Caroline Lund

[Psychogenic non-epileptic seizures].

BACKGROUND Psychogenic non-epileptic seizure is the term used for epilepsy-like seizures assumed to have psychological causes. Many patients with such seizures are misdiagnosed with epilepsy, and are consequently treated with antiepileptic drugs for many years. Assessment of a thorough medical history and ictal EEG-recordings will lead to the right diagnosis in most cases. The article provides an overview of this condition, which often represents large diagnostic and therapeutic challenges and is the most frequent differential diagnosis in epilepsy. MATERIAL AND METHODS The article is based on literature identified through a non-systematic search in PubMed up to January 2009. RESULTS Much literature is available in the field. 10-20 % of those referred to epilepsy centers because of therapy-resistant epilepsy, have psychogenic non-epileptic seizures. 70-80 % of these patients are women. The attacks may resemble all types of epileptic seizures, from absence-like episodes to tonic-clonic-like seizures. INTERPRETATION Such seizures may have a wide spectre of causes, including chronic psychological conflicts and psychotraumas. Treatment should therefore be tailored to individuals.

CHD2 mutations in Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy with a heterogeneous etiology. In this study, we aimed to explore the role of CHD2 in LGS, as CHD2 mutations have been described recently in various epileptic encephalopathies. We have previously identified one patient with a large deletion affecting the CHD2 gene in a group of 22 patients with LGS or LGS-like epilepsy. In the remaining 17 patients without known etiology, Sanger sequencing revealed a de novo 1-bp duplication in the CHD2 gene in another patient. This mutation leads to a frameshift and, consequently, a premature stop codon 49bp downstream of the mutation. The patient had prominent myoclonic seizures and photosensitivity, thus, sharing phenotypic features with previously reported patients with CHD2-related epilepsy. In our original material of 22 patients with LGS features, we have now found two (9%) with mutations in the CHD2 gene. Our findings suggest that CHD2 mutations are important in the etiological spectrum of LGS.

Copy number variants in adult patients with Lennox–Gastaut syndrome features

PURPOSE Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy with complex etiology. To explore possible genetic predispositions and causes of LGS, we have searched for copy number variants (CNVs). METHODS We studied 21 patients with LGS or LGS-like epilepsy for CNVs using whole-genome array comparative genomic hybridization (aCGH). KEY FINDINGS Eight patients (38%) carried rare CNVs that might contribute to their phenotype. The pathogenicity could be questioned in some of them, but in four patients (19%) a causative role was considered highly probable. Three had CNVs and clinical features consistent with known genetic syndromes: 22q13.3 deletion, 2q23.1 deletion, and MECP2 duplication. SIGNIFICANCE There is a high frequency of rare CNVs in adult patients with LGS-like epilepsy. The phenotypes of these background disorders may be obscured by the effects of intractable seizures and massive antiepileptic drug treatment. Previously, syndromic disorders were primarily identified by their clinical features; however, a genome wide approach with identification of the genotype might shed light on the phenotype.

SCN1A mutation screening in adult patients with Lennox–Gastaut syndrome features

Mutations in the SCN1A gene have been identified in a variety of epilepsy phenotypes, from severe encephalopathies such as Dravet syndrome to milder familial forms such as generalized epilepsy with febrile seizures plus. In a previous study, an SCN1A mutation was also identified in a patient with Lennox-Gastaut syndrome (LGS), and the aim of our study was to investigate the importance of mutations in the SCN1A gene in Norwegian patients with clinical features of LGS. We screened 22 adult patients for SCN1A mutations by direct sequencing of DNA and for micro-rearrangements with multiplex ligation-dependent probe amplification. In one patient a mutation was found, which demonstrates a clinical overlap between LGS and Dravet syndrome. This finding emphasizes the significance of SCN1A mutations also in epileptic disorders with features of LGS, particularly in the myoclonic variant of the disorder.

Efficacy and tolerability of long-term treatment with vagus nerve stimulation in adolescents and adults with refractory epilepsy and learning disabilities.

The long-term effects of vagus nerve stimulation (VNS) on seizure frequency were studied in 50 patients with epilepsy and learning disabilities. Mean observation time was 4.6 years. At follow-up, none of the patients was seizure-free, 25% had more than 50% seizure reduction, and 46% had some seizure reduction, but less than 50%. The discontinuation rate was 18%. Our results indicate that, like antiepileptic drugs, VNS does not have such a good seizure-reducing effect in patients with epilepsy and learning disabilities compared with the general epilepsy population.

Aicardi Syndrome: An Epidemiologic and Clinical Study in Norway

BACKGROUND Aicardi syndrome is a rare neurodevelopmental disorder. The main diagnostic features are agenesis of corpus callosum, chorioretinal lacunae, and infantile spasms. The outcome is in general severe, with poor cognitive development and difficult-to-treat epilepsy. The aim of this study was to perform a nationwide epidemiologic survey of patients with Aicardi syndrome and describe their clinical features. Norway is a small country with a well-developed health system, making epidemiologic studies of rare diseases feasible and reliable. METHODS We aimed at identifying all patients diagnosed with Aicardi syndrome in Norway. Prevalence of Aicardi syndrome was calculated for January 1, 2011. All available patients were examined, and their medical records were scrutinized. RESULTS Six females aged 7 to 27 years with the diagnosis of Aicardi syndrome were identified. With a female population of 949,578 in ages 0 to 29 years, we found an age-adjusted prevalence of 0.63 per 100,000 females. One patient never had epileptic seizures. The other five had all experienced infantile spasms, all had at some point hypsarrhythmia in electroencephalography, two had a clear picture of suppression burst, whereas three had periods of suppression. Four of the five patients with seizure disorders experienced a marked improvement with time. CONCLUSION We found an age-adjusted prevalence of 0.63 per 100,000 females with Aicardi syndrome and that their seizure disorder appeared to improve with age.

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

Aicardi syndrome (AS) is a well-characterized neurodevelopmental disorder with an unknown etiology. In this study, we performed whole-exome sequencing in 11 female patients with the diagnosis of AS, in order to identify the disease-causing gene. In particular, we focused on detecting variants in the X chromosome, including the analysis of variants with a low number of sequencing reads, in case of somatic mosaicism. For 2 of the patients, we also sequenced the exome of the parents to search for de novo mutations. We did not identify any genetic variants likely to be damaging. Only one single missense variant was identified by the de novo analyses of the 2 trios, and this was considered benign. The failure to identify a disease gene in this study may be due to technical limitations of our study design, including the possibility that the genetic aberration leading to AS is situated in a non-exonic region or that the mutation is somatic and not detectable by our approach. Alternatively, it is possible that AS is genetically heterogeneous and that 11 patients are not sufficient to reveal the causative genes. Future studies of AS should consider designs where also non-exonic regions are explored and apply a sequencing depth so that also low-grade somatic mosaicism can be detected.

Dravet syndrome as a cause of epilepsy and learning disability

BACKGROUND Dravet syndrome is a severe, genetic epileptic encephalopathy with seizures starting during the first year of life. We present a review of the genetic and clinical picture along with treatment aspects. MATERIAL AND METHODS This review is based on a non-systematic literature search in PubMed until April 2011 and the personal experiences of the authors. RESULTS Dravet syndrome should be suspected in children with febrile hemiconvulsions or tonic-clonic seizures in the first year of life. Non-febrile seizures also occur, and other seizure types gradually appear, e.g. myoclonic jerks, atypical absences or focal seizures. In adulthood the clinical picture is less characteristic. The clinical diagnosis is supported by genetic testing; 70-80% of the patients have mutations in the sodium channel subunit gene SCN1A. Seizure control is difficult to achieve, but valproate, benzodiazepines and stiripentol may cause improvement, whereas sodium channel blockers, such as lamotrigine and carbamazepine may aggravate the tendency towards seizures. INTERPRETATION Dravet syndrome appears to be an under-recognised condition among both children and adults with severe epilepsy and learning disability. Clinical information from the first years of life is essential in making the diagnosis. A correct diagnosis at an early age is essential for appropriate treatment and genetic counselling.

Aicardi syndrome and cognitive abilities: A report of five cases

Aicardi syndrome is a rare neurodevelopmental disorder with agenesis of corpus callosum, chorioretinal lacunae, and infantile spasms as the main features. The outcome is in general severe, with poor cognitive development and difficult-to-treat epilepsy. In this study, we assessed the level of cognitive function of five girls with Aicardi syndrome, using normed population based tests and questionnaires. Their cognitive abilities varied from mild to profound intellectual disabilities. The more severe the epilepsy, the poorer were the cognitive skills. To the best of our knowledge, this is the first study that systematically applies validated cognitive assessment tools to study patients with this syndrome. Knowledge about cognitive functioning is crucial for providing optimal special education and finding appropriate alternative communication with parents and caregivers.