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1.
Seizure ; 83: 181-186, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33171342

RESUMO

OBJECTIVE: We aimed to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum perampanel concentration and to correlate the concentration with clinical response and tolerability. METHODS: A total of 4224 serum samples were obtained from 763 pediatric, adolescent, and adult patients for routine therapeutic drug monitoring. We compared the extent of enzyme induction between cytochrome P450 3A4 (CYP3A4) inducer regimens and built a statistical model to estimate the serum perampanel concentration that considered use of CYP3A4 inducers and inhibitors. To assess the tolerability and clinical effectiveness of perampanel therapy, we used the nested case-control approach. The case group was matched with the control group for age, sex, epilepsy type, and perampanel exposure periods. RESULTS: Concomitant use of the inducers phenytoin, carbamazepine, and phenobarbital dose-dependently reduced the perampanel concentration by 51 %, 67 %, and 37 %, respectively. The estimate model showed a good correlation between the predicted and measured concentrations (r2 = 0.62, p < 0.001). In 206 patients, the seizure reduction from baseline was > 50 % and the median perampanel concentration was 351 ng/mL (interquartile range, 191-603 ng/mL). Adverse events, such as somnolence, dizziness, and irritability, were experienced by 185 patients. The responder odds ratio was 5.1-fold higher in patients with a serum concentration > 600 ng/mL than in those with a serum concentration < 200 ng/mL; however, the former group had a 7.9-fold higher incidence of adverse events. CONCLUSION: Therapeutic drug monitoring is clinically useful to assess drug interactions between perampanel and CYP3A4 inducers and inhibitors. We recommend that the target concentration of perampanel is initially set at 200-600 ng/mL. Serum concentrations > 600 ng/mL were associated with greater anti-seizure effects but had an increased risk of adverse events.

2.
Hum Mutat ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131168

RESUMO

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.

3.
J Neuroimmunol ; 349: 577427, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091764

RESUMO

To characterize internalization of NMDA-type glutamate receptors (GluRs) by antibodies to NMDA-type GluRs, we produced rabbit antibodies to N-terminals of human GluN1 and GluN2B, and examined internalization of NMDA-type GluRs in HEK293T cells using confocal microscopy. Internalization of NMDA-type GluRs occurred from at least 10 min after incubation with antibodies to GluN1 and or GluN2B and was temperature-dependent. These findings confirm that antibodies to N-terminals of GluN1 and GluN2B present in the cerebrospinal fluid of patients with NMDAR encephalitis can mediate prompt internalization of NMDA-type GluR complexes.

4.
Ther Drug Monit ; 42(5): 754-759, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32941398

RESUMO

BACKGROUND: Lacosamide is a novel anticonvulsant that acts by enhancing sodium channel slow inactivation. The aims of this study were to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum lacosamide concentration and explore the relationship between lacosamide serum concentration and both clinical response and adverse effects. METHODS: The authors analyzed 649 serum samples from 426 Japanese patients with epilepsy. The concentration-to-dose (CD) ratio of lacosamide was compared among patients on various AED regimens. Clinical information about seizure frequency and adverse events was obtained from clinical records. RESULTS: In patients who did not receive enzyme-inducing AEDs, the CD ratio (mean ± SD) of lacosamide was 1.84 ± 0.68. By contrast, the CD ratio in patients who received phenytoin, carbamazepine, and phenobarbital was 1.42 ± 0.66 (22.8% lower), 1.46 ± 0.40 (20.7% lower), and 1.36 ± 0.38 (26.1% lower), respectively. Seventy-four patients (17.3%) achieved >50% seizure reduction. The median lacosamide concentration in patients who received and did not receive a sodium channel blocker was 6.6 mcg/mL (26.4 µmol/L) and 8.4 mcg/mL (33.6 µmol/L), respectively. Adverse events, including dizziness, somnolence, diplopia, and anorexia, were reported by 70 patients (16.4%). The incidence rate in patients treated with sodium channel blockers was significantly higher than that in patients not treated with these drugs (21.1% vs. 10.3%; P < 0.005), and the median lacosamide concentration in these patient groups was 5.1 (20.4 µmol/L) and 7.5 mcg/mL (30 µmol/L), respectively. CONCLUSIONS: Therapeutic drug monitoring of lacosamide is clinically useful because it allows physicians to estimate the extent of drug interactions and adjust the dose in individual AED regimens.

5.
J Neurodev Disord ; 12(1): 24, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873244

RESUMO

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters.

7.
Epileptic Disord ; 22(4): 455-461, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32782230

RESUMO

To evaluate changes in the pharmacokinetics of perampanel after discontinuation of carbamazepine. We enrolled 13 patients receiving perampanel who discontinued carbamazepine therapy between June 2016 and December 2018. Data on serum concentrations were obtained from the therapeutic drug monitoring database of the National Epilepsy Center (Shizuoka, Japan). To compare the pharmacokinetics of perampanel before and after discontinuation of carbamazepine, we determined the concentration/dose (CD) ratio of perampanel (serum level [ng/mL] divided by the dose [mg/kg]). The follow-up period was set to eight weeks following the discontinuation of carbamazepine therapy. The mean baseline CD ratio of perampanel was 1,247 ng/mL/mg/kg which increased markedly over time after discontinuation of carbamazepine, with a mean CD ratio at Weeks 1-2, Weeks 3-4, and Weeks 5-8 of 2,683, 3,914, and 4,220, respectively. At eight weeks, the mean CD ratio of perampanel had increased by 276%. Eleven patients developed adverse events, including dizziness, somnolence, irritability, and ataxia. Five of these 11 patients required perampanel dose reduction within eight weeks after discontinuation of carbamazepine. Two patients achieved seizure-free status at Weeks 5-8. The serum perampanel concentration began to increase from one week after discontinuation of carbamazepine, and continued to rise for eight weeks. Based on these findings, we recommend frequent monitoring of serum perampanel concentration for at least eight weeks after stopping carbamazepine therapy. Monitoring is required as a guide for dose adjustment in order to achieve a safe and effective therapeutic dose of perampanel.

8.
Intern Med ; 59(18): 2301-2306, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32522922

RESUMO

We herein report a 50-year-old man with alcoholic cirrhosis who developed loss of consciousness and tremor of the upper limbs. Magnetic resonance imaging findings were suggestive of limbic encephalitis with bilateral hippocampal damage, and a cerebrospinal fluid (CSF) examination confirmed anti-N-methyl-D-aspartate (NMDA) and anti-glutamate receptor antibodies. Despite initial corticosteroid therapy, meningeal irritation symptoms appeared, owing to the development of cryptococcal meningitis (CM), diagnosed by the detection of cryptococcal capsular polysaccharide antigen in the follow-up CSF analysis. Cerebral infarction with reversible stenosis of major cerebral arteries during the clinical course was also observed. Following administration of antifungals and corticosteroids, the number of cells in the CSF gradually declined, and NMDA receptor antibodies disappeared. Our study demonstrates the unique coexistence of CM with anti-NMDA receptor encephalitis in adults.

9.
Brain Dev ; 42(9): 686-690, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32591173

RESUMO

BACKGROUND: The clinical spectrum of glucose transporter type 1 deficiency syndrome (GLUT1DS) has broadened, with increasing recognition of a milder phenotype. Antibodies targeting the subunits of glutamate receptors (GluRs), including GluN1, GluN2B, and GluD2, have been detected in various neurological disorders. Anti-GluD2 antibodies in particular may be associated with cerebellar symptoms. CASE REPORT: A 3-year-5-month-old boy with normal development exhibited myoclonus refractory to antiepileptic drugs from one year ago. He developed tremor and ataxia. Cerebrospinal fluid (CSF) revealed fasting-state glucose 50 mg/dl (CSF/blood glucose ratio of 0.50). Single photon emission computed tomography with 123I-iodoamphetamine revealed hypoperfusion in the cerebellum. At age 4 years and 5 months, treatment with intravenous methylprednisolone (IVMP) relieved his symptoms and improved the cerebellar hypoperfusion. However, his symptoms reappeared at age 5 years and 1 month. Treatment with IVMP was repeated, resulting in transient disappearance of symptoms. At age 6 years and 9 months, he was diagnosed with GLUT1DS by genetic analysis, and treatment with modified Atkins diet was started with efficacy. Levels of anti-GluN1, -GluN2B, and -GluD2 antibodies in the serum and CSF were measured 4 times. All antibodies in the CSF were elevated over 2 standard deviations above controls, and the levels fluctuated along with the severity of his symptoms. The level of anti-GluD2 antibodies in CSF declined to the normal range only after starting the modified Atkins diet. CONCLUSION: Treatment with IVMP transiently improved this patient's symptoms. Levels of anti-GluR antibodies may be associated with symptom severity.

10.
Ther Drug Monit ; 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32366813

RESUMO

BACKGROUND: Lacosamide is a novel anticonvulsant that acts by enhancing sodium channel slow inactivation. The aims of this study were to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum lacosamide concentration and explore the relationship between lacosamide serum concentration and both clinical response and adverse effects. METHODS: The authors analyzed 649 serum samples from 426 Japanese patients with epilepsy. The concentration-to-dose (CD) ratio of lacosamide was compared among patients on various AED regimens. Clinical information about seizure frequency and adverse events was obtained from clinical records. RESULTS: In patients who did not receive enzyme-inducing AEDs, the CD ratio (mean ± SD) of lacosamide was 1.84 ± 0.68. In contrast, the CD ratio in patients who received phenytoin, carbamazepine, and phenobarbital was 1.42 ± 0.66 (22.8% lower), 1.46 ± 0.40 (20.7% lower), and 1.36 ± 0.38 (26.1% lower), respectively. Seventy-four patients (17.3%) achieved >50% seizure reduction. The median lacosamide concentration in patients who received and did not receive a sodium channel blocker was 6.6 µg/mL (26.4 µmol/L) and 8.4 µg/mL (33.6 µmol/L), respectively. Adverse events, including dizziness, somnolence, diplopia, and anorexia, were reported by 70 patients (16.4%). The incidence rate in patients treated with sodium channel blockers was significantly higher than that in patients not treated with these drugs (21.1% vs. 10.3%; P < 0.005), and the median lacosamide concentration in these patient groups was 5.1 (20.4 µmol/L) and 7.5 µg/mL (30 µmol/L), respectively. CONCLUSIONS: Therapeutic drug monitoring of lacosamide is clinically useful because it allows physicians to estimate the extent of drug interactions and adjust the dose in individual AED regimens.

11.
Epilepsy Behav ; 109: 107116, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32388139

RESUMO

PURPOSE: We investigated the efficacy of methylprednisolone pulse therapy (MP) and responder characteristics in patients with refractory epilepsy. METHODS: We reviewed medical records of our center to identify patients with refractory epilepsy treated with MP other than continuous spikes and waves during slow sleep (CSWS), Landau-Kleffner syndrome (LKS), or Rasmussen's syndrome (RS) between 2004 and 2015. A course of MP consisted of intravenous methylprednisolone (30 mg/kg/day) on three consecutive days. Patients received multiple courses at intervals of four weeks. We examined seizure outcome, developmental outcome, antibodies to N-methyl-d-aspartate (NMDA)-type glutamate receptors (GluRs), cerebral spinal fluid (CSF)-albumin/serum-albumin ratio, and interictal electroencephalograms (EEGs). Responder to MP was defined as maintaining seizure reduction rate (SRR) ≥50% for three months after the first course of MP. RESULTS: Thirty-one consecutive patients treated with MP at our center were studied. Seizure types were focal onset impaired awareness seizure (FIAS) only (n = 23), FIAS with epileptic spasms (ES) (n = 7), and ES only (n = 1). Responder rate was 32.2% (10/31 patients), and seizure-free rate was 9.7% (3/31). Responders constituted 43.5% of patients without ES. No patient with ES was responder. Behavior and cognition also improved in 6 of 10 responders. History of seizure aggravation after inactivated vaccine before MP was found significantly higher rate in responder patients, comparing with nonresponder patients (p = 0.01). CONCLUSION: Methylprednisolone pulse therapy may be considered for possible treatment in patients with focal epilepsy with drug-resistant seizures without ES, and it may improve cognitive function and behavioral comorbidities.

15.
J Clin Neurosci ; 76: 243-245, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32284291

RESUMO

Alice in wonderland syndrome (AIWS) is a rare perceptual disorder characterized by subjective distortions of visual and somatosensory perception. Symptoms of AIWS are attributable to functional and structural changes of the visual and somatosensory perceptual system; however, few reports have investigated the pathophysiology of AIWS with regard to epilepsy, especially ictal electroencephalogram (EEG) changes. Herein, we describe the case of an 82-year-old woman with focal onset epilepsy presenting with AIWS, whose seizures were documented by video-EEG monitoring. Video-EEG revealed multiple focal impaired awareness seizures, and ictal EEG changes arose from the right occipital region with small periodic positive discharges with evolution towards the right centro-parietal regions. Our case highlights not only a relationship between epileptic seizures and AIWS but also provides pathological insight into AIWS.


Assuntos
Síndrome de Alice no País das Maravilhas/fisiopatologia , Epilepsias Parciais/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Eletroencefalografia , Feminino , Humanos , Lobo Occipital/fisiopatologia , Lobo Parietal/fisiopatologia , Transtornos da Percepção/fisiopatologia , Convulsões/fisiopatologia
16.
EJNMMI Res ; 10(1): 29, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198578

RESUMO

BACKGROUND: Functional somatic syndrome (FSS) is a disorder characterized by clusters of medically unexplained symptoms. Some women suffer from persistent FSS after human papillomavirus (HPV) vaccination. However, a causal relationship has not been established, and the pathophysiology of FSS remains elusive. Here, we aimed to identify the brain regions showing altered cerebral metabolism and neuroinflammation in patients with FSS and to correlate the measures of positron emission tomography (PET) with clinical data. Twelve women diagnosed with FSS following HPV vaccination (FSS group) underwent both [18F]FDG-PET to measure glucose metabolism and [11C]DPA713-PET to measure neuroinflammation. [18F]FDG standardized uptake value ratio (SUVR) and [11C]DPA713 binding potential (BPND) values were compared voxel-wise between the FSS and control groups (n = 12 for [18F]FDG, n = 16 for [11C]DPA713). A region-of-interest (ROI)-based analysis was performed to correlate PET parameters with clinical scores. Statistical significance was set at p < 0.05 corrected for multiple comparisons. RESULTS: Statistical parametric mapping revealed a concomitant significant decrease of [18F]FDG SUVR and increase of [11C]DPA713 BPND in the regions covering the thalamus, mesial temporal area, and brainstem in the FSS group. Correlation analysis revealed that intelligence and memory scores were significantly positively correlated with [18F]FDG SUVR and negatively so with [11C]DPA713 BPND in these regions. A direct comparison between [18F]FDG SUVR and [11C]DPA713 BPND revealed a significant positive correlation in the right hippocampus and amygdala. CONCLUSIONS: Cerebral hypometabolism with neuroinflammation occurring in the thalamo-limbic-brainstem region may reflect the pathophysiology of FSS.

17.
Int J Hematol ; 112(2): 254-257, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32200528

RESUMO

Various central nervous system (CNS) complications may occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which can result in severe clinical problems. Diagnosis is often difficult, as distinctive clinical symptoms may be absent and different neurological disorders may exhibit similar symptoms. Despite the fact that antibodies responding to brain cell surface antigens have become well recognized in several CNS disorders, cases of autoimmune CNS disorders after allo-HSCT have rarely been reported. Here, we report on a patient who developed encephalitis associated with antibodies against N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR) after allo-HSCT. To the best of our knowledge, this is the first report of the involvement of antibodies against NMDA-type GluR in post-transplantation encephalitis. Autoimmunity to NMDA-type GluR may have contributed to neurological complications after transplantation in unresolved cases.


Assuntos
Autoanticorpos/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Encefalite Límbica/etiologia , Encefalite Límbica/imunologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/imunologia , Receptores de Glutamato/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Autoimunidade , Feminino , Humanos , Pessoa de Meia-Idade , Transplante Homólogo/efeitos adversos
18.
Ther Drug Monit ; 42(2): 302-308, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31318844

RESUMO

BACKGROUND: Stiripentol is a strong inhibitor of CYP2C19 and CYP3A4. This study compared the effect of stiripentol on the pharmacokinetics of clobazam and N-desmethyl-clobazam (NCLB; an active metabolite of clobazam) between different CYP2C19 phenotypes. We also evaluated the clinical impact of CYP2C19 phenotypes in Japanese patients with Dravet syndrome receiving a combination of valproic acid, clobazam, and stiripentol. METHODS: We retrospectively reviewed 241 blood samples from 64 patients (aged 1-40 years) and calculated the concentration/dose (CD) ratio [serum level (ng/mL) divided by dose (mg/kg)] for clobazam and NCLB. Based on their CYP2C19 genotypes, patients were classified as extensive metabolizers (EM group: CYP2C19*1/*1, *1/*2, or *1/*3) or poor metabolizers (PM group: CYP2C19*2/*2, *3/*3, or *2/*3). We also reviewed the clinical records of 56 patients who commenced stiripentol therapy and calculated the retention rate for stiripentol therapy over an observation period of 208 weeks. RESULTS: Concomitant administration of stiripentol led to a marked increase in the CD ratio of clobazam (1.8-fold in the EM group and 1.5-fold in the PM group). In addition, stiripentol increased the CD ratio of NCLB by 6.6-fold in the EM group, but decreased it by 0.7-fold in the PM group. The estimated retention rate with stiripentol therapy was higher, and the duration of retention was longer in the EM group than in the PM group (1378 versus 933 days, P < 0.001). In patients with the PM phenotype, the adjusted hazard ratio for ceasing stiripentol therapy was 6.7 (95% confidence interval: 1.8-24.7, P < 0.005). CONCLUSIONS: The effect of stiripentol on the pharmacokinetics of NCLB was significantly different between patients with the EM and PM phenotypes, which could influence the clinical response of Japanese patients with Dravet syndrome receiving the combination of valproic acid, clobazam, and stiripentol.

19.
Brain Dev ; 42(3): 264-269, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31843295

RESUMO

OBJECTIVE: Some pediatric patients with autoimmune encephalitis (AE) experience sequelae in spite of immunotherapy. In this study, we aimed to evaluate the association of serum matrix metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels with the neurological prognosis of AE. METHODS: We retrospectively included 13 patients with AE who had been referred to Saitama Children's Medical Center from February 2011 to May 2019. We compared serum MMP-9 levels, TIMP-1 levels, and MMP-9/TIMP-1 ratio in the acute period (within 30 days from the onset of AE) and subacute period (30-day period following the acute period). We also compared these biomarker levels between patients with (group A) and without sequelae (group B). Sequelae were evaluated at discharge or the last visit. RESULTS: Group A (median age, 7.8 years; range, 5.3-10.7 years) and group B (median age, 13.3 years; range, 11.1-15.4 years) had 6 patients each; 1 patient was excluded because the time of AE onset was unknown. In the acute period, there were no significant differences in MMP-9 levels, TIMP-1 levels, and MMP-9/TIMP-1 ratio between groups A and B. In the subacute period, serum MMP-9/TIMP-1 ratio was higher in group A than in group B (p < 0.01). There were no significant differences in MMP-9 and TIMP-1 levels between groups A and B. CONCLUSIONS: Patients with sequelae of AE showed a high MMP-9/TIMP-1 ratio in the subacute period. Our study demonstrates that elevation of serum MMP-9/TIMP-1 ratio in the subacute period may be a predictive factor of sequelae of AE.


Assuntos
Doenças Autoimunes do Sistema Nervoso/sangue , Encefalite/sangue , Metaloproteinase 9 da Matriz/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Retrospectivos
20.
Front Neurol ; 10: 1182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798515

RESUMO

Introduction: The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to provide insights into the clinical characteristics of patients with Tuberous Sclerosis Complex (TSC). The aims of this study were to identify issues that arose during the design, execution, and publication phases of TOSCA, and to reflect on lessons learnt that may guide future registries in rare and complex diseases. Methods: A questionnaire was designed to identify the strengths, weaknesses, and issues that arose at any stage of development and implementation of the TOSCA registry. The questionnaire contained 225 questions distributed in 7 sections (identification of issues during registry planning, during the operation of the registry, during data analysis, during the publication of the results, other issues, assessment of lessons learnt, and additional comments), and was sent by e-mail to 511 people involved in the registry, including 28 members of the Scientific Advisory Board (SAB), 162 principal investigators (PIs), and 321 employees of the sponsor belonging to the medical department or that were clinical research associate (CRA). Questionnaires received within the 2 months from the initial mailing were included in the analysis. Results: A total of 53 (10.4%) questionnaires were received (64.3% for SAB members, 12.3% for PIs and 4.7% for employees of the sponsor), and the overall completeness rate for closed questions was 87.6%. The most common issues identified were the limited duration of the registry (38%) and issues related to handling of missing data (32%). In addition, 25% of the respondents commented that biases might have compromised the validity of the results. More than 80% of the respondents reported that the registry improved the knowledge on the natural history and manifestations of TSC, increased disease awareness and helped to identify relevant information for clinical research in TSC. Conclusions: This analysis shows the importance of registries as a powerful tool to increase disease awareness, to produce real-world evidence, and to generate questions for future research. However, there is a need to implement strategies to ensure patient retention and long-term sustainability of patient registries, to improve data quality, and to reduce biases.

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