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1.
Eur J Paediatr Neurol ; 23(3): 404-409, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30885501

RESUMO

PURPOSE: Epilepsy in GLUT1 deficiency syndrome is generally drug-resistant; ketogenic diet (KD) therapy is the mainstay of therapy, as production of ketones provides the brain with an alternative energy source, bypassing the defect in GLUT1. Failure of KD therapy and risk factors for failure have been sparsely published. METHODS: We performed a retrospective study of GLUT1DS patients with refractory epilepsy failing on KD therapy, to identify their clinical characteristics. RESULTS: Failure of the ketogenic diet was due to KD inefficacy (poor effect despite adequate ketosis), as well as intolerance and an inability to attain ketosis. Our cohort of seven patients in whom KD therapy failed stood out for their advanced age at seizure onset, i.e. almost 4 years vs 8 months in large series, female sex, as well as their advanced age at diagnosis and initiation of KD therapy. EEG recordings during KD therapy can aid in the assessment of effectiveness of the KD therapy. CONCLUSIONS: GLUT1DS is generally described as a treatable disorder and existing case series do not provide details of treatment failure. In select patients with GLUT1DS, KD therapy fails, rendering GLUT1DS an essentially untreatable disorder. Failure of the ketogenic diet was due to KD inefficacy (poor effect despite adequate ketosis), as well as intolerance and an inability to attain ketosis. Failure to reduce seizure frequency with deterioration of the EEG findings should lead to consideration of cessation of KD therapy.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/dietoterapia , Dieta Cetogênica , Proteínas de Transporte de Monossacarídeos/deficiência , Adolescente , Erros Inatos do Metabolismo dos Carboidratos/complicações , Criança , Epilepsia Resistente a Medicamentos/dietoterapia , Epilepsia Resistente a Medicamentos/etiologia , Feminino , Humanos , Masculino , Estudos Retrospectivos
3.
Am J Hum Genet ; 104(1): 139-156, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595372

RESUMO

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

4.
Epilepsia ; 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30525188

RESUMO

OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.

5.
J Neurol ; 265(8): 1934-1936, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29931545

RESUMO

There is mounting evidence for the role of the gut microbiota and gut-brain interactions in neurological diseases. We present six patients with drug-resistant epilepsy who attained temporary seizure freedom during antibiotic treatment. The effect on seizure frequency waned within 2 weeks after cessation of antibiotic treatment. We hypothesized that antibiotic treatments may have a short-term effect, through gut microbiota disruption, on gut-brain interactions and ultimately seizure frequency. This observed impact of antibiotics on seizure frequency hints at a possible role of the gut microbiota in epilepsy and its manifestations. This begs the question: can epilepsy be treated by antibiotics? Or perhaps in a broader sense: can alterations in the gut microbiota be used as a treatment modality in drug-resistant epilepsy? This concept and the six intriguing cases provide interesting leads for epilepsy management.


Assuntos
Antibacterianos/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Dieta Cetogênica , Epilepsia Resistente a Medicamentos/dietoterapia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Convulsões/dietoterapia , Convulsões/tratamento farmacológico
7.
Ned Tijdschr Geneeskd ; 159: A7980, 2015.
Artigo em Holandês | MEDLINE | ID: mdl-25563779

RESUMO

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a neurological syndrome characterized by elevated intracranial pressure in the absence of intracerebral abnormalities or hydrocephalus. CASE DESCRIPTION: A 17-year-old girl gained more than 25 kg in weight during treatment with risperidone and subsequently developed headache, diplopia and loss of vision due to IIH. After insertion of a ventriculoperitoneal drain and discontinuation of risperidone she lost weight and her symptoms improved. Her visual functions recovered almost fully during follow-up. CONCLUSION: Patients with IIH are mainly overweight young women who present with raised intracranial pressure evidenced by headache, nausea, vomiting and vision disturbances. Prescribed medication-induced weight gain may lead to IIH. Treatment of IIH should be focused on the prevention of severe and irreversible loss of vision.


Assuntos
Antipsicóticos/efeitos adversos , Obesidade/complicações , Pseudotumor Cerebral/diagnóstico , Risperidona/efeitos adversos , Ganho de Peso , Adolescente , Antipsicóticos/uso terapêutico , Feminino , Cefaleia , Humanos , Obesidade/induzido quimicamente , Pseudotumor Cerebral/etiologia , Risperidona/uso terapêutico
8.
PLoS One ; 9(3): e90068, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24594874

RESUMO

In childhood frontal lobe epilepsy (FLE), cognitive impairment and educational underachievement are serious, well-known co-morbidities. The broad scale of affected cognitive domains suggests wide-spread network disturbances that not only involves, but also extends beyond the frontal lobe. In this study we have investigated whole brain connectional properties of children with FLE in relation to their cognitive impairment and compared them with healthy controls. Functional connectivity (FC) of the networks was derived from dynamic fluctuations of resting state fMRI and structural connectivity (SC) was obtained from fiber tractograms of diffusion weighted MRI. The whole brain network was characterized with graph theoretical metrics and decomposed into modules. Subsequently, the graph metrics and the connectivity within and between modules were related to cognitive performance. Functional network disturbances in FLE were related to increased clustering, increased path length, and stronger modularity compared to healthy controls, which was accompanied by stronger within- and weaker between-module functional connectivity. Although structural path length and clustering appeared normal in children with FLE, structural modularity increased with stronger cognitive impairment. It is concluded that decreased coupling between large-scale functional network modules is a hallmark for impaired cognition in childhood FLE.


Assuntos
Epilepsia do Lobo Frontal/patologia , Epilepsia do Lobo Frontal/fisiopatologia , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Adolescente , Envelhecimento/patologia , Estudos de Casos e Controles , Criança , Transtornos Cognitivos/complicações , Transtornos Cognitivos/fisiopatologia , Epilepsia do Lobo Frontal/complicações , Humanos , Imagem por Ressonância Magnética
9.
Epilepsia ; 54(3): 446-54, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23253092

RESUMO

PURPOSE: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls. METHODS: Thirty-two children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired. KEY FINDINGS: Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia. SIGNIFICANCE: Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE.


Assuntos
Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/fisiopatologia , Epilepsia do Lobo Frontal/epidemiologia , Epilepsia do Lobo Frontal/fisiopatologia , Lobo Frontal/fisiologia , Rede Nervosa/fisiologia , Adolescente , Criança , Transtornos Cognitivos/psicologia , Estudos de Coortes , Epilepsia do Lobo Frontal/psicologia , Feminino , Humanos , Masculino , Vias Neurais/fisiologia , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologia , Sistema de Registros
10.
Epilepsia ; 53(10): 1690-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22889330

RESUMO

Cognitive impairment is the most common comorbidity in children with epilepsy, but its pathophysiology and predisposing conditions remain unknown. Clinical epilepsy characteristics are not conclusive in determining cognitive outcome. Because many children with epilepsy do not have macrostructural magnetic resonance imaging (MRI) abnormalities, the underlying substrate for cognitive impairment may be found at the microstructural or functional level. In the last two decades, new MRI techniques have been developed that have the potential to visualize microstructural or functional abnormalities associated with cognitive impairment. These include volumetric MRI, voxel-based morphometry (VBM), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and functional MRI (fMRI). All of these techniques have shed new light on various aspects associated with, or underlying, cognitive impairment, although their use in epilepsy has been limited and focused mostly on adults. Therefore, in this review, the use of all these different MRI techniques to unravel cognitive impairment in epilepsy is discussed both in adults and children with epilepsy. Volumetric MRI and VBM have revealed significant volume losses in the area of the seizure focus as well as in distant areas. DTI adds evidence of loss of integrity of connections from the seizure focus to distant areas as well as between distant areas. MRS and fMRI have shown impaired function both in the area of the seizure focus as well as in distant structures. For this review we have compiled and compared findings from the various techniques to conclude that cognitive impairment in epilepsy results from a network disorder in which the (micro)structures as well as the functionality can be disturbed.


Assuntos
Encéfalo/irrigação sanguínea , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Epilepsia/complicações , Imagem por Ressonância Magnética , Encéfalo/patologia , Humanos , Processamento de Imagem Assistida por Computador , Oxigênio/sangue , PubMed/estatística & dados numéricos
11.
Eur J Paediatr Neurol ; 16(6): 707-15, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22748634

RESUMO

BACKGROUND: Frontal Lobe Epilepsy (FLE) is the second most frequent type of partial epilepsy and its onset is generally in childhood. Though cognitive and behavioural impairments have been described as co-morbid disorders in epilepsy, their extent in FLE, particularly in children, remains unknown. AIMS: In this study, we assess cognitive skills and behaviour in a cohort of paediatric FLE patients. METHODS: We measured the performance of 71 children with cryptogenic FLE on intelligence tests, neuropsychological tests, and behavioural questionnaires. Age-dependent normative values were used for reference. Results were related to epilepsy-factors including age at epilepsy onset, duration of epilepsy, seizure frequency, localisation of the epileptic focus and drug load. RESULTS: Paediatric FLE patients performed worse on intellectual and neuropsychological tests compared to reference values, and had a delay in school achievement. The performance of patients was typically worse on tasks measuring visual-spatial functions, memory, psychomotor speed and alertness. High seizure frequency was associated with lower scores on the arithmetic subtest of the intelligence scale; the other epilepsy-factors had no statistically significant influence on intelligence test or neuropsychological test outcome. Behavioural problems included attention problems, anxiety and internalising behaviour. These were not significantly related to epilepsy-factors. CONCLUSIONS: Children with cryptogenic FLE show a broad range of cognitive and behavioural impairments, compared to reference values. While high seizure frequency may affect performance on selected cognitive measures, other epilepsy-factors do not seem to influence cognition and behaviour. Study of micro-structural or functional brain abnormalities that underlie these cognitive and behavioural impairments are warranted.


Assuntos
Comportamento Infantil , Cognição/fisiologia , Epilepsia do Lobo Frontal/psicologia , Adolescente , Atenção/fisiologia , Criança , Estudos de Coortes , Escolaridade , Feminino , Humanos , Testes de Inteligência , Imagem por Ressonância Magnética , Masculino , Memória de Longo Prazo/fisiologia , Testes Neuropsicológicos , Desempenho Psicomotor/fisiologia , Percepção Espacial/fisiologia
12.
PLoS One ; 7(4): e34125, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22485157

RESUMO

INTRODUCTION: The reproducibility of tractography is important to determine its sensitivity to pathological abnormalities. The reproducibility of tract morphology has not yet been systematically studied and the recently developed tractography contrast Tract Density Imaging (TDI) has not yet been assessed at the tract specific level. MATERIALS AND METHODS: Diffusion tensor imaging (DTI) and probabilistic constrained spherical deconvolution (CSD) tractography are performed twice in 9 healthy subjects. Tractography is based on common space seed and target regions and performed for several major white matter tracts. Tractograms are converted to tract segmentations and inter-session reproducibility of tract morphology is assessed using Dice similarity coefficient (DSC). The coefficient of variation (COV) and intraclass correlation coefficient (ICC) are calculated of the following tract metrics: fractional anisotropy (FA), apparent diffusion coefficient (ADC), volume, and TDI. Analyses are performed both for proximal (deep white matter) and extended (including subcortical white matter) tract segmentations. RESULTS: Proximal DSC values were 0.70-0.92. DSC values were 5-10% lower in extended compared to proximal segmentations. COV/ICC values of FA, ADC, volume and TDI were 1-4%/0.65-0.94, 2-4%/0.62-0.94, 3-22%/0.53-0.96 and 8-31%/0.48-0.70, respectively, with the lower COV and higher ICC values found in the proximal segmentations. CONCLUSION: For all investigated metrics, reproducibility depended on the segmented tract. FA and ADC had relatively low COV and relatively high ICC, indicating clinical potential. Volume had higher COV but its moderate to high ICC values in most tracts still suggest subject-differentiating power. Tract TDI had high COV and relatively low ICC, which reflects unfavorable reproducibility.


Assuntos
Imagem de Tensor de Difusão , Adulto , Anisotropia , Tronco Encefálico/anatomia & histologia , Corpo Caloso/anatomia & histologia , Feminino , Giro do Cíngulo/anatomia & histologia , Humanos , Masculino , Córtex Motor/anatomia & histologia , Vias Neurais , Reprodutibilidade dos Testes , Vias Visuais , Adulto Jovem
13.
Epilepsia ; 52(5): 849-56, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21480882

RESUMO

Frontal lobe epilepsy (FLE) is considered the second most common type of the localization-related epilepsies of childhood. Still, the etiology of FLE in children, its impact on cognitive functioning and behavior, as well as the response to antiepileptic drug treatment in children has not been sufficiently studied. This review focuses on these aspects of FLE in childhood, and reveals that FLE in childhood is most often cryptogenic, and impacts on a broad range of cognitive functions. The nature and severity of cognitive deficits are highly variable, although impaired attention and executive functions are most frequent. Young age at seizure onset is the only potential risk factor for poor cognitive outcome that has been consistently reported. The behavioral disturbances associated with FLE are also highly variable, although attention deficit/hyperactivity disorder seems most frequent. In 40% of children with FLE satisfactory seizure control could not be achieved. This is a higher percentage than reported for the general population of children with epilepsy. Therefore, pediatric FLE, even if cryptogenic in nature, is frequently complicated by impairment of cognitive function, behavioral disturbances, and therapy-resistance. Given the impact of these complications, there is a need for studies of the etiology of frontal lobe epilepsy-associated cognitive and behavioral disturbances, as well as pharmacotherapy-resistance.


Assuntos
Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/epidemiologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Epilepsia do Lobo Frontal/diagnóstico , Epilepsia do Lobo Frontal/epidemiologia , Idade de Início , Anticonvulsivantes/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Pré-Escolar , Comorbidade , Resistência a Medicamentos , Epilepsia do Lobo Frontal/tratamento farmacológico , Feminino , Humanos , Masculino , Testes Neuropsicológicos
14.
BMC Neurol ; 10: 30, 2010 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-20459819

RESUMO

BACKGROUND: The aetiology of central nervous system lesions observed in cerebral cyclosporine neurotoxicity remains controversial. CASE PRESENTATION: We report a 48-year-old woman with a non-severe aplastic anaemia who presented with stroke-like episodes while on cyclosporine treatment.Transcranial Doppler ultrasound revealed severely elevated flow velocities in several cerebral vessels, consistent with vasospasm. Immediately after reducing the cyclosporine dose, the stroke-like episodes disappeared. Only after cyclosporine withdrawal the transcranial Doppler ultrasound abnormalities fully resolved. CONCLUSIONS: This case demonstrates a significant role of vasospasm in the pathway of cyclosporine-induced neurotoxicity. Transcranial Doppler ultrasound is an effective tool for the diagnosis and follow-up of cyclosporine-induced vasospasm.


Assuntos
Antifúngicos/efeitos adversos , Ciclosporina/efeitos adversos , Síndromes Neurotóxicas/complicações , Síndromes Neurotóxicas/etiologia , Vasoespasmo Intracraniano/etiologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Acidente Vascular Cerebral/tratamento farmacológico , Ultrassonografia Doppler Transcraniana/métodos , Vasoespasmo Intracraniano/diagnóstico por imagem
15.
J Stroke Cerebrovasc Dis ; 19(1): 73-4, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20123230

RESUMO

We report a case of a 93-year-old man, who presented with limb-shaking transient ischemic attacks (TIAs) after orthostatic position change or turning his head to the left. The limb-shaking TIAs resulted from external compression of the carotid artery. Contrast-enhanced magnetic resonance angiography of the head and neck and Doppler ultrasound examination of the thyroid gland revealed a large cystic nodule in the right thyroid lobe, resulting in compression and posterior displacement of the right common carotid artery. Clinicians should be aware that limb-shaking TIAs can not only result from obstructive extracerebral or intracerebral artery disease, but also from external compression of the carotid artery.


Assuntos
Arteriopatias Oclusivas/etiologia , Doenças das Artérias Carótidas/etiologia , Cistos/complicações , Ataque Isquêmico Transitório/etiologia , Nódulo da Glândula Tireoide/complicações , Tremor/etiologia , Idoso de 80 Anos ou mais , Arteriopatias Oclusivas/diagnóstico , Doenças das Artérias Carótidas/diagnóstico , Constrição Patológica , Meios de Contraste , Cistos/diagnóstico , Humanos , Angiografia por Ressonância Magnética , Masculino , Nódulo da Glândula Tireoide/diagnóstico , Ultrassonografia Doppler
17.
Neurology ; 66(7): 1094-6, 2006 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-16606924

RESUMO

The authors report a case of human African trypanosomiasis with CNS involvement caused by Trypanosoma brucei rhodesiense in a 52-year-old woman, which relapsed after melarsoprol treatment. After a second regimen, she developed a severe toxic polyneuropathy, progressing to coma and eventually death. MRI revealed rapidly progressive multiple white matter lesions as well as damage of the central gray matter and cortex. The autopsy results confirmed the diagnosis of human African trypanosomiasis.


Assuntos
Tripanossomíase Africana/patologia , Evolução Fatal , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Países Baixos , Tanzânia , Viagem , Tripanossomíase Africana/diagnóstico
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