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1.
Epilepsy Behav ; 102: 106826, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31816477

RESUMO

PURPOSE: Limited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. METHODS: Children six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) were eligible for enrollment. Children receiving clobazam were excluded. After baseline overnight video-electroencephalography (vEEG) to confirm diagnosis and ascertain hypsarrhythmia, patients were treated with synthetic CBD oral solution (20 mg/kg/day). Overnight video-EEG was repeated after 14 days, and both baseline and repeat video-EEGs were completely de-identified and reviewed in a pairwise fashion by an independent, blinded pediatric electroencephalographer. The primary efficacy endpoint was freedom from spasms and hypsarrhythmia on day 14. RESULTS: Nine patients were enrolled, comprising an older (median age = 23 months) cohort with long-standing IS (median duration = 13 months) and numerous prior treatment failures (median = 6). One patient responded to therapy and eight patients exhibited neither clinical nor electrographic response. CONCLUSIONS: The immediate but temporary response in a single patient suggests that CBD oral solution is not particularly effective in highly refractory cases, but may, nevertheless, be effective in younger patients with shorter durations of IS. Further study, examining both short- and long-term outcomes, is warranted to further evaluate the efficacy and safety of CBD oral solution in the treatment of IS.

2.
Neurol Clin Pract ; 8(5): 412-420, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30564495

RESUMO

Background: EXamining everolimus In a Study of Tuberous sclerosis 3 (EXIST-3) demonstrated significantly reduced seizure frequency (SF) with everolimus vs placebo. In this study, we evaluate the long-term efficacy and safety of everolimus for tuberous sclerosis complex (TSC)-associated treatment-refractory seizures. Methods: After completion of the core phase, patients could enter an open-label extension phase and receive everolimus (target exposure, 3-15 ng/mL) for ≥48 weeks. Efficacy end points included change from baseline in average weekly SF expressed as response rate (RR, ≥50% reduction) and median percentage reduction (PR). Results: Of 366 patients, 361 received everolimus in core/extension phases. The RR was 31% (95% CI, 26.2-36.1; N = 352) at week 18, 46.6% (95% CI, 40.9-52.5; N = 298) at 1 year, and 57.7% (95% CI, 49.7-65.4; N = 163) at 2 years. Median PR in SF was 31.7% (95% CI, 28.5-36.1) at week 18, 46.7% (95% CI, 40.2-54) at 1 year, and 56.9% (95% CI, 50-68.4) at 2 years. Ninety-five patients (26.3%) discontinued everolimus before 2 years; 103 (28.5%) had <2 years of follow-up at study cutoff, and 40% were exposed to everolimus for ≥2 years. An analysis classifying discontinued patients as nonresponders showed an RR of 30.2% (95% CI, 25.5-35.2; N = 361) at week 18, 38.8% (95% CI, 33.7-44.1; N = 358) at 1 year, and 41% (95% CI, 34.6-47.7; N = 229) at 2 years, suggesting sustained benefit over time. The incidence of grade 3/4 adverse events (AEs) (any cause) was 40.2%, and 13% discontinued because of AEs (pneumonia [1.7%] and stomatitis [1.4%]). Two deaths were suspected to be treatment-related (pneumonia and septic shock). Conclusions: Sustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile was consistent with the core phase with no new safety concerns. Classification of evidence: This study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.

3.
Lancet Child Adolesc Health ; 2(7): 495-504, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30169322

RESUMO

BACKGROUND: Epilepsy occurs in 70-90% of patients with tuberous sclerosis complex. We aimed to assess the efficacy and safety of adjunctive everolimus for treatment-refractory seizures associated with tuberous sclerosis complex in paediatric patients enrolled in the EXIST-3 trial, a double-blind, placebo-controlled, randomised, phase 3 study. METHODS: This post-hoc analysis focused on paediatric patients (age <18 years) in the EXIST-3 trial, which consisted of baseline (8 weeks), core (18 weeks), and extension phases (≥48 weeks) and was done at 99 centres in 25 countries worldwide. Briefly, patients with tuberous sclerosis complex-associated treatment-refractory seizures, who were receiving a stable dose of one to three antiepileptic drugs, were randomly assigned (1:1:1) to receive placebo, low-exposure everolimus (3-7 ng/mL), or high-exposure everolimus (9-15 ng/mL). Following the core phase, patients could enter the extension phase to receive everolimus at a targeted exposure range of 3-15 ng/mL up to 48 weeks after the last patient had completed the core phase. Efficacy endpoints were response rate (≥50% of reduction from baseline in average weekly seizure frequency) and median percentage reduction in seizure frequency during the 12-week maintenance period of the core phase, and at 12-week intervals throughout the extension phase. This study is registered with ClinicalTrials.gov, number NCT01713946. FINDINGS: Between July 3, 2013, and May 29, 2015, 299 paediatric patients enrolled in the trial. In the younger subgroup (<6 years; n=104), 34 received placebo, 33 low-exposure everolimus, and 37 high-exposure everolimus; in the older subgroup (≥6 years to <18 years; n=195), 62 received placebo, 63 low-exposure everolimus, and 70 high-exposure everolimus. At the end of the core phase, response rate was higher in the treatment groups than placebo in both the younger subgroup (17·6% [6·8-34·5] for placebo vs 30·3% [95% CI 15·6-48·7; p=0·2245] for low-exposure everolimus vs 59·5% [42·1-75·2; p=0·0003] for high-exposure everolimus) and the older subgroup (12·9% [5·7-23·9] vs 27·0% [16·6-39·7; p=0·0491] vs 30·0% [19·6-42·1; p=0·0179]), as were median reduction in seizure frequency (12·3% [95% CI -10·1 to 24·8] vs 29·3% [95% CI 13·4 to 46·3; p=0·0474] vs 54·7% [43·5 to 73·1; p<0·0001] in younger patients; 13·5% [-3·0 to 26·8] vs 31·0% [16·1 to 42·9; p=0·0128] vs 34·8% [26·7 to 41·3; p=0·0006] in older patients). The efficacy persisted, with sustained seizure reduction after 1 year of treatment across both paediatric subgroups (response rate 48·9% [95% CI 38·1-59·8] for the younger subgroup vs 47·2% [39·3-55·2] for the older subgroup; median percentage reduction in seizure frequency 48·4% [95% CI 34·3-73·6] vs 48·0% [38·2-57·5]). At the cutoff date for the extension phase, grade 3 or 4 adverse events were reported in 45 (45%) younger patients (commonly pneumonia [n=16]) and 74 (38%) older patients (commonly pneumonia [n=8] and stomatitis [n=6]). Two deaths (pneumonia, which was suspected to be treatment-related, and sudden unexplained death due to epilepsy) were reported. INTERPRETATION: Adjunctive everolimus resulted in sustained reductions in seizure frequency after 1 year and was well tolerated in paediatric patients with treatment-refractory seizures associated with tuberous sclerosis complex. FUNDING: Novartis Pharmaceuticals Corporation.


Assuntos
Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Everolimo/uso terapêutico , Esclerose Tuberosa/complicações , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Estudos Prospectivos
4.
Pediatr Neurol ; 87: 48-56, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30174244

RESUMO

BACKGROUND: No large-scale studies have specifically evaluated the outcomes of infantile spasms (IS) of unknown cause, previously known as cryptogenic or idiopathic. The Epilepsy Phenome/Genome Project aimed to characterize IS of unknown cause by phenotype and genotype analysis. METHODS: We undertook a retrospective multicenter observational cohort of 133 individuals within the Epilepsy Phenome/Genome Project database met criteria for IS of unknown cause with at least six months of follow-up data. Clinical medical records, imaging, and electroencephalography were examined. RESULTS: Normal development occurred in only 15% of IS of unknown cause. The majority (85%) had clinically documented developmental delay (15% mild, 20% moderate, and 50% severe) at last assessment (median 2.7 years; interquartile interval 1.71-6.25 years). Predictors of positive developmental outcomes included no delay prior to IS (P < 0.001), older age of IS onset (median six months old), and resolution of IS after initial treatment (P < 0.001). Additional seizures after IS occurred in 67%, with predictors being seizures prior to IS (P = 0.018), earlier age of IS onset (median five months old), and refractory IS (P = 0.008). On a research basis, whole exome sequencing identified 15% with de novo variants in known epilepsy genes. Individuals with a genetic finding were more likely to have poor developmental outcomes (P = 0.035). CONCLUSIONS: The current study highlights the predominately unfavorable developmental outcomes and that subsequent seizures are common in children with IS of unknown cause. Ongoing genetic evaluation of IS of seemingly unknown cause is likely to yield a diagnosis and provide valuable prognostic information.


Assuntos
Desenvolvimento Infantil/fisiologia , Deficiências do Desenvolvimento/fisiopatologia , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Idade de Início , Criança , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Feminino , Humanos , Lactente , Masculino , Fenótipo , Prognóstico , Estudos Retrospectivos , Espasmos Infantis/complicações , Sequenciamento Completo do Exoma
5.
Brain Dev ; 40(8): 693-698, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29754875

RESUMO

PURPOSE: This study was performed 1) to determine the timing of spike normalization in patients with benign epilepsy with centrotemporal spikes (BECTS); 2) to identify relationships between age of seizure onset, age of spike normalization, years of spike persistence and treatment; and 3) to assess final outcomes between groups of patients with or without spikes at the time of medication tapering. METHODS: Retrospective analysis of BECTS patients confirmed by clinical data, including age of onset, seizure semiology and serial electroencephalography (EEG) from diagnosis to remission. Age at spike normalization, years of spike persistence, and time of treatment onset to spike normalization were assessed. Final seizure and EEG outcome were compared between the groups with or without spikes at the time of AED tapering. RESULTS: One hundred and thirty-four patients were included. Mean age at seizure onset was 7.52 ±â€¯2.11 years. Mean age at spike normalization was 11.89 ±â€¯2.11 (range: 6.3-16.8) years. Mean time of treatment onset to spike normalization was 4.11 ±â€¯2.13 (range: 0.24-10.08) years. Younger age of seizure onset was correlated with longer duration of spike persistence (r = -0.41, p < 0.001). In treated patients, spikes persisted for 4.1 ±â€¯1.95 years, compared with 2.9 ±â€¯1.97 years in untreated patients. No patients had recurrent seizures after AED was discontinued, regardless of the presence/absence of spikes at time of AED tapering. CONCLUSION: Years of spike persistence was longer in early onset BECTS patients. Treatment with AEDs did not shorten years of spike persistence. Persistence of spikes at time of treatment withdrawal was not associated with seizure recurrence.


Assuntos
Encéfalo/fisiopatologia , Eletroencefalografia , Epilepsia Rolândica/fisiopatologia , Epilepsia Rolândica/terapia , Adolescente , Fatores Etários , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Criança , Feminino , Seguimentos , Humanos , Masculino , Indução de Remissão , Estudos Retrospectivos , Tempo para o Tratamento
6.
Epilepsia ; 58(11): 1861-1869, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28980702

RESUMO

OBJECTIVE: A prospective multicenter phase III trial was undertaken to evaluate the performance and tolerability in the epilepsy monitoring unit (EMU) of an investigational wearable surface electromyographic (sEMG) monitoring system for the detection of generalized tonic-clonic seizures (GTCSs). METHODS: One hundred ninety-nine patients with a history of GTCSs who were admitted to the EMU in 11 level IV epilepsy centers for clinically indicated video-electroencephalographic monitoring also received sEMG monitoring with a wearable device that was worn on the arm over the biceps muscle. All recorded sEMG data were processed at a central site using a previously developed detection algorithm. Detected GTCSs were compared to events verified by a majority of three expert reviewers. RESULTS: For all subjects, the detection algorithm detected 35 of 46 (76%, 95% confidence interval [CI] = 0.61-0.87) of the GTCSs, with a positive predictive value (PPV) of 0.03 and a mean false alarm rate (FAR) of 2.52 per 24 h. For data recorded while the device was placed over the midline of the biceps muscle, the system detected 29 of 29 GTCSs (100%, 95% CI = 0.88-1.00), with a detection delay averaging 7.70 s, a PPV of 6.2%, and a mean FAR of 1.44 per 24 h. Mild to moderate adverse events were reported in 28% (55 of 199) of subjects and led to study withdrawal in 9% (17 of 199). These adverse events consisted mostly of skin irritation caused by the electrode patch that resolved without treatment. No serious adverse events were reported. SIGNIFICANCE: Detection of GTCSs using an sEMG monitoring device on the biceps is feasible. Proper positioning of this device is important for accuracy, and for some patients, minimizing the number of false positives may be challenging.


Assuntos
Eletromiografia/métodos , Epilepsia Tônico-Clônica/diagnóstico , Epilepsia Tônico-Clônica/fisiopatologia , Monitorização Ambulatorial/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
7.
Neurology ; 89(4): 385-394, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28667181

RESUMO

OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. RESULTS: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.


Assuntos
Encefalopatias/genética , Encefalopatias/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Proteínas de Homeodomínio , Humanos , Lactente , Masculino , Modelos Moleculares , Fenótipo , Proteína de Homoeobox de Baixa Estatura , Irmãos , Vesículas Sinápticas/metabolismo , Adulto Jovem
8.
Pediatr Crit Care Med ; 18(3): 249-257, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28099234

RESUMO

OBJECTIVE: We aimed to determine the prevalence and risk factors for electrographic seizures in neonates and children requiring extracorporeal membrane oxygenation support. DESIGN: Prospective quality improvement project. SETTING: Quaternary care pediatric institution. PATIENTS: Consistent with American Clinical Neurophysiology Society electroencephalographic monitoring recommendations, neonates and children requiring extracorporeal membrane oxygenation support underwent clinically indicated electroencephalographic monitoring. INTERVENTIONS: We performed a 2-year quality improvement study from July 2013 to June 2015 evaluating electrographic seizure prevalence and risk factors. MAIN RESULTS: Ninety-nine of 112 patients (88%) requiring extracorporeal membrane oxygenation support underwent electroencephalographic monitoring. Electrographic seizures occurred in 18 patients (18%), of whom 11 patients (61%) had electrographic status epilepticus and 15 patients (83%) had exclusively electrographic-only seizures. Electrographic seizures were more common in patients with low cardiac output syndrome (p = 0.03). Patients with electrographic seizures were more likely to die prior to discharge (72% vs 30%; p = 0.01) and have unfavorable outcomes (54% vs 17%; p = 0.004) than those without electrographic seizures. CONCLUSIONS: Electrographic seizures occurred in 18% of neonates and children requiring extracorporeal membrane oxygenation support, often constituted electrographic status epilepticus, and were often electrographic-only thereby requiring electroencephalographic monitoring for identification. Low cardiac output syndrome was associated with an increased risk for electrographic seizures. Electrographic seizures were associated with higher mortality and unfavorable outcomes. Further investigation is needed to determine whether electrographic seizures identification and management improves outcomes.


Assuntos
Cuidados Críticos , Eletroencefalografia , Oxigenação por Membrana Extracorpórea/efeitos adversos , Convulsões/diagnóstico , Convulsões/etiologia , Adolescente , Criança , Pré-Escolar , Cuidados Críticos/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica , Masculino , Prevalência , Estudos Prospectivos , Melhoria de Qualidade , Fatores de Risco , Convulsões/epidemiologia , Estado Epiléptico/diagnóstico , Estado Epiléptico/epidemiologia , Estado Epiléptico/etiologia
9.
Lancet ; 388(10056): 2153-2163, 2016 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-27613521

RESUMO

BACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2-65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01713946. FINDINGS: Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2-22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3-37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5-49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1-21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8-41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0-48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group. INTERPRETATION: Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures. FUNDING: Novartis Pharmaceuticals Corporation.


Assuntos
Anticonvulsivantes/uso terapêutico , Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Convulsões/tratamento farmacológico , Esclerose Tuberosa/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Terapia Combinada , Relação Dose-Resposta a Droga , Método Duplo-Cego , Everolimo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Neurology ; 86(23): 2171-8, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27164704

RESUMO

OBJECTIVE: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. METHODS: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. RESULTS: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. CONCLUSIONS: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.


Assuntos
Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Estudos de Coortes , Consanguinidade , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/metabolismo , Oócitos , Fenótipo , Convulsões/genética , Convulsões/metabolismo , Xenopus laevis
11.
Pediatr Crit Care Med ; 17(6): 547-57, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27097270

RESUMO

OBJECTIVES: To determine 1) whether early electroencephalographic background features were associated with survival and neurologic outcomes among children resuscitated from cardiac arrest and not treated with therapeutic hypothermia and 2) if addition of electroencephalographic background to commonly used clinical criteria is more predictive of outcome than clinical criteria alone. DESIGN: Retrospective study. SETTING: PICU and Cardiac ICUs of a tertiary children's hospital. PATIENTS: Patients resuscitated from in-hospital or out-of-hospital cardiac arrest who underwent clinically indicated electroencephalographic monitoring and were not treated with therapeutic hypothermia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One-hundred twenty-eight patients underwent electroencephalographic monitoring within 1 day of return of spontaneous circulation. Background category was normal in four subjects (3%), slow-disorganized in 58 subjects (45%), discontinuous-burst suppression in 24 subjects (19%) and attenuated-flat in 42 subjects (33%). Forty-six subjects (36%) had a reactive electroencephalography. Twenty subjects (15%) had a seizure during electroencephalographic monitoring. Absence of reactivity (p < 0.001) and seizures (p = 0.04) were associated with worse electroencephalographic background category. After controlling for covariates, for each incrementally worse background score, the odds of death was 3.63 (95% CI, 2.18-6.0; p < 0.001) and the odds of unfavorable neurologic outcome was 4.38 (95% CI, 2.51-7.17; p = 0.001). CONCLUSIONS: Worse electroencephalographic background early after resuscitation from both in-hospital and out-of-hospital cardiac arrest is associated with increased odds of death and unfavorable neurologic outcomes at hospital discharge. These electroencephalographic background patterns may be used in addition to clinical criteria to support prognostic decision making.


Assuntos
Reanimação Cardiopulmonar , Técnicas de Apoio para a Decisão , Eletroencefalografia , Parada Cardíaca/diagnóstico , Parada Cardíaca/fisiopatologia , Adolescente , Criança , Pré-Escolar , Feminino , Parada Cardíaca/mortalidade , Parada Cardíaca/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos , Convulsões/diagnóstico , Convulsões/etiologia
12.
Epilepsia ; 57(5): 786-95, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26949220

RESUMO

OBJECTIVES: We aimed to determine whether implementation of a structured multidisciplinary electroencephalography (EEG) monitoring pathway improved the timeliness of administration of antiseizure medication in response to electrographic seizures in encephalopathic critically ill children. METHODS: A multidisciplinary team developed a pathway to standardize EEG monitoring and seizure management in encephalopathic critically ill children, aiming to decrease the time from electrographic seizure onset to antiseizure medication administration. Data were collected to inform the team of improvement opportunities, which were then provided by an institutional pathway, staff education, and streamlined communication. Measurements were obtained before and after pathway implementation to assess for improvement. RESULTS: We collected data on 41 patients before and 21 after pathway implementation. There were no differences between the baseline and pathway groups in demographic characteristics, acute encephalopathy etiologies, or antiseizure medications utilized. The median duration [interquartile range, IQR] from seizure onset to antiseizure medication administration was shorter for patients treated with the pathway (64 min [50, 101]) compared to patients treated prior to pathway implementation (139 min [71, 189]; p = 0.0006). The median [IQR] interval from seizure onset to antiseizure medication order was shorter for the pathway group (31 min [20, 49]) than the baseline group (71 min [33, 131]; p = 0.003). The median [IQR] interval from antiseizure medication order to administration was shorter for the pathway group (30 min [19, 40]) than the baseline group (40 min [17, 68]) (p = 0.047). Seizure termination was more likely to occur following initial antiseizure medication administration in the pathway than baseline group (67% vs. 27%, p = 0.002). SIGNIFICANCE: Implementation of the pathway resulted in a significant reduction in the duration between electrographic seizure onset and antiseizure medication administration, and a significant increase in the rate of electrographic seizure termination following an initial antiseizure medication. Further study is needed to determine whether these changes are associated with improved outcomes.


Assuntos
Eletroencefalografia , Unidades de Terapia Intensiva , Monitorização Fisiológica , Convulsões/diagnóstico , Convulsões/terapia , Anticonvulsivantes/uso terapêutico , Criança , Feminino , Humanos , Masculino , Convulsões/mortalidade , Estatísticas não Paramétricas , Fatores de Tempo
13.
Epilepsy Behav ; 49: 88-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26076945

RESUMO

Neonatal status epilepticus occurs within the substrate of the hyperexcitable newborn brain and is usually provoked by acute CNS derangements, although status can also be the presentation of early-life epilepsy. Provoked neonatal status usually resolves within a few days, with or without treatment, but new data suggests that status is associated with adverse outcomes, even after controlling for underlying disease severity and MRI structural brain injury. Novel treatments may be needed to improve seizure control and outcome, given the characteristics of neurotransmission in the newborn brain. This article is part of a Special Issue entitled "Status Epilepticus".


Assuntos
Papel do Médico , Estado Epiléptico/diagnóstico , Estado Epiléptico/fisiopatologia , Anti-Infecciosos/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Humanos , Recém-Nascido , Estado Epiléptico/induzido quimicamente
14.
J Thorac Cardiovasc Surg ; 150(1): 169-78; discussion 178-80, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25957454

RESUMO

OBJECTIVES: The American Clinical Neurophysiology Society recommends continuous electroencephalographic monitoring after neonatal cardiac surgery because seizures are common, often subclinical, and associated with worse neurocognitive outcomes. We performed a quality improvement project to monitor for postoperative seizures in neonates with congenital heart disease after surgery with cardiopulmonary bypass. METHODS: We implemented routine continuous electroencephalographic monitoring and reviewed the results for an 18-month period. Clinical data were collected by chart review, and continuous electroencephalographic tracings were interpreted using standardized American Clinical Neurophysiology Society terminology. Electrographic seizures were classified as electroencephalogram-only or electroclinical seizures. Multiple logistic regression was used to assess associations between seizures and potential clinical and electroencephalogram predictors. RESULTS: A total of 161 of 172 eligible neonates (94%) underwent continuous electroencephalographic monitoring. Electrographic seizures occurred in 13 neonates (8%) beginning at a median of 20 hours after return to the intensive care unit after surgery. Neonates with all types of congenital heart disease had seizures. Seizures were electroencephalogram only in 11 neonates (85%). Status epilepticus occurred in 8 neonates (62%). In separate multivariate models, delayed sternal closure or longer deep hypothermic circulatory arrest duration was associated with an increased risk for seizures. Mortality was higher among neonates with than without seizures (38% vs 3%, P < .001). CONCLUSIONS: Continuous electroencephalographic monitoring identified seizures in 8% of neonates after cardiac surgery with cardiopulmonary bypass. The majority of seizures had no clinical correlate and would not have been otherwise identified. Seizure occurrence is a marker of greater illness severity and increased mortality. Further study is needed to determine whether seizure identification and management lead to improved outcomes.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Eletroencefalografia , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/epidemiologia , Cardiopatias/congênito , Cardiopatias/cirurgia , Monitorização Neurofisiológica , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Epilepsias Parciais/etiologia , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Cuidados Pós-Operatórios , Fatores de Risco
15.
Epilepsy Behav ; 49: 238-44, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25908325

RESUMO

PURPOSE: Electrographic seizures (ESs) and electrographic status epilepticus (ESE) are common in children with acute neurologic conditions in pediatric intensive care units (PICUs), and ESE is associated with worse functional and quality-of-life outcomes. As an exploratory study, we aimed to determine if ESE was associated with worse outcomes using more detailed neurobehavioral measures. METHODS: Three hundred children with an acute neurologic condition and altered mental status underwent clinically indicated EEG monitoring and were enrolled in a prospective observational study. We obtained follow-up data from subjects who were neurodevelopmentally normal prior to PICU admission. We evaluated for associations between ESE and adaptive behavior (Adaptive Behavior Assessment System-II, ABAS-II), behavioral and emotional problems (Child Behavior Checklist, CBCL), and executive function (Behavior Rating Inventory of Executive Function, BRIEF) using linear regression analyses. A p-value of <0.05 was considered significant. RESULTS: One hundred thirty-seven of 300 subjects were neurodevelopmentally normal prior to PICU admission. We obtained follow-up data from 36 subjects for the CBCL, 32 subjects for the ABAS-II, and 20 subjects for the BRIEF. The median duration from admission to follow-up was 2.6 years (IQR: 1.2-3.8). There were no differences in the acute care variables (age, sex, mental status category, intubation status, paralysis status, acute neurologic diagnosis category, seizure category, EEG background category, or short-term outcome) between subjects with and without follow-up data for any of the outcome measures. On univariate analysis, significant differences were not identified for CBCL total problem (ES coefficient: -4.1, p = 0.48; ESE coefficient: 8.9, p = 0.13) or BRIEF global executive function (ES coefficient: 2.1, p = 0.78; ESE coefficient: 14.1, p = 0.06) scores, although there were trends toward worse scores in subjects with ESE. On univariate analysis, ESs were not associated with worse scores (coefficient: -21.5, p = 0.051), while ESE (coefficient: -29.7, p = 0.013) was associated with worse ABAS-II adaptive behavioral global composite scores. On multivariate analysis, when compared to subjects with no seizures, both ESs (coefficient: -28, p=0.014) and ESE (coefficient: -36, p = 0.003) were associated with worse adaptive behavioral global composite scores. DISCUSSION: Among previously neurodevelopmentally normal children with acute neurologic disorders, ESs and ESE were associated with worse adaptive behavior and trends toward worse behavioral-emotional and executive function problems. This was a small exploratory study, and the impact of ESs and ESE on these neurobehavioral measures may be clarified by subsequent larger studies. This article is part of a Special Issue entitled "Status Epilepticus".


Assuntos
Comportamento Infantil , Estado Terminal , Doenças do Sistema Nervoso/fisiopatologia , Estado Epiléptico/terapia , Sintomas Afetivos/etiologia , Sintomas Afetivos/psicologia , Criança , Transtornos do Comportamento Infantil/etiologia , Transtornos do Comportamento Infantil/psicologia , Pré-Escolar , Bases de Dados Factuais , Eletroencefalografia , Função Executiva , Feminino , Seguimentos , Humanos , Lactente , Masculino , Doenças do Sistema Nervoso/etiologia , Testes Neuropsicológicos , Estudos Prospectivos , Convulsões/complicações , Convulsões/fisiopatologia , Convulsões/psicologia , Estado Epiléptico/fisiopatologia , Estado Epiléptico/psicologia , Resultado do Tratamento
16.
Epilepsy Res ; 112: 18-26, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25847334

RESUMO

OBJECTIVE: To evaluate the effectiveness of rufinamide (RFM) in patients with Lennox-Gastaut Syndrome (LGS) compared to those with other epilepsy syndromes using time to treatment failure (retention rate) as the outcome measure. METHODS: In this retrospective cohort study, characteristics and outcomes of all patients receiving RFM in 2009 and 2010 were recorded. The primary outcome measure was RFM failure, defined as discontinuation of RFM or initiation of an additional antiepileptic therapy. The secondary outcome measure was discontinuation of RFM. Kaplan-Meier method survival curves were generated for time to RFM failure, for all patients and by the presence or absence of Lennox Gastaut Syndrome (LGS). The impact of age, seizure type, fast or slow drug titration, and concomitant therapy with valproate on retention rate were evaluated using Cox regression models. RESULTS: One hundred thirty-three patients were included, 39 (30%) of whom had LGS. For all patients, the probability of remaining on RFM without additional therapy was 45% at 12 months and 30% at 24 months. LGS diagnosis was an independent predictor of time to RFM failure (HR 0.51, 95% CI 0.31-0.83), with a median time to failure of 18 months in LGS compared to 6 months in all others (p=0.006). CONCLUSIONS: In a broad population of children with refractory epilepsy, around half will continue taking the medication for at least a year without additional therapy. Patients with LGS are two times more likely to continue RFM without additional therapy compared to those without LGS.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Síndrome de Lennox Gastaut/tratamento farmacológico , Resultado do Tratamento , Triazóis/uso terapêutico , Adolescente , Criança , Estudos de Coortes , Epilepsia/complicações , Epilepsia/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Síndrome de Lennox Gastaut/complicações , Síndrome de Lennox Gastaut/mortalidade , Masculino
17.
Pediatr Crit Care Med ; 16(5): 461-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25651050

RESUMO

OBJECTIVE: To determine the accuracy and reliability of electroencephalographic seizure detection by critical care providers using color density spectral array electroencephalography. DESIGN: Tutorial and questionnaire. SUBJECTS: Critical care providers (attending physicians, fellow trainees, and nurses). INTERVENTIONS: A standardized powerpoint color density spectral array tutorial followed by classification of 200 color density spectral array images as displaying seizures or not displaying seizures. MEASUREMENTS AND MAIN RESULTS: Using conventional electroencephalography recordings obtained from patients who underwent electroencephalography monitoring after cardiac arrest, we created 100 color density spectral array images, 30% of which displayed seizures. The gold standard for seizure category was electroencephalographer determination from the full montage conventional electroencephalography. Participants did not have access to the conventional electroencephalography tracings. After completing a standardized color density spectral array tutorial, images were presented to participants in duplicate and in random order. Twenty critical care physicians (12 attendings and eight fellows) and 19 critical care nurses classified the color density spectral array images as having any seizure(s) or no seizures. The 39 critical care providers had a color density spectral array seizure detection sensitivity of 70% (95% CI, 67-73%), specificity of 68% (95% CI, 67-70%), positive predictive value of 46%, and negative predictive value of 86%. The sensitivity of color density spectral array detection of status epilepticus was 72% (95% CI, 69-74%). CONCLUSION: Determining which post-cardiac arrest patients experience electrographic seizures by critical care providers is feasible after a brief training. There is moderate sensitivity for seizure and status epilepticus detection and a high negative predictive value.


Assuntos
Eletroencefalografia/métodos , Parada Cardíaca/complicações , Convulsões/diagnóstico , Convulsões/etiologia , Cuidados Críticos/métodos , Feminino , Humanos , Capacitação em Serviço , Masculino , Corpo Clínico Hospitalar , Recursos Humanos de Enfermagem no Hospital , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador
18.
J Acquir Immune Defic Syndr ; 69(2): 193-9, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25647527

RESUMO

BACKGROUND: Seizures are common among patients with HIV/AIDS in the developing world and are associated with significant morbidity and mortality. Early treatment with combination antiretroviral therapy (cART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. METHODS: A case-control study of new-onset epilepsy among children aged 0-18 years with perinatally acquired HIV/AIDS followed in Gaborone, Botswana, during the period 2003-2009 was conducted. Children with epilepsy were identified and compared with age- and sex-matched controls without epilepsy with respect to timing of cART initiation. Early treatment was defined as treatment with cART before the age of 12 months, at a CD4% of greater than 25 in children aged 1-5 years, or at an absolute CD4 count of >350 cell per cubic millimeter in children aged 5 years and older. RESULTS: We identified 29 cases of new-onset epilepsy and 58 age- and sex-matched controls. The most common identified etiologies for epilepsy were central nervous system infections and direct HIV neurotoxicity. Only 8 (28%) of the children who developed epilepsy received early treatment compared with 31 (53%) controls (odds ratio: 0.36, 95% confidence interval: 0.14 to 0.92, P = 0.03). This effect was primarily driven by differences in rates of epilepsy among children who initiated treatment with cART between the ages of 1 and 5 years (11% vs. 53%, odds ratio: 0.11, 95% confidence interval: 0.01 to 1.1, P = 0.06). CONCLUSIONS: Earlier initiation of cART may be protective against epilepsy in children with HIV.


Assuntos
Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Epilepsia/epidemiologia , Epilepsia/prevenção & controle , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Prevenção Secundária/métodos , Adolescente , Botsuana , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
19.
Seizure ; 25: 104-11, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25458097

RESUMO

PURPOSE: Electrographic seizures are common in encephalopathic critically ill children, but identification requires continuous EEG monitoring (CEEG). Development of a seizure prediction model would enable more efficient use of limited CEEG resources. We aimed to develop and validate a seizure prediction model for use among encephalopathic critically ill children. METHOD: We developed a seizure prediction model using a retrospectively acquired multi-center database of children with acute encephalopathy without an epilepsy diagnosis, who underwent clinically indicated CEEG. We performed model validation using a separate prospectively acquired single center database. Predictor variables were chosen to be readily available to clinicians prior to the onset of CEEG and included: age, etiology category, clinical seizures prior to CEEG, initial EEG background category, and inter-ictal discharge category. RESULTS: The model has fair to good discrimination ability and overall performance. At the optimal cut-off point in the validation dataset, the model has a sensitivity of 59% and a specificity of 81%. Varied cut-off points could be chosen to optimize sensitivity or specificity depending on available CEEG resources. CONCLUSION: Despite inherent variability between centers, a model developed using multi-center CEEG data and few readily available variables could guide the use of limited CEEG resources when applied at a single center. Depending on CEEG resources, centers could choose lower cut-off points to maximize identification of all patients with seizures (but with more patients monitored) or higher cut-off points to reduce resource utilization by reducing monitoring of lower risk patients (but with failure to identify some patients with seizures).


Assuntos
Modelos Neurológicos , Convulsões/diagnóstico , Criança , Pré-Escolar , Estado Terminal , Bases de Dados Factuais , Eletroencefalografia , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Prognóstico , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Convulsões/fisiopatologia , Sensibilidade e Especificidade
20.
Pediatr Radiol ; 45(5): 714-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25359434

RESUMO

BACKGROUND: Electroencephalographic monitoring is being used with increasing frequency in critically ill children who may require frequent and sometimes urgent brain CT scans. Standard metallic disk EEG electrodes commonly produce substantial imaging artifact, and they must be removed and later reapplied when CT scans are indicated. OBJECTIVE: To determine whether conductive plastic electrodes caused artifact that limited CT interpretation. MATERIAL AND METHODS: We describe a retrospective cohort of 13 consecutive critically ill children who underwent 17 CT scans with conductive plastic electrodes during 1 year. CT images were evaluated by a pediatric neuroradiologist for artifact presence, type and severity. RESULTS: All CT scans had excellent quality images without artifact that impaired CT interpretation except for one scan in which improper wire placement resulted in artifact. CONCLUSION: Conductive plastic electrodes do not cause artifact limiting CT scan interpretation and may be used in critically ill children to permit concurrent electroencephalographic monitoring and CT imaging.


Assuntos
Cuidados Críticos , Eletroencefalografia , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Artefatos , Criança , Pré-Escolar , Estudos de Coortes , Estado Terminal , Desenho de Equipamento , Feminino , Humanos , Lactente , Masculino , Plásticos , Reprodutibilidade dos Testes , Estudos Retrospectivos
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