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1.
Neurotherapeutics ; 16(3): 848-857, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054119

RESUMO

Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.

2.
Mol Genet Genomic Med ; 7(7): e00727, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31144463

RESUMO

BACKGROUND: Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants. METHODS: Five different SCN1A promoter-haplotypes were functionally assessed in SH-SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter-region of their unaffected allele were investigated. RESULTS: All non-wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter-region (65%-80%, p = 0.039-0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter-haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes. CONCLUSION: The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter-haplotypes.

4.
Epilepsia ; 60(3): 419-428, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30740695

RESUMO

OBJECTIVE: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. METHODS: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. RESULTS: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

5.
Epilepsy Behav ; 90: 252-259, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30527252

RESUMO

PURPOSE: Differentiating between Dravet syndrome and non-Dravet SCN1A-related phenotypes is important for prognosis regarding epilepsy severity, cognitive development, and comorbidities. When a child is diagnosed with genetic epilepsy with febrile seizures plus (GEFS+) or febrile seizures (FS), accurate prognostic information is essential as well, but detailed information on seizure course, seizure freedom, medication use, and comorbidities is lacking for this milder patient group. In this cross-sectional study, we explore disease characteristics in milder SCN1A-related phenotypes and the nature, occurrence, and relationships of SCN1A-related comorbidities in both patients with Dravet and non-Dravet syndromes. METHODS: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated, consisting of 116 patients with Dravet syndrome and 48 patients with either GEFS+, febrile seizures plus (FS+), or FS. Clinical data were collected from medical records, semi-structured telephone interviews, and three questionnaires: the Functional Mobility Scale (FMS), the Pediatric Quality of Life Inventory (PedsQL) Measurement Model, and the Child or Adult Behavior Checklists (CBCL/ABCL). RESULTS: Walking disabilities and severe behavioral problems affect 71% and 43% of patients with Dravet syndrome respectively and are almost never present in patients with non-Dravet syndromes. These comorbidities are strongly correlated to lower quality-of-life (QoL) scores. Less severe comorbidities occur in patients with non-Dravet syndromes: learning problems and psychological/behavioral problems are reported for 27% and 38% respectively. The average QoL score of the non-Dravet group was comparable with that of the general population. The majority of patients with non-Dravet syndromes becomes seizure-free after 10 years of age (85%). CONCLUSIONS: Severe behavioral problems and walking disabilities are common in patients with Dravet syndrome and should receive specific attention during clinical management. Although the epilepsy course of patients with non-Dravet syndromes is much more favorable, milder comorbidities frequently occur in this group as well. Our results may be of great value for clinical care and informing newly diagnosed patients and their parents about prognosis.


Assuntos
Epilepsias Mioclônicas/epidemiologia , Epilepsias Mioclônicas/genética , Epilepsia/epidemiologia , Epilepsia/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Estudos Transversais , Epilepsias Mioclônicas/diagnóstico , Epilepsia/diagnóstico , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/epidemiologia , Síndromes Epilépticas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Convulsões Febris/diagnóstico , Convulsões Febris/epidemiologia , Convulsões Febris/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/epidemiologia , Espasmos Infantis/genética , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
6.
Am J Hum Genet ; 103(5): 666-678, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30343943

RESUMO

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

8.
Genet Med ; 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30093711

RESUMO

PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

10.
Epilepsia ; 59(6): 1154-1165, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29750338

RESUMO

OBJECTIVE: Pathogenic variants in SCN1A can give rise to extremely variable disease severities that may be indistinguishable at their first presentation. We aim to find clinical features that can help predict the evolution of seizures into Dravet syndrome and clinical features that predict cognitive outcome in Dravet syndrome. We specifically investigate the role of contraindicated medication (CIM) as a possible modifier of cognitive decline. METHODS: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated. Clinical data were collected from medical records and semistructured telephone interviews. Cognitive function was classified by a child neurologist, neuropsychologist, and clinical geneticist. Several clinical variables, including duration of CIM use in the first 5 years of disease, were evaluated in univariate and multivariate analyses. RESULTS: A longer duration of CIM use in the first 5 years after seizure onset was significantly associated with a worse cognitive outcome at time of inclusion, and with lower interpolated intelligence quotient/developmental quotient scores after the first 5 years of disease in Dravet syndrome patients. CIM use remained a significant predictor for cognitive outcome in a multivariate regression model, as did age at the first observation of developmental delay and age at first afebrile seizure. Age at first afebrile seizure was the most accurate predictor for evolution of seizures into Dravet syndrome for the complete cohort. SIGNIFICANCE: Our data suggest that a longer CIM use in the first 5 years of disease can have negative effects on cognitive outcome in Dravet syndrome. An early diagnosis is essential to avoid these drugs. Furthermore, we identified age at first afebrile seizure as an important predictor for evolution of seizures into Dravet syndrome and for the severity of Dravet syndrome, which can be used to counsel parents of young patients with SCN1A-related seizures.

11.
Epilepsia ; 59(3): 690-703, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29460957

RESUMO

OBJECTIVE: Phenotypes caused by de novo SCN1A pathogenic variants are very variable, ranging from severely affected patients with Dravet syndrome to much milder genetic epilepsy febrile seizures plus cases. The most important determinant of disease severity is the type of variant, with variants that cause a complete loss of function of the SCN1A protein (α-subunit of the neuronal sodium channel Nav1.1) being detected almost exclusively in Dravet syndrome patients. However, even within Dravet syndrome disease severity ranges greatly, and consequently other disease modifiers must exist. A better prediction of disease severity is very much needed in daily practice to improve counseling, stressing the importance of identifying modifying factors in this patient group. We evaluated 128 participants with de novo, pathogenic SCN1A variants to investigate whether mosaicism, caused by postzygotic mutation, is a major modifier in SCN1A-related epilepsy. METHODS: Mosaicism was investigated by reanalysis of the pathogenic SCN1A variants using single molecule molecular inversion probes and next generation sequencing with high coverage. Allelic ratios of pathogenic variants were used to determine whether mosaicism was likely. Selected mosaic variants were confirmed by droplet digital polymerase chain reaction and sequencing of different tissues. Developmental outcome was classified based on available data on intelligence quotient and school functioning/education. RESULTS: Mosaicism was present for 7.5% of de novo pathogenic SCN1A variants in symptomatic patients. Mosaic participants were less severely affected than nonmosaic participants if only participants with truncating variants are considered (distribution of developmental outcome scores, Mann-Whitney U, P = .023). SIGNIFICANCE: Postzygotic mutation is a common phenomenon in SCN1A-related epilepsies. Participants with mosaicism have on average milder phenotypes, suggesting that mosaicism can be a major modifier of SCN1A-related diseases. Detection of mosaicism has important implications for genetic counseling and can be achieved by deep sequencing of unique reads.


Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Variação Genética/genética , Mosaicismo , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Clin Neurophysiol ; 128(4): 661-666, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28130057

RESUMO

OBJECTIVE: Diagnostic value and efficacy of re-interpretation of previous EEGs in 100 patients admitted to a tertiary epilepsy center with EEG results conflicting with the clinical diagnosis after the first visit. METHODS: EEGs were reclassified. A matched control group was included to assess the efficiency of the re-interpretation process. Efficacy was assessed by questionnaires and costs as number of technician hours needed. RESULTS: In 85 patients the previous EEG conclusion was known. In 43 the conclusion was altered. In 23 the epileptic activity changed from positive to negative (17) or the reverse (6). In 15 the focus changed (7 originally classified as generalized epileptic activity). In 5 the syndrome changed. 57% of the re-interpretation group needed no extra EEG afterwards. 96% of the re-interpretations were considered useful by requesting and 72% by not involved neurologists. The average time per EEG technologist per patient was 8,81h in controls and 5,40 in the re-interpretation group. CONCLUSIONS: In 43 from the 85 patients (51%) re-interpretation of 'controversial' EEGs led to a different opinion. The re-interpretations were useful and less time consuming, compared to new EEGs in controls. SIGNIFICANCE: Re-interpretation of 'controversial' EEGs is useful and cost effective.


Assuntos
Eletroencefalografia/normas , Epilepsia/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Erros de Diagnóstico/prevenção & controle , Erros de Diagnóstico/estatística & dados numéricos , Eletroencefalografia/economia , Eletroencefalografia/métodos , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Centros de Atenção Terciária/estatística & dados numéricos
13.
Epilepsia ; 56(9): e114-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26122718

RESUMO

Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.


Assuntos
Epilepsias Parciais/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Morte Súbita do Lactente/genética
14.
Epilepsy Behav ; 47: 39-44, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26021464

RESUMO

OBJECTIVES: This study aimed to describe seizure precipitants in Dravet syndrome (DS) compared with other epilepsies. METHODS: Seizure precipitants as reported in a Dutch cohort of patients with DS with pathogenic SCN1A mutations (n=71) were compared with those of a cohort with childhood epilepsy (n=149) and of a community-based cohort with epilepsy (n=248); for all three Dutch cohorts, the same type of questionnaire was used. Seizure precipitants were categorized as 'fever', 'visual stimuli', 'sleep deprivation', 'stress, including physical exercise', 'auditory stimuli', and 'other'. RESULTS: For 70 (99%) of 71 patients with DS, at least one seizure precipitant was recalled by parents. Seizure precipitants that were reported in more than half of the cohort with DS were as follows: having a fever (97%), having a cold (68%), taking a bath (61%), having acute moments of stress (58%), and engaging in physical exercise (56%). Seizure precipitants freely recalled by parents were often related to ambient warmth or cold-warmth shifts (41%) and to various visual stimuli (18%). Patients with DS had more positive seizure precipitant categories (median 4) compared with the cohort with childhood epilepsy (median 2) and the community-based cohort with epilepsy (median 0) (p<0.001) and showed the highest percentage in each category (all p<0.001). Within the category 'stress, including physical exercise', physical exercise was more often reported to provoke seizures in stress-sensitive patients in the cohort with DS than in the cohort with childhood epilepsy (78% vs. 35%, p<0.001). In the cohort with childhood epilepsy, physical exercise was more often reported in fever-sensitive children than in other children (25% vs. 12%, p=0.042). CONCLUSIONS: Our study shows a high prevalence of a range of seizure precipitants in DS. Our results underscore elevated body temperature as an important seizure precipitant, whether caused by fever, warm bath, ambient warmth, or physical exercise. Knowledge of these seizure precipitants may improve preventive strategies in the otherwise difficult treatment of DS.


Assuntos
Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões/epidemiologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Epilepsias Mioclônicas/epidemiologia , Feminino , Febre/complicações , Febre/epidemiologia , Temperatura Alta/efeitos adversos , Humanos , Masculino , Mutação , Países Baixos/epidemiologia , Estimulação Luminosa/efeitos adversos , Prevalência , Convulsões/etiologia , Convulsões/fisiopatologia , Privação do Sono/complicações , Privação do Sono/epidemiologia , Estresse Psicológico/complicações , Estresse Psicológico/epidemiologia , Inquéritos e Questionários
15.
Epilepsia ; 50(12): 2538-48, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19519798

RESUMO

PURPOSE: A nonlinear association and a source localization technique were used to describe the onset and propagation of spike-and-slow-wave discharges (SWDs) in children with absence seizures. Previous studies have emphasized a leading cortical role in the generation of absence seizures in genetic epileptic rats. METHODS: Synchronization between all magnetoencephalography (MEG) sensor-couples before and during SWDs in five patients was investigated over time. A source localization [beamformer, SAM(g(2))] technique was used to find brain regions associated with the origin of the spikes of the SWDs. RESULTS: The onset of SWDs was characterized by high associations at left and right frontal regions. An alternating pattern of high synchronization was found during trains of SWDs: generalized during the wave and localized during the spike; the origin of the spike was different from the onset of SWDs, more frontal lateral and medial parietal. The localization of this latter region was confirmed with SAM(g(2)). DISCUSSION: The outcome of the nonlinear association techniques demonstrated that SWDs have a local cortical onset, whereas the association and beamformer technique support a local or even a focal cortical involvement in the occurrence of the spike in a train of SWDs. In all, the cortex contains local frontal and parietal sites relevant before the onset of the generalized pattern of SWDs and other ones that might contain the driving force behind the spike in trains of 3-4 Hz SWDs.


Assuntos
Córtex Cerebral/fisiopatologia , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/fisiopatologia , Magnetoencefalografia/estatística & dados numéricos , Adolescente , Animais , Mapeamento Encefálico/estatística & dados numéricos , Criança , Eletrodos Implantados , Eletroencefalografia/estatística & dados numéricos , Feminino , Lobo Frontal/fisiopatologia , Lateralidade Funcional/fisiologia , Humanos , Imagem por Ressonância Magnética/estatística & dados numéricos , Masculino , Vias Neurais/fisiopatologia , Dinâmica não Linear , Lobo Parietal/fisiopatologia , Ratos , Ratos Endogâmicos , Processamento de Sinais Assistido por Computador
16.
Seizure ; 17(1): 92-7, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17697789

RESUMO

We describe four children with Dravet syndrome treated with the combination of valproic acid (VPA) and topiramate (TPM) who developed transient liver toxicity. The time-interval between fever, administration of acetaminophen, epileptic status and liver enzyme disturbances in our four cases suggests that accumulation of toxic acetaminophen-metabolites is possibly responsible for liver toxicity. If acetaminophen and its metabolites cause those liver problems in children treated with the combination of VPA and TPM, the advice to use acetaminophen for treating fever in children using this combination, should be changed. Only future clinical observations and research can solve this clinical dilemma.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Entorpecentes/efeitos adversos , Anticonvulsivantes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Deficiências do Desenvolvimento/complicações , Frutose/análogos & derivados , Epilepsia Mioclônica Juvenil/complicações , Ácido Valproico/efeitos adversos , Acetaminofen/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Anticonvulsivantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Quimioterapia Combinada , Enzimas/sangue , Feminino , Frutose/efeitos adversos , Frutose/uso terapêutico , Humanos , Lactente , Influenza Humana/complicações , Testes de Função Hepática , Masculino , Epilepsia Mioclônica Juvenil/tratamento farmacológico , Canal de Sódio Disparado por Voltagem NAV1.1 , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Síndrome , Topiramato , Ácido Valproico/uso terapêutico
17.
J Abnorm Child Psychol ; 31(3): 301-13, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12774863

RESUMO

In a previous paper we showed that community children with hyperactive behavior were more inconsistent than controls in the temporal organization of their motor output. In this study we investigated: (1) various aspects of motor timing processes in 13 clinically diagnosed boys with attention deficit hyperactivity disorder (ADHD) who were compared to 11 community boys with hyperactive behavior and to a control group and (2) the effect of methylphenidate on the motor timing processes in the clinical group with ADHD in a double blind, cross-over, medication-placebo design, including 4 weeks of medication. The clinical group with ADHD, like the community group with hyperactivity, showed greater variability in sensorimotor synchronization and in sensorimotor anticipation relative to controls. The clinical group was also impaired in time perception, which was spared in the community group with hyperactivity. The persistent, but not the acute dose, of methylphenidate reduced the variability of sensorimotor synchronization and anticipation, but had no effect on time perception. This study shows that motor timing functions are impaired in both clinical and community children with hyperactivity. It is the first study to show the effectiveness of persistent administration of methylphenidate on deficits in motor timing in ADHD children and extends the use of methylphenidate from the domain of attentional and inhibitory functions to the domain of executive motor timing.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Metilfenidato/uso terapêutico , Análise de Variância , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Estudos Cross-Over , Discriminação (Psicologia) , Método Duplo-Cego , Humanos , Masculino , Destreza Motora/efeitos dos fármacos , Características de Residência , Percepção do Tempo/efeitos dos fármacos
18.
Psychopharmacology (Berl) ; 159(3): 335-40, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11862367

RESUMO

RATIONALE: Tablets sold as ecstasy often contain not only 3,4-methylenedioxymethamphetamine (MDMA) but other compounds well known to cause dopaminergic neurotoxicity, such as (meth)amphetamine. Furthermore, the use of ecstasy in the Netherlands is often combined with the use of amphetamine. However, little is known about the effects of ecstasy use or the combination of ecstasy and amphetamine use on dopamine (DA) neurones in the human brain. OBJECTIVES: This study was designed to investigate the effects of ecstasy as well as the combined use of ecstasy and amphetamine on the density of nigrostriatal DA neurones. METHODS: [123I]beta-CIT SPECT was used to quantify striatal DA transporters. Striatal [123I]beta-CIT binding ratios of control subjects ( n=15) were compared with binding ratios of ecstasy users ( n=29) and individuals with a history of combined ecstasy and amphetamine use ( n=9) after adjustment for age. RESULTS: Striatal [123I]beta-CIT binding ratios were significantly lower in combined ecstasy and amphetamine users compared to sole ecstasy users (6.75 versus 8.46, respectively: -20.2%, P=0.007). Binding ratios were significantly higher in ecstasy users when compared to controls (8.46 versus 7.47, respectively: +13.2%, P=0.045). CONCLUSIONS: These initial observations suggest that the sole use of ecstasy is not related to dopaminergic neurotoxicity in humans. In contrast, the reported use of amphetamine by regular users of ecstasy seems to be associated with a reduction in nigrostriatal DA neurones.


Assuntos
Anfetamina/metabolismo , Cocaína/metabolismo , Corpo Estriado/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras/metabolismo , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , Proteínas do Tecido Nervoso , Tomografia Computadorizada de Emissão de Fóton Único/estatística & dados numéricos , Adolescente , Inibidores da Captação Adrenérgica/metabolismo , Adulto , Análise de Variância , Cocaína/análogos & derivados , Intervalos de Confiança , Proteínas da Membrana Plasmática de Transporte de Dopamina , Inibidores da Captação de Dopamina/metabolismo , Feminino , Humanos , Radioisótopos do Iodo/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos
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