Benign epilepsy with centrotemporal spikes - Current concepts of diagnosis and treatment.

Benign epilepsy with centrotemporal spikes (BECTS) is the most common focal epilepsy of the childhood and also one of the best known. It has a proclivity to start at a particular age and remit spontaneously before adolescence. Majority of patients may avoid long-term treatment, because of the mild course and very good outcome. Only few patients may present cognitive deficits if the proper treatment is not implied. BECTS is a part of heterogeneous group of syndromes that consists of Landau-Kleffner Syndrome (LKS), Continuous Spike-and-Wave during Sleep (CSWS) and Atypical benign partial epilepsy (ABPE). These syndromes may be also a result of various trajectories that BECTS may evolve to. Disease is suggested to have genetic origins, as some patients have relatives with different types of epilepsy. The discovery of the pathogenic mechanism of the disease and implementation of targeted therapy belong to the main challenges in the treatment of these patients.

Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures.

Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1ß expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL-1ß and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL-1ß stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL-1ß signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro- or anti-inflammatory effects, respectively. This study provides supportive evidence that inflammation-related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte-mediated inflammatory response, with miR146a as most interesting anti-inflammatory therapeutic candidate.

Systemic effects of treatment with mTOR inhibitors in tuberous sclerosis complex: a comprehensive review.

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder associated with constitutive overactivation of the mammalian target of rapamycin (mTOR) pathway and characterized by development of benign tumours in various organs. mTOR inhibitors have proven to be effective in the targeted therapy of certain TSC-associated pathologies such as subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas (AMLs). Accumulating experimental and clinical data suggest that mTOR inhibitors might have a systemic, disease-modifying influence on affected individuals. This systematic review provides an analysis of available clinical data concerning systemic effect of mTOR inhibitors and the influence of mTOR inhibition on different manifestations of TSC in individual patients.

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.

Acute fright induces onset of symptoms in vanishing white matter disease-case report.

Vanishing white matter disease is a newly recognised leukoencephalopathy of identified genetic background, characterised by cystic degeneration and progressive vanishing of white matter. The characteristic clinical symptoms are spasticity and ataxia with relatively preserved cognitive functions. A characteristic feature of the disease is the occurrence of the symptoms after a physical stress situation such as mild head trauma or febrile infection. We would like to present a case of a 6-year-old girl whose first symptoms of the disease occurred after being frightened by a horse.

Immunohistochemical and microscopic studies on giant cells in tuberous sclerosis.

Tuberous sclerosis (TSC) is an autosomal dominant disease, caused by mutations in TSC1 or TSC2 genes, encoding hamartin and tuberin, respectively. The clinical picture of the disease is connected with the formation of hamartomas, mainly in the heart, kidneys and the brain. In three types of brain lesions: cortical tubers, subependymal nodules and subependymal giant-cell astrocytoma (SEGA) characteristic, so-called "giant cells" are found. In the present review we summarise immunohistochemical findings of two types of studies performed on giant cells aiming at establishing the expression of hamartin and tuberin level and determining the presence of neuron- or astrocyte-specific markers. Moreover, we support our argument with the summary of ultrastructural research done with the purpose of demonstrating structures characteristic of neural and/or glial cells. We conclude that giant cells in cortical tubers and SEGAs are the same undifferentiated cells that, depending on individual determination, can show neural or glial features.

Poor mental development in patients with tuberous sclerosis complex: clinical risk factors.

OBJECTIVE: To identify clinical risk factors for poor mental development among patients with tuberous sclerosis complex (TSC). DESIGN: Case-control analysis of a clinic population. SETTING: Specialty clinic in a hospital. PATIENTS: One hundred six patients with TSC consecutively seen between January 1984 and December 1995 at the Child Neurology Clinic of the Children's Memorial Health Institute in Warsaw, Poland. STUDY VARIABLES: Seizure type, age at seizure onset, sex, and history of diphtheria, tetanus, and pertussis immunization. MAIN OUTCOME MEASURE: Moderate to profound developmental delays. RESULTS: Seizure type (ie, infantile spasms) was the only analyzed risk factor that showed a consistent and independent association with poor mental development (adjusted odds ratio, 3.0; 95% confidence interval, 1.1-8.4; P =.03). Age at seizure onset, which initially showed a significant association with poor mental development, was no longer significantly associated after adjustment for seizure type (adjusted odds ratio, 1.6; P = .43). Neither sex (odds ratio, 1.1; P = .96) nor history of diphtheria, tetanus, and pertussis immunization (odds ratio, 1.0; P = .80) showed evidence of being a risk factor for poor mental development among patients with TSC. CONCLUSIONS: Infantile spasms, as the type of seizure on initial examination, is a significant risk factor for poor mental development in patients with TSC. Age at time of first seizure is not an independent risk factor but reflects the early ages at which these patients are seen with infantile spasms. Neither sex nor history of diphtheria, tetanus, and pertussis immunization is a risk factor for the subsequent development of poor mental development among patients with TSC.

Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients.

The Tuberous Sclerosis Complex 1998 Consensus Conference clinical criteria represent an important advance in the diagnosis of tuberous sclerosis complex. Since many findings regarded as highly specific for tuberous sclerosis complex are not apparent until late childhood or adulthood, refinements by age may prove of value. We have stratified 106 children into five age groups (0 to 2 years of age, above 2 to 5 years, above 5 to 9 years, above 9 to 14 years, and above 14 to 18 years). Physicians should be alerted as to the frequency of the criteria in different stages of children.

Denaturing high-performance liquid chromatography (DHPLC) is a highly sensitive, semi-automated method for identifying mutations in the TSC1 gene.

Sensitive and automated methods for the detection of DNA sequence variation are required for a wide variety of genetic studies. Diagnostic testing in human genetic disorders is one application of such methods. Tuberous sclerosis complex (TSC) is an autosomal dominant familial tumor syndrome characterized by the development of benign tumors (hamartomas) in multiple organs (OMIM # 19110, #191092). There is a high frequency of sporadic cases and significant demand from patients and families for genetic testing information. Two TSC genes have been identified (TSC1 and TSC2) and together account for all cases [1,2]. Here we report our methods for DHPLC analysis of the TSC1 gene and demonstrate the high sensitivity of this method in a blinded analysis of 21 TSC patients with known TSC1 mutations. In this series, DHPLC detected 27/28 (96%) known TSC1 sequence variations. The only sequence variation not identified by DHPLC in this study is a mosaic case.

Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy.

Lamotrigine is a broad-spectrum antiepileptic drug that blocks sodium channels, thereby inhibiting the pre-synaptic release of excitatory neurotransmitters. The primary aim of the study was to evaluate lamotrigine add-on therapy and consecutive monotherapy in patients with epilepsy whose seizures were not controlled by carbamazepine or valproate. One hundred and twenty six epilepsy patients at 18 centres in Poland were recruited into a lamotrigine substitution study. In all patients, existing seizures were poorly controlled with valproate (n= 63) or carbamazepine (n= 63) monotherapy. The study consisted of four phases: (1) a 4-week lamotrigine dose-escalation phase, (2) an 8-week lamotrigine add-on phase, (3) an 8-week carbamazepine/valproate withdrawal phase, and (4) an 8-week lamotrigine monotherapy phase. Of 126 patients recruited into the study, 107 (85%) completed dose-escalation and add-on therapy with lamotrigine and 85 (68%) completed lamotrigine monotherapy. Fifty percent of patients during add-on therapy and 53% during lamotrigine monotherapy experienced at least 50% reduction in total seizures (responders) compared to the pre-study period. Approximately 20% of patients during add-on therapy and 27% during lamotrigine monotherapy were seizure free. Total well-being was assessed using a Visual Analogue Scale with 62% of patients during add-on therapy and 60% in lamotrigine monotherapy reporting improvement in scores. Lamotrigine was generally well tolerated. Treatment was discontinued in 7% because of adverse events. In conclusion, lamotrigine is an effective AED in add-on therapy and monotherapy, it is safe and well tolerated, and successful conversion from add-on to monotherapy can be achieved in many cases. An additive effect between lamotrigine and valproate was observed.

Lentigo.

A lentigo is a small pigmented macule with a sharply circumscribed border. There are multiple clinical and etiologic forms. Lentigines are often initially identified shortly after birth, although they may appear later in childhood. Certain varieties are associated with systemic abnormalities. Histologic findings include epidermal hyperplasia with increased pigmentation of the basal layer.

[The usefulness of clinical signs and selected diagnostic methods in the diagnosis of tuberous sclerosis in children]. / Ocena przydatnosci objawów klinicznych oraz wybranych badan pomocniczych w rozpoznawaniu stwardnienia guzowatego u dzieci.

55 children took part in the study. Besides depigmented naevi and epilepsy, echocardiography plays the most significant role in the diagnosis of tuberous sclerosis in children below 2 years of age. In older children, besides dermatologic examination, cranial computerized tomography and abdominal ultrasonography are the most effective methods. This study suggests that the diagnostic effectiveness of different clinical signs and examinations depends on the age of the examined children. An appropriate diagnostic procedure may lead to earlier diagnostic and allows to avoid excessive examinations.

[Oligosymptomatic presentation of tuberous sclerosis in two pedigrees]. / Skapoobjawowe wystepowanie stwardnienia guzowatego w dwóch rodowodach.

The authors describe clinical course of tuberous sclerosis in seven family members from two pedigrees. They stress the importance of careful medical anamnesis and skin examination in family members of persons affected with tuberous sclerosis. It is pointed out that in contrast to widespread stereotype of a patient with tuberous sclerosis-a person with epilepsy, mental retardation and multiple skin and organ involvement, much more common than it was previously thought, the course of the disease may be oligosymptomatic and the affected person may properly function in society. All 7 affected persons presented in the paper were mentally normal and only two of them suffered from epilepsy.

[Problems with diagnosis and treatment of brain tumors in children with tuberous sclerosis]. / Problemy zwiazane z rozpoznawaniem i leczeniem nowotworów mózgu u dzieci ze stwardnieniem guzowatym.

Problems are discussed connected with the occurrence of brain tumours in children with tuberous sclerosis with a survey of the most modern Polish and foreign literature. For illustration two cases of such tumours are reported in a group of over 50 children with tuberous sclerosis. The authors discuss also the problems related to surgical treatment in cases of brain tumours developing in tuberous sclerosis.

[Phacomatoses: structural substare of epilepsy]. / Fakomatozy--strukturalne podloze padaczki.

AIM: Evaluation of frequency and characteristics of seizures in the most frequent phacomatoses and assessment of relationship between fits and structural changes in CNS. MATERIAL AND METHODS: 135 children with tuberous sclerosis (TS), 73 with NF-1 and 30 with Sturge-Weber syndrome took part in the study. Except for careful anamnesis in all patients with fits were done brain CT or MR studies. RESULTS: Seizures were reported in 128 of 135 (95%) patients with TS, usually, between 3rd and 6th month of life. Their early presentation was related to developmental delay. Cortical and subcortical lesions detected in neuroimaging studies were responsible for drug-resistant epilepsy in the children. 13 of 73 (18%) children with NF-1 had seizures. In 9 of them CNS lesions were detected on neuroimaging. In Sturge-Weber syndrome inherited meningo-encephalic lesions correlated with hemilateral seizures, even in first months of life. Most children did not show apparent developmental delay. CONCLUSIONS: Epileptic seizures in phacomatoses had their own specificity. They were correlated with structural lesions in CNS.

[Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in adult patients with epilepsy resistant carbamazepine and valproate]. / Otwarte badanie oceniajace skutecznosc i bezpieczenstwo stosowania lamotriginy w terapii dodanej z przejsciem na monoterapie u pacjentów doroslych z padaczka z napadami opornymi na karbamazepine lub walproinian.

UNLABELLED: Lamotrigine is a broad-spectrum antiepileptic drug which is thought to act in part via a use-dependent blockade of voltage-sensitive sodium channels to stabilise the neuronal membrane. This results in the inhibition of the excessive release of excitatory amino acids, such as glutamate, during epileptic activity. An open, multicentre, prospective trial of lamotrigine was carried out in adult patients with drug-resistant epilepsy on monotherapy with carbamazepine or valproate. The primary aim of the study was to assess add-on lamotrigine withdrawing to monotherapy. 28-week clinical trial was divided into 4 phases: (1) Dose escalation period (4 weeks), (2) Add-on period (8 weeks), (3) Standard AED withdrawal period (8 weeks), (4) Lamotrigine monotherapy (8 weeks). Thirty-three patients were previously treated with valproate, 44 with carbamazepine. Of 77 patients recruited into the study, 64 patients (83%) completed add-on therapy, 49 patients (64%) completed lamotrigine monotherapy. 44% of all patients during the add-on phase and 48% during lamotrigine monotherapy had a reduction in seizure frequency of at least 50% compared with pre-study period. 13% of all patients achieved seizure freedom during add-on therapy and 18% during monotherapy. Improvement of Visual Analogue Scale (VAS) scores was observed in 65% and 57% patients respectively. A significant proportion of patients could be successfully converted to lamotrigine monotherapy. Lamotrigine was also generally well tolerated. 23 patients (30%) had at least one adverse event (AE), but only 1/4 of all AEs might be reasonably regarded as an effect of the medication. 7 patients (9%) discontinued prematurely from the study due to adverse event. More AEs were observed in add-on therapy than in lamotrigine monotherapy. The safety profile was consistent with that seen during other clinical trials with lamotrigine. CONCLUSIONS: 1. Lamotrigine is effective AED in add-on and monotherapy (responders rate--44% and 48% respectively). 2. In most cases conversion from add-on therapy to monotherapy can be done successfully. 3. Lamotrigine is a safe and well-tolerated drug.

[Gabitril as an additive drug in therapy of intractable epileptic seizures in children]. / Gabitril w terapii dodanej w opornych napadach czesciowych zlozonych i wtórnie uogólnionych u dzieci. Doniesienie wstepne.

Tiagabine (Gabitril, Sanofi Synlhelabo) new antiepileptic drug was used in add-on therapy in 25 children with resistant partial complex and secondary generalized seizures. Treatment was carried out in children aged 4-17 years with low dose escalation from 5 to 45 mg/day, in three doses until good clinical effects were obtained. In 3 patients aged 4 years, in 11 children aged 5-12 years and in 11 children aged above 17 years Gabitril was used. Follow up period was 8-10 months. Frequency of epileptic seizures before implementation of Gabitril treatment, even during polytherapy with 2 or more antiepileptic drugs was several to hundred per day (status epilepticus was observed in 2 children with Rasmussen syndrome). During the observation 5 children became seizure free, in 11 patients reduction in seizures frequency above 50% was observed and in 9 children effects of treatment were not good enough. Gabitril was well tolerated, and any adverse events were observed in add-on therapy. Preliminary observation and good results of add-on therapy with Gabitril are positive. Drug is safe and generally well-tolerated with good effects at add-on therapy in 64% children with resistant partial complex and secondary generalized seizures.

[Immunohistochemical and ultrastructural studies of subependymal giant cell astrocytomas in children with tuberous sclerosis]. / Badania immunohistochemiczne i ultrastrukturalne podwysciólkowych gwiazdziaków olbrzymiokomórkowych wystepujacych u dzieci ze stwardnieniem guzowatym.

Ten cases of subependymal giant cell astrocytoma associated with sclerosis tuberosa were reevaluated in order to assess their phenotyping and biologic features. All tumours were multifocal, located within lateral ventricles, often overlying the head of the caudate nucleus or protruding into the third ventricle. The phenotype of SGCA disclosed a complex pattern: giant cells were GFAP positive, some of them were stained with antibodies against neurofilament and NSE. Ultrastructurally, the cells of SGCA contained frequent dense bodies, numerous intermediate filaments and microtubules. Biologically SGCA is not malignant, although its appearance may suggest otherwise. No patient had an apparent recurrence within 3-5 years of observation.

[A case of renal clear cell sarcoma in a child with tuberous sclerosis]. / Przypadek miesaka jasnokomórkowego nerki u dziecka ze stwardnieniem guzowatym.

A 10-year-old girl with sclerosis tuberosa was admitted to the Children's Health Centre for febrile states of unclear origin. Ultrasonography revealed the presence of renal tumour of clear cell sarcoma character in histopathological examination. Despite nephrectomy the child died several weeks after the operation. The authors pay attention to the fact that both clear cell sarcoma and most lesions observed in sclerosis tuberosa have common origin from the nervous crest so their coexistence seems no accidental. In view of the observed in sclerosis tuberosa proneness to neoformation, the authors stress the necessity of periodical examinations of the brain and internal organs, mainly kidneys and liver.

[The Landau-Kleffner syndrome]. / Zespól Landau-Kleffnera.

The variable aetiology and complicated pathogenesis of aphasia during epilepsy in children cause many diagnostic and therapeutic difficulties. The authors describe two children with aphasia and epileptic seizures and with high titre of toxoplasma antibodies. The role of toxoplasmosis in this syndrome is discussed. The small number of publications on the Landau-Kleffner syndrome in the available literature, especially Polish, is stressed.