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.

EEG abnormalities preceding the epilepsy onset in tuberous sclerosis complex patients - a prospective study of 5 patients.

Tuberous sclerosis complex (TSC) is a multisystem, autosomal dominant disorder characterized by multiple hamartomas development. Epilepsy is the most common symptom appearing in 80-90% of the patients mainly in the first year of life. A prompt and early seizure control is crucial and can prevent development of an epileptic encephalopathy and secondary mental retardation. Therefore the very early identification of seizures seems to be of a great importance. We present the cases of 5 patients diagnosed with TSC prenatally or perinatally and regularly monitored (at 4-6 weeks intervals) with EEG before the epilepsy onset. The patients' age at baseline varied from 9 days to 9 weeks. In all of the patients epileptiform discharges preceded the epilepsy onset. The time interval between abnormality detection on EEG and the epilepsy onset varied from 1 to 8 days. The patient's age at the epilepsy onset ranged from the 17th day to the 5th month of life. In one patient the EEG was abnormal from the beginning and in this patient the epileptic seizures started from the neonatal period. In the rest of the patients (4/5) the EEG remained normal throughout the first months of life. In all of the children epilepsy started with focal motor seizures. Our study is the first prospective one showing the results of the EEG monitoring in TSC patients and the natural evolution of the EEG patterns in patients with the seizures types other than infantile spasms.

Tuberous sclerosis complex: advances in diagnosis, genetics, and management

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, heart, kidneys, liver, and lungs. Two-thirds of patients represent sporadic mutations. The classic triad is seizures, mental retardation, and cutaneous angiofibromas. However, the full triad occurs in only 29 por cento of patients; 6por cento of them lack all three of them. Two tumor suppressor genes responsible for TSC have been identified: TSC1 gene on chromosome 9 and TSC2 on chromosome 16. This article highlights the most recent significant advances in the diagnosis and genetics of TSC, along with a discussion on the limitations and the usefulness of the revised 1998 clinical criteria for the tuberous sclerosis complex. The [quot ]ash leaf[quot ] macule often comes in other shapes, such as round; most are polygonal, usually 0.5 cm to 2.0 cm in diameter, resembling a thumbprint. Since the death of its describer, Thomas Fitzpatrick, we call each a [quot ]Fitzpatrick patch.[quot ] Special attention is paid in this work to TSC treatment options, including therapeutic trials with rapamycin, also known as sirolimus. LEARNING OBJECTIVE: After completing this learning activity, participants should familiar with tuberous sclerosis complex, its cutaneous signs and systemic findings stratified by patient age, its genetics, and the potential for meaningful therapeutic intervention.

Apparent diffusion coefficient is increased in children with tuberous sclerosis complex personal experience and review of the literature.

Diffusion-weighted imaging (DWI) provides information on tissue integrity and shows increased sensivity in detecting brain white matter disease compared to traditional T2-weighted MRI. We compared apparent diffusion coefficient (ADC) values in brain lesions and normal appearing white matter (NAWM) in patients with tuberous sclerosis complex (TSC) to normal brain tissue in the control group. MRI and DWI were performed in 14 patients with TSC (age range 7-16 years) and in 18 age-matched normal control subjects. ADC values measured from 44 supratentorial cortical tubers, 37 white matter lesions, 80 NAWM were compared to those in control subjects. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests. The highest ADCs were measured in cortical tubers (mean ADC, 1.24×10-3 mm(2)/s), followed in descending order by WM lesions (mean ADC, 1.07×10-3 mm(2)/s), NAWM (mean ADC, 0.83×10-3 mm(2)/s). We found a significant difference in ADC values of gray, WM lesions and NAWM in TSC patients compared to the control group (p<0,0001). Elevated ADC values in NAWM in TSC patients may be caused by subtle depletion of myelin sheaths and looseness of structures within the brain parenchyma due to underlying migration disorders.

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.

Cerebellar lesions in children with tuberous sclerosis complex.

Cerebellar lesions in tuberous sclerosis complex are less frequent than cerebral findings. We present the magnetic resonance (MR) features of uncommon cerebellar changes found in a large series of children with tuberous sclerosis complex (TSC). MR examinations of 73 children (38 males and 35 females) with TSC were reviewed. Twelve patients with cerebellar lesions were selected. Patients' ages ranged from 2.5 years to 21.25 (median: 10.6). The number, anatomic location, signal intensity and contrast enhancement of these lesions were evaluated. MR studies were performed with a 1.5 T scanner obtaining T1, T2-weighted images and FLAIR sequences. Gadolinium was administrated in all cases. Cerebellar tubers were found in 12 patients (16.4%). The total number of cerebellar tubers was 21. Most cerebellar tubers were hyperintense on T2-weighted and FLAIR images and slightly hypointense on T1-weighted images. Eleven of these lesions (52.38%) revealed contrast enhancement. None of cortical cerebral tubers showed contrast enhancement. Atrophy of seven cerebellar tubers was noticed. The mutation in TSC2 gene was confirmed in eight patients. Cerebellar tubers are uncommon. They were not found in the absence of cerebral tubers and may associated with parenchymal volume loss.

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.

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.

[Tests for loss of heterozygosity in tuberous sclerosis]. / Badania nad utrata heterozygotycznosci w stwardnieniu guzowatym.

The authors assessed loss of heterozygosity in TSC1 and TSC2 genes in three patients undergoing resection of TSC hamartomas: two sub-ependymal giant cell astrocytomas and one kidney angiomyolipoma. Loss with heterozygosity was found only in the patient with kidney angiomyolipoma. A germline mutation, TSC2 E35 645 > A 1549Y > N missense mutation was identified by DHPLC and direct genome sequencing in the blood and loss of the normal allele was demonstrated in the tumor. In one of the patients with brain tumors no germline mutation was identified in the blood, but a heterozygous TSC2 E14 1516C > T 505R > X nonsense mutation was found in the SEGA. Another patient demonstrated germline mutation in TSC2 E38 5116C > T 1706R > C, but tumor DNA indicated that there was retention of heterozygosity for this mutation. The presence of LOH in internal organ tumors is consistent with the Knudson's two-hit model in TS. The frequency of LOH depends on the type of tumor and type of mutation (TSC1 or TSC2).

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.

The neurological basis of motor deficits in cerebral palsy.

This article describes the classifications of cerebral palsy most commonly used in daily clinical practice. Special attention is paid to the topographic aspects of the cerebral lesions that cause the clinical manifestations of cerebral palsy. Different types of hypoxic and ischemic encephalopathies in newborns are discussed, along with the clinical outcome.

Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.

Tuberous sclerosis (TSC) is a relatively common hamartoma syndrome caused by mutations in either of two genes, TSC1 and TSC2. Here we report comprehensive mutation analysis in 224 index patients with TSC and correlate mutation findings with clinical features. Denaturing high-performance liquid chromatography, long-range polymerase chain reaction (PCR), and quantitative PCR were used for mutation detection. Mutations were identified in 186 (83%) of 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. A standardized clinical assessment instrument covering 16 TSC manifestations was used. Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations and was somewhat distinct from patients with TSC1 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as-yet-unidentified locus with a relatively mild clinical phenotype.

[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.

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.

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.

[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.