cases we additionally determined the LTG-concentration in breast milk. RESULTS The median LTG-clearance was elevated by 197% during the first trimester, 236% and 248% during the second and third trimester respectively. A maximum of 264% was reached at delivery. An average LTG-dose increase by 250% had to be undertaken in order to obtain therapeutic serum levels. In puerperium LTG-clearance decreased again to reach the initial concentrations approximately at the third week postpartum. The median LTG-concentration ratio of the umbilical cord blood to maternal serum was 1.01 (range: 0.56-1.42), while the median LTG-concentration ratio of breast milk to maternal serum was 0.59 (range: 0.35-0.86). DISCUSSION Our study confirms the therapeutic relevant changes of LTG-clearance during pregnancy and lactation in women on LTG-monotherapy. Since LTG crosses the placenta, a close monitoring of both mother and newborn is indispensable.

Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism.

Juvenile absence epilepsy (JAE) is a common subtype of idiopathic generalized epilepsy (IGE). Hereditary factors play a major role in its etiology. The important function of glutamate receptors (GluRs) in excitatory neurotransmission, synaptic plasticity, and neurodevelopment suggests their involvement in epileptogenesis. A tetranucleotide repeat polymorphism in the non-coding region of the kainate-selective GluR5 receptor gene (GRIK1) on chromosome 21q22.1 provides the tool to investigate this candidate gene. The present association and linkage study tested the hypothesis that allelic variants of GRIK1 confer genetic susceptibility to the pathogenesis of JAE. Our family-based association analysis using the haplotype-based haplotype relative risk statistic revealed an association of JAE with the nine-repeat containing allele of the GRIK1 tetranucleotide polymorphism (chi2 = 8.31, df = 1, P = 0.004). Supportive evidence for linkage to a JAE related IGE spectrum (Zmax = 1.67 at GRIK1) under an autosomal dominant mode of inheritance and significant allele sharing (P < 0.05) among the affected family members suggest that allelic variants of GRIK1 contribute a major genetic determinant to the pathogenesis of JAE-related phenotypes.