Dorothée Kasteleijn-Nolst Trenité

Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.

Epilepsy in low-grade gliomas: the impact on cognitive function and quality of life.

Low‐grade gliomas frequently are associated with epilepsy. The purpose of this study is to determine the impact of epilepsy and antiepileptic drug (AED) treatment on cognitive functioning and health‐related quality of life (HRQOL) in these patients. One hundred fifty‐six patients without clinical or radiological signs of tumor recurrence for at least 1 year after histological diagnosis and with an epilepsy burden (based on seizure frequency and AED use) ranging from none to severe were compared with healthy controls. The association between epilepsy burden and cognition/HRQOL was also investigated. Eighty‐six percent of the patients had epilepsy and 50% of those using AEDs actually were seizure‐free. Compared with healthy controls, glioma patients had significant reductions in information processing speed, psychomotor function, attentional functioning, verbal and working memory, executive functioning, and HRQOL. The increase in epilepsy burden that was associated with significant reductions in all cognitive domains except for attentional and memory functioning could primarily be attributed to the use of AEDs, whereas the decline in HRQOL could be ascribed to the lack of complete seizure control. In conclusion, low‐grade glioma patients suffer from a number of neuropsychological and psychological problems that are aggravated by the severity of epilepsy and by the intensity of the treatment.

Visual sensitivity and epilepsy: a proposed terminology and classification for clinical and EEG phenomenology.

*Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands; †Division of Clinical Neuroscience, Guy’s, King’sand St. Thomas’ School of Medicine, King’s College Hospital-University of London, London, and ‡Department ofClinical Neurophysiology, Guy’s, King’s and St. Thomas’ School of Medicine, Denmark Hill, England; and§Centre St. Paul, Marseille, France

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.

The Effectiveness of Cognitive Rehabilitation for Attention Deficits in Focal Seizures: A Randomized Controlled Study

Summary:  Purpose: Cognitive deficits are one of the major limiting factors in the everyday life functioning of patients with focal seizures. Although cognitive rehabilitation methods have been successfully applied to patients with other central nervous system (CNS) lesions, these methods have not yet been evaluated in cognitively impaired patients with epilepsy. The present study evaluated the effectiveness of two commonly used methods for attention deficits: (a) the Retraining Method, aimed at retraining impaired cognitive functions; and (b) the Compensation Method, aimed at teaching compensatory strategies while taking neuronal loss for granted.

'Ictal epileptic headache' : Recent concepts for new classifications criteria

Dear Sir, More frequently associated than expected on the basis of coincidence, headache and epilepsy are both characterized by transient paroxysmal episodes of altered brain function with clinical, pathophysiological and therapeutic overlap. Cortical spreading depression (CSD) is probably the connection point between these two conditions. In fact, CSD and an epileptic focus are able to facilitate each other (1–3), and in the central nervous system there is a hierarchical organization based on ‘neuronal networks’ (cortical and subcortical) which may be more or less prone to CSD (migraine) and/or an epileptic focal discharge (i.e. seizures). Hyperexcitation occurs in epilepsy, in migraine hypoexcitation followed by hyperexcitation, as rebound phenomenon (spreading depression) (1–3). Moreover, a disexcitability condition (hyperand hypoexcitation in the same patient at different points in time) has even been demonstrated (1–3). The International Classification of Headache Disorders (ICHD-2) committee recognizes three nosographic entities concerning the relationship between epilepsy and headache (Table 1). The International League Against Epilepsy (ILAE) classification fully

Migralepsy, hemicrania epileptica, post-ictal headache and “ictal epileptic headache”: a proposal for terminology and classification revision

Despite the fact that migraine and epilepsy are among the commoner brain diseases and that comorbidity of these conditions is well known, only few reports of migralepsy and hemicrania epileptica (HE) have been published according to the current ICHD-II criteria. Particularly, ICHD-II describes “migraine-triggered seizure” (i.e., migralepsy) among complications of migraine at “1.5.5” (as a rare event in which a seizure happens during migrainous aura), while hemicrania epileptica (coded at “7.6.1”) and post-ictal headache (coded at “7.6.2”) are described among headaches attributed to epileptic seizure. However, to date neither the International Headache Society nor the International League against Epilepsy mention that headache/migraine may be the sole ictal epileptic manifestation. Based on the current knowledge, migralepsy is highly unlikely to exist as such. We, therefore, propose to delete this term until clear evidence its existence is provided. Moreover, we herein propose a revision of terminology and classification criteria to properly represent the migraine/headache relationships. We suggest the term “ictal epileptic headache” in cases in which headache/migraine is the sole ictal epileptic manifestation.

Methodology of photic stimulation revisited: Updated European algorithm for visual stimulation in the EEG laboratory

Intermittent photic stimulation (IPS) is a common procedure performed in the electroencephalography (EEG) laboratory in children and adults to detect abnormal epileptogenic sensitivity to flickering light (i.e., photosensitivity). In practice, substantial variability in outcome is anecdotally found due to the many different methods used per laboratory and country. We believe that standardization of procedure, based on scientific and clinical data, should permit reproducible identification and quantification of photosensitivity. We hope that the use of our new algorithm will help in standardizing the IPS procedure, which in turn may more clearly identify and assist monitoring of patients with epilepsy and photosensitivity. Our algorithm goes far beyond that published in 1999 (Epilepsia, 1999a, 40, 75; Neurophysiol Clin, 1999b, 29, 318): it has substantially increased content, detailing technical and logistical aspects of IPS testing and the rationale for many of the steps in the IPS procedure. Furthermore, our latest algorithm incorporates the consensus of repeated scientific meetings of European experts in this field over a period of 6 years with feedback from general neurologists and epileptologists to improve its validity and utility. Accordingly, our European group has provided herein updated algorithms for two different levels of methodology: (1) requirements for defining photosensitivity in patients and in family members of known photosensitive patients and (2) requirements for tailored studies in patients with a clear history of visually induced seizures or complaints, and in those already known to be photosensitive.

A case with atypical childhood occipital epilepsy "Gastaut type": an ictal migraine manifestation with a good response to intravenous diazepam.

We report the history of a 14‐year‐old girl with atypical childhood occipital epilepsy “Gastaut type” whose first generalized tonic–clonic seizure was preceded by migraine without aura and followed by a status migrainosus. This status lasted for 3 days despite standard analgesic therapy. An EEG recording revealed an occipital status epilepticus during her migraine complaints. Seven minutes after intravenous administration of 10 mg diazepam under continuous EEG recording, a suppression of the epileptiform discharges over the right occipital was seen, while the headache subsided 3 min later. After precise questioning about the circumstances that possibly could have led to these events, it appeared that she had played for hours with a play station on the new color TV and she had visited an exhibition of Matisse and Bonnard with bright colors and contrast‐rich text. Standardized extensive intermittent photic stimulation (IPS), 2 days after the status migrainosus, evoked besides asymmetrical right‐sided driving, green spots in her left visual field, while in the EEG sharp waves were recorded over the right parietotemporal region. After further IPS with 20 Hz (eye closure), she started complaining of a light pulsating headache right occipitally and in the EEG right parietotemporal sharp‐waves were seen. This lasted for about 10 min. Later, an interictal routine EEG was normal except for some theta over the right temporooccipital area. The most likely diagnosis is an atypical form of occipital epilepsy “Gastaut type.” We would therefore advocate recording EEGs with photic stimulation in patients with atypical migraneous features.

Survival of Patients with Epilepsy: An Estimate of the Mortality Risk

Summary:  Purpose: To investigate the extent and causes of the differences in mortality found in studies on mortality in epilepsy based on a quantitative review of the literature.