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1.
Seizure ; 85: 6-11, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33360040

RESUMEN

PURPOSE: We aimed to study the efficacy of adrenocorticotropic hormone (ACTH) treatment on infantile spasms with different aetiologies. In particular, we were interested in patients with structural-acquired aetiology. METHODS: Patients with infantile spasms, who were treated with ACTH, were divided into three groups based on the aetiologies: unknown aetiology with normal development (unknown-normal), structural-acquired, and combined-congenital aetiologies that included genetic, metabolic, structural-congenital, or unknown aetiology with developmental delay. RESULTS: Of the 107 patients included (58 males, 49 females), 25 patients had unknown-normal aetiology [median age at onset 5 months, standard deviation (SD) 3.12, range 2-16 months]; 20 patients had structural-acquired aetiology (median age at onset 6.5 months, SD 3.85 months, range 4-17 months); and 62 patients had combined-congenital aetiologies (median age at onset 5 months, SD 2.73 months, range 2-16 months). The efficacy of ACTH was 64.0 %, 65 %, and 30.6 % in the unknown-normal aetiology, structural-acquired aetiology, and combined-congenital aetiologies, respectively (p < 0.01). Multivariate analysis showed a statistically significant higher efficacy in the unknown-normal aetiology [Odds ratio (OR) 4.63, 95 % confidence interval (CI) 1.60-13.30] and structural-acquired aetiology (OR 3.41, 95 % CI 1.01-11.50) compared to that in the combined-congenital aetiologies. CONCLUSION: Infantile spasms with structural-acquired aetiology had greater response to ACTH treatment than those with combined-congenital aetiologies. The efficacy of standard therapy of infantile spasms should be considered based on aetiology.

2.
Hum Mutat ; 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-33131168

RESUMEN

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 Child Neurol ; 35(10): 667-673, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32476572

RESUMEN

BACKGROUND: Migraines are a broad spectrum of disorders classified by the type of aura with some requiring attentive treatment. Vasoconstrictors, including triptans, should be avoided in the acute phase of migraines with brainstem aura, in hemiplegic migraine, and in retinal migraine. This study investigated the characteristics and burden of these migraines. METHODS: Medical charts of 278 Japanese pediatric patients with migraines were retrospectively reviewed. Migraine burden of migraines with brainstem aura, hemiplegic migraines, and retinal migraine was assessed using the Headache Impact Test-6™ (HIT-6) and the Pediatric Migraine Disability Assessment scale (PedMIDAS). RESULTS: Of 278 patients screened, 12 (4.3%) patients with migraines with brainstem aura (n = 5), hemiplegic migraines (n = 2), and retinal migraine (n = 5) were enrolled in the study. All patients had migraine with/without typical aura, whereas some patients had coexisting migraine with another type of headache (chronic tension-type headache in 3 patients, and 1 each with frequent episodic tension-type headache, headache owing to medication overuse, and chronic migraine). Migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients with coexisting headaches had higher HIT-6 or PedMIDAS scores, whereas migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients without coexisting headache did not show high HIT-6 or PedMIDAS scores. CONCLUSION: All migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients experienced migraine with or without typical aura, and some patients having other coexisting headaches also had high PedMIDAS and HIT-6 scores. PedMIDAS and HIT-6 should not be considered diagnostic indicators of migraines with brainstem aura, hemiplegic migraines, or retinal migraine. In clinical practice for headaches in children, careful history taking and proactive assessment of the aura are needed for accurate diagnosis of migraines with brainstem aura, hemiplegic migraines, and retinal migraine.

4.
Brain Dev ; 42(7): 523-528, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32336482

RESUMEN

BACKGROUND: Riboflavin may prevent migraine episodes; however, there is limited evidence of its effectiveness in pediatric populations. This study investigated the effectiveness of riboflavin and clinical predictors of response in children with migraines. METHODS: We retrospectively reviewed data from 68 Japanese children with migraines, of whom 52 also exhibited another type of headache. Patients received 10 or 40 mg/day of riboflavin. We evaluated the average migraine frequency per month as a baseline and after 3 months of riboflavin therapy to determine the effectiveness and clinical predictors of response. RESULTS: The frequency of migraine episodes was significantly lower at 3 months than at baseline (median, [interquartile range], 5.2 (3-7) vs. 4.0 (2-5); p < 0.01). Twenty-five patients (36.7%) showed 50% or greater reduction in episode frequency (responders), while 18 (26.5%) showed a 25%-50% reduction. We compared responders (n = 25) and non-responders (n = 43) and found no significant differences in sex, familial history, riboflavin dose, migraine type (i.e., presence or absence of aura), age at headache onset, or age at consultation. However, non-responders were more likely to have co-morbid non-migraine headaches (odds ratio, 4.11; 95% confidence interval [CI], 1.27-13.33; p = 0.02); this variable was also significant in a multivariate analysis (adjusted odds ratio, 3.8; 95% CI, 1.16-12.6; p = 0.03). Of the co-morbid headache types, only tension headaches were significant (odds ratio, 0.176; 95% CI, 0.04-0.73; p = 0.013). No adverse effects of riboflavin were identified. CONCLUSIONS: Low-dose riboflavin is safe and modestly effective for migraines in children. It may be especially beneficial for children without other co-morbid headache types.

5.
Neuropediatrics ; 51(6): 417-420, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32176929

RESUMEN

BACKGROUND: Nonketotic hyperglycinemia is a severe form of early onset epileptic encephalopathy caused by disturbances in the glycine cleavage system; the neurological damage is mainly attributed to overstimulation of the N-methyl-D-aspartate receptor. CASE: The patient presented with a severe form of nonketotic hyperglycinemia and experienced frequent epileptic spasms and focal seizures, which were resistant to vigabatrin, adrenocorticotropic hormone therapy, and combined dextromethorphan and sodium benzoate treatments. By 9 months of age, perampanel reduced epileptic spasms by >50%. At 14 months of age, the ketogenic diet markedly reduced focal seizures and glycine levels in the cerebrospinal fluid. CONCLUSION: Perampanel reduced fast excitatory neuronal activity, which was induced by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, followed by prolonged electrical depolarizations due to an N-methyl-D-aspartate receptor. Furthermore, the ketogenic diet may have modulated the excessive neurotoxic cascade through the N-methyl-D-aspartate receptor. Perampanel and ketogenic diet were effective for seizure control in our patient.

6.
Epileptic Disord ; 22(1): 73-82, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32020895

RESUMEN

This study aimed to investigate the general presentation of epileptic spasms without hypsarrhythmia (ESwoH) and retrospectively determine whether there are differences in treatment effects related to ACTH therapy, long-term seizure outcome, and evolution of EEG features according to pre-treatment EEG patterns. According to the pattern of background activity, we divided our cohort into two groups: Group 1: normal background activity or with localized intermittent slow waves; Group 2: intermittent slow waves appearing generalized or in two or more lobes. Subjects included 22 children (Group 1: n=10; Group 2: n=12) diagnosed with ESwoH who received treatment from 2007 to 2017. The median age at onset of epileptic spasms was 5.5 months and the follow-up period lasted for 40.5 months. ACTH therapy was performed for seven patients from Group 1 and eight patients from Group 2. Only one patient from Group 2 responded to ACTH. Patients receiving effective treatments at early stages had excellent seizure outcome. Refractory cases included six patients in Group 1 and eight patients in Group 2; subsequent follow-up EEGs indicated hypsarrhythmia in one patient in Group 1 (17%) and six patients (75%) in Group 2, including one patient whose EEG pattern indicated progression to Lennox-Gastaut syndrome. Overall, ACTH is ineffective for patients with epileptic spasms without hypsarrhythmia. The EEG may indicate possible future development of hypsarrhythmia if epileptic spasms are resistant to treatment, especially in patients with diffuse slow waves on pre-treatment EEG. The efficacy of treatment introduced at early stages from onset may predict long-term seizure outcome.


Asunto(s)
Hormona Adrenocorticotrópica/farmacología , Ondas Encefálicas/fisiología , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/fisiopatología , Niño , Preescolar , Progresión de la Enfermedad , Electroencefalografía , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios Retrospectivos , Resultado del Tratamiento
7.
Neuropediatrics ; 51(2): 154-159, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31935762

RESUMEN

Some studies have shown that sedative antihistamines prolong febrile seizure duration. Although the collective evidence is still mixed, the Japanese Society of Child Neurology released guidelines in 2015 that contraindicated the use of sedative antihistamines in patients with febrile seizure. Focused on addressing limitations of previous studies, we conducted a cross-sectional study to evaluate the relationship between febrile seizure duration and the use of sedative antihistamines. Data were collected from patients who visited St. Luke's International Hospital due to febrile seizure between August 2013 and February 2016. Patients were divided into groups based on their prescribed medications: sedative antihistamine, nonsedative antihistamine, and no antihistamine. Seizure duration was the primary outcome and was examined using multivariate analyses. Of the 426 patients included, sedative antihistamines were administered to 24 patients. The median seizure duration was approximately 3 minutes in all three groups. There was no statistical difference in the bivariate (p = 0.422) or multivariate analyses (p = 0.544). Our results do not support the relationship between sedative antihistamine use and prolonged duration of febrile seizure. These results suggest that the use of antihistamines may be considered for patients with past history of febrile seizure, when appropriate.

8.
PLoS One ; 15(1): e0227796, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31929600

RESUMEN

BACKGROUND: Intravenous immunoglobulin (IVIG) therapy is used in the treatment of various diseases, and IVIG-related adverse effects (IVIG-AEs) vary from mild to severe. However, the mechanisms underlying IVIG-AEs and the potential predictive factors are not clear. This study investigated whether certain IVIG-AEs can be predicted before IVIG administration. STUDY DESIGN AND METHODS: This retrospective cohort study at the Division of Neurology, Saitama Children's Medical Center included patients enrolled from 2008 to 2018 who were < 18 years old and received IVIG for the first time. IVIG-AEs were classified according to the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 104 patients fulfilled the inclusion criteria. The rate of IVIG-AEs was 37.5% (39/104). The most frequent IVIG-AEs were fever (41.0% [16/39]) and headache (38.5% [15/39]). AEs were below grade 2 in all except one patient and there were no grade 4 AEs. High serum total protein (TP) level was significantly related to the occurrence of IVIG-AEs (odds ratio, 14.8; 95% confidence interval, 2.4-90.5; P < 0.01). The optimal cutoff TP level was 6.7 g/dL. Although low WBC count and immunoglobulin G level may be predictive risk factors of IVIG-AEs, it was not confirmed in this study. CONCLUSION: IVIG-AEs occurred in 37.5% of cases, and most were mild. TP was the best predictive risk factor of IVIG-AEs before IVIG administration. These results may aid in elucidating the mechanism underlying IVIG-AEs.


Asunto(s)
Inmunoglobulinas Intravenosas/efectos adversos , Niño , Preescolar , Exantema/inducido químicamente , Femenino , Fiebre/inducido químicamente , Cefalea/inducido químicamente , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Incidencia , Lactante , Masculino , Náusea/inducido químicamente , Factores Protectores , Estudios Retrospectivos , Vómitos/inducido químicamente
9.
Brain Dev ; 42(3): 264-269, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31843295

RESUMEN

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.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/sangre , Encefalitis/sangre , Metaloproteinasa 9 de la Matriz/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Retrospectivos
10.
Oncol Lett ; 17(3): 3323-3329, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30867766

RESUMEN

Recent genome-wide analysis of neuroblastoma (NBL) revealed amplification and heterozygous mutation of anaplastic lymphoma kinase (ALK) are responsible for oncogenicity, frequently observed during relapses. A 3-year-old girl with relapsed high-risk NBL had a heterozygous ALK F1245L mutation at diagnosis, which became homozygous due to uniparental disomy (UPD) of the entire chromosome 2, confirmed by single nucleotide polymorphism array and variant allele frequency of this mutation. The ALK inhibitor, crizotinib, failed to control the tumor and the patient died of the disease. Further genomic analysis using targeted capture sequencing for 381 genes related to pediatric cancers identified more alterations acquired at relapse, such as TSC complex subunit 2 and protein tyrosine phosphatase receptor type D. In addition to these several acquired mutations, this extremely rare duplication of ALK mutation might explain the aggressive clinical course after relapse, because acquired UPD, resulting in the duplication of an oncogenic mutation, has been reported for various neoplasms. Although a clinical benefit of ALK inhibitors in patients with NBL has not been confirmed yet, a treatment based on the ALK mutation status will be promising in future using more potent next-generation ALK inhibitors.

11.
Brain Dev ; 41(5): 413-419, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30528382

RESUMEN

OBJECTIVE: To evaluate the efficacy and safety of pyridoxal for treating West syndrome. METHODS: We retrospectively investigated pyridoxal's efficacy and safety in 117 patients with West syndrome at Saitama Children's Medical Center from July 1993 to May 2016. Pyridoxal was administered at doses of 10-50 mg/kg/day. We evaluated seizure outcomes and electroencephalographic findings at 4 weeks after pyridoxal therapy. The responders were those with complete cessation of spasms for more than 4 weeks and those with resolution of hypsarrhythmia on EEG at 1-4 weeks after pyridoxal therapy. RESULTS: Five of the 117 patients (4.3%) were responders. The median duration between pyridoxal therapy to spasm cessation was 6 (5-13) days. Among the responders, four had hypsarrhythmia resolution, no spasm relapse, and no other seizure types more than 2 years after pyridoxal therapy. One responder had partial seizures and spasm relapse. No serious adverse effects occurred. There were no significant differences in sex, etiologies, complication, other seizure types preceding the spasms, onset age of spasms, age of pyridoxal therapy, treatment lag, initial and maintenance doses of pyridoxal, and adverse effects between pyridoxal responders and non-responders. CONCLUSIONS: The efficacy rate of pyridoxal monotherapy as first-line treatment for West syndrome was low. However, pyridoxal therapy showed a rapid response within 1 week and was safe. We consider pyridoxal therapy as a kind of challenge therapy during the evaluation period concerning differential diagnosis and etiologies of West syndrome and immunological risks before adrenocorticotrophic hormone therapy or vigabatrin therapy.


Asunto(s)
Evaluación de Resultado en la Atención de Salud , Piridoxal/farmacología , Espasmos Infantiles/tratamiento farmacológico , Complejo Vitamínico B/farmacología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Piridoxal/administración & dosificación , Piridoxal/efectos adversos , Estudios Retrospectivos , Complejo Vitamínico B/administración & dosificación , Complejo Vitamínico B/efectos adversos
12.
Epileptic Disord ; 20(4): 313-318, 2018 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-30078785

RESUMEN

Mutation of the gene encoding ubiquitin-like modifier-activating enzyme 5 (UBA5) causes autosomal recessive early-onset epileptic encephalopathy. UBA5 acts as an E1-activating enzyme in the ubiquitin-fold modifier 1 pathway, which is important for unfolded protein elimination and regulation of apoptosis, and has been linked to human diseases. We identified biallelic mutations in UBA5 in a Japanese boy with intractable West syndrome, profound failure to thrive, and severe cerebral and cerebellar atrophy. The boy presented with epileptic spasms and hypsarrhythmia at the age of three months. He was diagnosed with West syndrome, however, treatments with adrenocorticotropic hormone and several antiepileptic drugs were ineffective. MRI findings were initially normal, but subsequently showed a progression of cerebellar and cerebral atrophy. By the age of seven years, he had not achieved any developmental milestones; he had daily epileptic spasms and tonic seizures and profound failure to thrive. Gene analysis revealed novel compound heterozygous mutations in UBA5; a microdeletion encompassing the entire UBA5 gene and a putative disease-causing missense mutation in the catalytic domain. These biallelic variants may have caused loss of function, accounting for the observed clinical symptoms. Intractable infantile epileptic spasms, failure to thrive, and severe neurological impairment may be characteristic of patients with UBA5 mutations.


Asunto(s)
Cerebelo/patología , Cerebro/patología , Insuficiencia de Crecimiento , Espasmos Infantiles , Enzimas Activadoras de Ubiquitina/genética , Atrofia/patología , Cerebelo/diagnóstico por imagen , Cerebro/diagnóstico por imagen , Niño , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Insuficiencia de Crecimiento/fisiopatología , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Mutación , Espasmos Infantiles/genética , Espasmos Infantiles/patología , Espasmos Infantiles/fisiopatología
13.
Rinsho Ketsueki ; 59(4): 389-394, 2018.
Artículo en Japonés | MEDLINE | ID: mdl-29743397

RESUMEN

An eight-year-old girl with myelodysplastic syndrome (refractory cytopenia) received a bone marrow transplant (BMT) from an unrelated donor because of immunosuppressive therapy failure. Following administration of foscarnet for cytomegalovirus reactivation at day40 post-BMT, serum creatinine increased, and proteinuria, hematuria, and hypertension gradually exacerbated and became prolonged. However, neither schistocytosis nor other organ damage was evident. At six months post-BMT, renal biopsy revealed diffuse glomerular damage with glomerular lobulation, a double contour of the glomerular basement membrane, erythrocyte congestion and thrombi in the glomerular endocapillaries, and mesangiolysis, confirming the diagnosis of transplantation-associated thrombotic microangiopathy (TA-TMA). We initiated strict controls regarding fluid balance, salt intake, and blood pressure. The patient's renal function improved 10 months post-BMT. TA-TMA often presents as non-specific symptoms, making diagnosis difficult. In cases of post-transplant renal damage, TA-TMA should be differentiated regardless of whether specific symptoms such as hemolytic anemia and other organ failure are evident, and a renal biopsy should, therefore, be considered.


Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Enfermedades Renales/diagnóstico , Microangiopatías Trombóticas/diagnóstico , Biopsia , Niño , Femenino , Humanos , Riñón/patología
14.
J Pediatr Hematol Oncol ; 39(3): e167-e172, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28002256

RESUMEN

Hospital-acquired Clostridium difficile infection (CDI) may cause life-threatening colitis for children with cancer, making identification of risk factors important. We described characteristics of pediatric cancer patients with primary and recurring CDI, and evaluated potential risk factors. Among 189 cancer patients, 51 cases (27%) of CDI and 94 matched controls of cancer patients without CDI were analyzed. Multivariable logistic regression was used to evaluate the association between CDI and several potential risk factors. Median age of CDI cases was lower (3.3 y; 0.60 to 16.2) than controls (7.7 y; 0.4 to 20.5). Median duration of neutropenia before CDI was longer for CDI cases (10.0 d; 0.0 to 30.0) compared with duration calculated from reference date in controls (6.0 d; 0.0 to 29.0). Multivariable analysis showed that older age was associated with reduced risk (≥7 vs. 0 to 3 y, odds ratio=0.11; 95% confidence interval, 0.02-0.54), and prolonged neutropenia was associated with increased risk (odds ratio=1.11; 95% confidence interval, 1.01-1.22). CDI recurred in 26% of cases. Younger age and prolonged neutropenia were risk factors for CDI in children with cancer. Increasing awareness to these risk factors will help to identify opportunities for CDI prevention in cancer patients.


Asunto(s)
Infecciones por Clostridium/etiología , Neoplasias/complicaciones , Adolescente , Factores de Edad , Estudios de Casos y Controles , Niño , Preescolar , Infecciones por Clostridium/virología , Humanos , Enfermedad Iatrogénica , Lactante , Neutropenia/complicaciones , Factores de Riesgo , Adulto Joven
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