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While fungal infections cause considerable morbidity and mortality, the performance of the current diagnostic tests for fungal infection is low. Even though fungal metagenomics or targeted next-generation sequencing have been investigated for various clinical samples, the real-time clinical utility of these methods still needs to be elucidated. In this study, we used internal transcribed spacer (ITS) and D1-D3 ribosomal DNA nanopore amplicon metagenomic sequencing to assess its utility in patients with fungal infections. Eighty-four samples from seventy-three patients were included and categorized into 'Fungal infection,' 'Fungal colonization,' and 'Fungal contamination' groups based on the judgement of infectious disease specialists. In the 'Fungal infection' group, forty-seven initial samples were obtained from forty-seven patients. Three fungal cases detected not by the sequencing but by conventional fungal assays were excluded from the analysis. In the remaining cases, the conventional fungal assay-negative/sequencing-positive group (n=11) and conventional fungal assay-positive/sequencing-positive group (n=33) were compared. Non-Candida and non-Aspergillus fungi infections were more frequent in the conventional-negative/sequencing-positive group (p-value = 0.031). We demonstrated the presence of rare human pathogens, such as Trichosporon asahii and Phycomyces blakesleeanus. In the 'Fungal infection' group and 'Fungal colonization' group, sequencing was faster than culturing (mean difference = 4.92 days, p-value < 0.001/ mean difference = 4.67, p-value <0.001). Compared to the conventional diagnostic methods including culture, nanopore amplicon sequencing showed a shorter turnaround time and a higher detection rate for uncommon fungal pathogens.
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Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder affecting ciliary structure and function. PCD exhibiting dynein regulatory complex subunit 1 (DRC1) exon 1-4 deletion has been reported in several Japanese PCD patients; however, no large scale studies have been performed. Here, we aimed to determine the prevalence and founder effect of this variant in the Korean population. Using an in-house copy number variation tool, we screened for DRC1 exon 1-4 deletion in 20 patients with PCD and exome data of 1435 patients in the Seoul National University Hospital repository. In cases of suspected DRC1 deletion, confirmatory gap-PCR was performed. In a PCD cohort, three of 20 (15%) patients were positive for DRC1 exon 1-4 deletion (NM_145038.5(DRC1): c.1-3952_540 + 1331del27748-bp) while pathogenic variants were found in CCDC39 (N = 1), DNAAF6 (N = 1), DNAH9 (N = 1). In the 1,435-sample exome data, seven patients (0.49%) were confirmed to have DRC1 exon 1-4 deletion. A chimeric sequence including the junction was searched from the 1000 Genomes Project data repository. One Japanese patient (0.96%) was found to have the same DRC1 exon 1-4 deletion, which was absent in other populations. This study demonstrated that the DRC1 exon 1-4 deletion is a founder mutation based on haplotype analysis. In summary, the prevalence of PCD based on DRC1 exon 1-4 deletion is particularly high in Korean and Japanese populations, which is attributed to the founder effect. Genetic testing for DRC1 exon 1-4 deletion should be considered as an initial screening tool for Korean and Japanese patients with PCD.
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Trastornos de la Motilidad Ciliar , Humanos , Trastornos de la Motilidad Ciliar/epidemiología , Trastornos de la Motilidad Ciliar/genética , Prevalencia , Efecto Fundador , Variaciones en el Número de Copia de ADN , Exones/genética , República de Corea/epidemiología , Mutación , Dineínas Axonemales/genética , Proteínas Asociadas a Microtúbulos/genéticaRESUMEN
BACKGROUND: We investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients. METHODS: From an institutional cohort, we analysed adult patients with MOGAE followed-up for more than 1 year. Disease severity was assessed using the modified Rankin scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis scores. Immunotherapy profiles, outcomes and disease relapses were evaluated along with serial brain MRI data. RESULTS: A total of 40 patients were enrolled and categorised into cortical encephalitis (18 patients), limbic encephalitis (LE, 5 patients) and acute disseminated encephalomyelitis (ADEM, 17 patients). 80.0% of patients achieved good clinical outcomes (mRS 0â2) and 40.0% relapsed. The LE subtype was associated with an older onset age (p=0.004) and poor clinical outcomes (p=0.014) than the other subtypes but with a low rate of relapse (0.0%). 21/25 (84.0%) relapse attacks were associated with an absence or short (≤6 months) immunotherapy maintenance. On MRI, the development of either diffuse cerebral or medial temporal atrophy within the first 6 month was correlated with poor outcomes. MOG-antibody (MOG-Ab) was copresent with anti-N-methyl-D-aspartate receptor (NMDAR)-antibody in 13 patients, in whom atypical clinical presentation (cortical encephalitis or ADEM, p<0.001) and disease relapse (46.2% vs 0.0%, p<0.001) were more frequent compared with conventional NMDAR encephalitis without MOG-Ab. CONCLUSIONS: Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Encefalitis , Encefalomielitis Aguda Diseminada , Humanos , Autoanticuerpos , Glicoproteína Mielina-Oligodendrócito , Recurrencia Local de Neoplasia , Encefalitis/diagnóstico , Encefalitis/terapia , Encefalitis/complicaciones , Fenotipo , Encefalitis Antirreceptor N-Metil-D-Aspartato/complicacionesRESUMEN
BACKGROUND AND AIMS: Gastric mucosal swab may be a more sensitive sampling method than a biopsy since Helicobacter pylori (H. pylori) resides within the mucus layer. We compared the diagnostic performance of the rapid urease test (RUT) and bacterial load of H. pylori between swabs and tissue biopsy. METHODS: Overall, 276 RUTs (138 swab-RUTs (S-RUT) and 138 tissue-RUTs (T-RUT)) were performed. To diagnose H. pylori infection, RUT, H. pylori PCR, and 16S ribosomal RNA gene sequencing of tissue and swab were used, and its infection was defined as at least two positives of the six test results. The diagnostic performances of RUTs and the H. pylori bacterial load using qPCR were compared between swab and biopsy. RESULTS: The positivity rates of S-RUT and T-RUT were 35.5% (49/138) and 25.4% (35/138), respectively. The sensitivity, specificity, and accuracy of S-RUT were 98.0%, 100.0%, and 99.2%, while those of T-RUT were 70.0%, 100%, and 89.1%, respectively. The sensitivity and accuracy were significantly higher for S-RUT than for T-RUT (p < 0.05). In the patients with atrophic gastritis and intestinal metaplasia, S-RUT showed significantly higher sensitivity than T-RUT. qPCR showed that the swab contained a significantly higher H. pylori bacterial load than tissue biopsy (22.92-fold and 31.61-fold in the antrum and body (p < 0.05), respectively). CONCLUSIONS: Gastric mucosal swabs showed higher RUT accuracy and H. pylori bacterial load than a tissue biopsy. This may be an alternative to a biopsy when diagnosing H. pylori infection during endoscopy is necessary. (ClinicalTrials.gov, NCT05349578).
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Infecciones por Helicobacter , Helicobacter pylori , Humanos , Biopsia/métodos , Endoscopía Gastrointestinal , Mucosa Gástrica/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Sensibilidad y Especificidad , UreasaRESUMEN
Seronegative autoimmune encephalitis is autoimmune encephalitis without any identifiable pathogenic antibody. Although it is a major subtype of autoimmune encephalitis, many unmet clinical needs exist in terms of clinical characteristics, treatments and prognosis. In this institutional cohort study, patients diagnosed with seronegative autoimmune encephalitis with available 2-year outcomes were analysed for the disease course, 2-year outcome prediction system, effect of immunotherapy, necessity of further immunotherapy at 6 or 12 months and pattern of brain atrophy. Seronegative autoimmune encephalitis was subcategorized into antibody-negative probable autoimmune encephalitis, autoimmune limbic encephalitis and acute disseminated encephalomyelitis. Poor 2-year outcome was defined by modified Rankin scale scores 3-6, and the 2-year serial data of Clinical Assessment Scales in Autoimmune Encephalitis score was used for longitudinal data analyses. A total of 147 patients were included. The frequency of achieving a good 2-year outcome (modified Rankin scale 0-2) was 56.5%. The antibody-negative probable autoimmune encephalitis subtype exhibited the poorest outcomes, although the baseline severity was similar among the subtypes. The RAPID score, consisting of five early usable clinical factors, refractory status epilepticus, age of onset ≥60 years, probable autoimmune encephalitis (antibody-negative probable autoimmune encephalitis subtype), infratentorial involvement and delay of immunotherapy ≥1 month, was associated with poorer 2-year outcomes. Any immunotherapy was associated with clinical improvement in the patients with low risk for poor 2-year outcomes (RAPID scores 0-1), and the combination immunotherapy of steroid, immunoglobulin, rituximab and tocilizumab was associated with better outcomes in the patients with high risk for poor 2-year outcomes (RAPID scores 2-5). In patients with persistent disease at 6 months, continuing immunotherapy was associated with more improvement, while the effect of continuing immunotherapy for more than 12 months was unclear. In the longitudinal analysis of MRI, the development of cerebellar atrophy indicated poor outcomes, while the absence of diffuse cerebral atrophy or medial temporal atrophy indicated the possibility of a good outcome. This study provides information about the clinical characteristics and courses, the effect of immunotherapy and its duration, and prognostic factors in seronegative autoimmune encephalitis.
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Encefalitis , Humanos , Persona de Mediana Edad , Rituximab/uso terapéutico , Estudios de Cohortes , Encefalitis/complicaciones , Factores Inmunológicos/uso terapéutico , Atrofia/complicacionesRESUMEN
Ventriculitis has serious complications and a high mortality rate, so it is important to early identification of the pathogen for appropriate treatment. We report case of ventriculitis caused by Talaromyces rugulosus, a rare pathogen, in South Korea. Affected patient was immunocompromised. Repeated cerebrospinal fluid culture tests were negative, but the pathogen was identified by fungal internal transcribed spacer amplicon nanopore sequencing. The pathogen was detected outside the endemic area of talaromycosis.
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Ventriculitis Cerebral , Micosis , Mielitis , Secuenciación de Nanoporos , Nanoporos , Humanos , Ventriculitis Cerebral/diagnóstico , Ventriculitis Cerebral/tratamiento farmacológico , Micosis/diagnóstico , Micosis/microbiologíaRESUMEN
OBJECTIVES: We investigated whether nanopore 16S amplicon sequencing is capable of bacterial identification in patients with knee prosthetic joint infection (PJI), and we compared its efficacy with conventional culture studies. METHODS: In total, 36 patients who had clinical manifestation suspected of PJI were enrolled in this study. To begin, synovial fluids were aspirated from the affected knee using aseptic technique and tissues specimens were obtained during the surgery. Next, DNA was extracted from the synovial fluid or tissues, and 16S rDNA PCR was performed. In PCR positive cases, nanopore amplicon sequencing was then performed for up to 3 h. The results of amplicon sequencing were compared to those of conventional culture studies. RESULTS: Of the 36 patients enrolled, 22 were classified as true infections according to the MSIS criteria whereas 14 were considered uninfected. Among the 22 PJI cases, 19 cases were culture positive (CP-PJI) while three cases were culture negative (CN-PJI). In 14 of 19 (73.7 %) CP- PJI cases, 16S sequencing identified concordant bacteria with conventional culture studies with a significantly shorter turnaround time. In some cases, nanopore 16S sequencing was superior to culture studies in the species-level identification of pathogen and detection of polymicrobial infections. Altogether, in the majority of PJI candidate patients (32 of 36, 88.9 %), 16S sequencing achieved identical results to cultures studies with a significantly reduced turnaround time (100.9 ± 32.5 h vs. 10.8 ± 7.7 h, p < 0.001). CONCLUSIONS: Nanopore 16S sequencing was found to be particularly useful for pathogen identification in knee PJI. Although the sensitivity was not superior to culture studies, the nanopore 16S sequencing was much faster, and species-level identification and detection of polymicrobial infections were superior to culture studies.
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Artritis Infecciosa , Coinfección , Infecciones Relacionadas con Prótesis , Humanos , Infecciones Relacionadas con Prótesis/diagnóstico , Infecciones Relacionadas con Prótesis/microbiología , ARN Ribosómico 16S/genética , Artritis Infecciosa/diagnóstico , Articulación de la Rodilla , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity. METHODS: Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected. RESULTS: The serum LCM concentration showed a linear correlation with the daily dose (r = .66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p = .01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 µg/ml, p = .024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1 µg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9 µg/ml). SIGNIFICANCE: Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.
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Anticonvulsivantes , Citocromo P-450 CYP2C19 , Epilepsia , Lacosamida , Humanos , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Citocromo P-450 CYP2C19/genética , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Lacosamida/farmacocinética , Lacosamida/uso terapéutico , Polimorfismo Genético , República de CoreaRESUMEN
INTRODUCTION: Gerstmann-Sträussler-Scheinker disease (GSS) is a rare genetic prion disease. Unlike sporadic Creutzfeldt-Jakob disease, GSS has diverse clinical phenotypes, including slowly progressive cerebellar ataxia. Due to this clinical feature and the extreme rarity of GSS, the disease can be misdiagnosed as hereditary cerebellar ataxia. CASE REPORT: We present the first familial cases of GSS in South Korea. Previously affected family members were misdiagnosed with hereditary cerebellar ataxia. Two siblings (patients #1 and #2) of this family were genetically diagnosed with P102L mutation GSS. Another sibling (patient #3) was not genetically confirmed, but based on the clinical course and diffusion-weighted imaging (DWI), the diagnosis of GSS will be certain. Despite the same genetic mutation, these siblings showed different clinical phenotypes of GSS. CONCLUSIONS: We genetically confirmed familial cases of GSS in South Korea. Although the disease is extremely rare, the PRNP gene test should be considered in undiagnosed autosomal dominant hereditary cerebellar ataxia. Phenotypical variability of GSS may be reflected in DWI of the early phase of the disease.
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Ataxia Cerebelosa , Síndrome de Creutzfeldt-Jakob , Enfermedad de Gerstmann-Straussler-Scheinker , Variación Biológica Poblacional , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagen , Síndrome de Creutzfeldt-Jakob/genética , Enfermedad de Gerstmann-Straussler-Scheinker/diagnóstico por imagen , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Humanos , Mutación , Proteínas Priónicas/genéticaRESUMEN
OBJECTIVES: We investigated whether nanopore amplicon sequencing of aqueous humor was capable of rapid pathogen identification in infectious endophthalmitis. METHODS: 5 cases of culture-positive bacterial endophthalmitis and 3 cases of fungal endophthalmitis (1 culture-positive and 2 presumed) were included. DNA was extracted from the aqueous humor and vitreous specimen, and PCR of bacterial rDNA (16S) and fungal rDNA (ITS1 and D1/2/3) was performed. Then, nanopore amplicon sequencing was performed for 2 h. The results of amplicon sequencing were compared to those of conventional culture studies. RESULTS: In all cases, pathogens were identified by amplicon sequencing of aqueous humor specimens. In 3 cases of bacterial endophthalmitis, the identified microbes were confirmed by culture studies of both aqueous humor and vitreous specimens. In 2 cases of bacterial and 1 case of fungal endophthalmitis, the identified pathogens were confirmed only by culture studies of vitreous specimens. In all cases, amplicon sequencing identified pathogen in a shorter turnaround time than culture studies. In 2 cases with negative culture results, amplicon sequencing of aqueous humor identified fungal pathogens. CONCLUSIONS: Our data demonstrates the potential of amplicon nanopore sequencing using aqueous humor to enable rapid, sensitive and less invasive microbial diagnosis of endophthalmitis.
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Endoftalmitis , Secuenciación de Nanoporos , Nanoporos , ADN Bacteriano/genética , Endoftalmitis/diagnóstico , Humanos , Cuerpo VítreoRESUMEN
This study aimed to evaluate the feasibility and added value of transcatheter dynamic contrast-enhanced magnetic resonance (MR) lymphangiography for nontraumatic lymphatic disorders. Five patients (2 males and 3 females; median age, 16.0 years; range, 3-74 years) who underwent both intranodal and transcatheter dynamic contrast-enhanced MR lymphangiography for suspected nontraumatic lymphatic leakages from June 2017 to January 2020 were included in this retrospective study. The imaging findings of both dynamic contrast-enhanced MR lymphangiography techniques were assessed for the presence of chylolymphatic reflux or direct sign of leakage. Intranodal dynamic contrast-enhanced MR lymphangiography demonstrated chylolymphatic reflux into the thoracic area in 2 patients (40%) but no direct evidence of leakage in any of the 5 patients. Transcatheter dynamic contrast-enhanced MR lymphangiography revealed chylolymphatic reflux and extravasation of the contrast agent in all 5 patients (100%). In conclusion, transcatheter dynamic contrast-enhanced MR lymphangiography may reveal additional signs of reflux and extravasation even when the findings of intranodal dynamic contrast-enhanced MR lymphangiography are negative.
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Vasos Linfáticos , Linfografía , Adolescente , Medios de Contraste , Estudios de Factibilidad , Femenino , Humanos , Linfografía/métodos , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Masculino , Estudios RetrospectivosRESUMEN
OBJECTIVE: Currently recommended dosing of lacosamide often necessitates long titration periods. However, the use of a regimen consisting of initial loading dose of 200â¯mg followed by a maintenance dose of 200â¯mg/day in practice suggests tolerability of more rapid titration schedules. We aimed to clarify whether the shortened titration schedule affects tolerability of lacosamide. METHODS: We evaluated the safety of two rapid titration protocols designed to reach the target dose of 400â¯mg/day within 1â¯week, and the conventional weekly titration protocol (reaching the target dose of 400â¯mg/day in three weeks). The ≥50% responder rate and steady-state plasma concentration of lacosamide were also analyzed. Adverse events were assessed at 1â¯week and 5â¯weeks after reaching the target dose. RESULTS: Seventy-five patients with epilepsy were enrolled and evenly distributed to three titration protocols, from which 5 patients were lost to follow-up and excluded from the safety analysis. Discontinuation of lacosamide or dose reductions due to adverse events occurred in 32 patients (46%), of whom a large majority (74%) had experienced adverse events after reaching 400â¯mg/day, demonstrating apparent dose-dependency. There was no difference in safety outcomes among the three titration groups. Concomitant use of sodium channel blockers significantly increased the risk of adverse events. CONCLUSION: Rapid titration protocols for lacosamide were not associated with an increased risk of adverse events compared to the conventional weekly titration protocol. Uptitration of lacosamide at shorter intervals to an effective target dosage may be feasible in appropriate clinical situations.
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Epilepsias Parciales , Acetamidas/efectos adversos , Anticonvulsivantes/efectos adversos , Epilepsias Parciales/tratamiento farmacológico , Humanos , Lacosamida/uso terapéutico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: There is no scale for rating the severity of autoimmune encephalitis (AE). In this study, we aimed to develop a novel scale for rating severity in patients with diverse AE syndromes and to verify the reliability and validity of the developed scale. METHODS: The key items were generated by a panel of experts and selected according to content validity ratios. The developed scale was initially applied to 50 patients with AE (development cohort) to evaluate its acceptability, reproducibility, internal consistency, and construct validity. Then, the scale was applied to another independent cohort (validation cohort, n = 38). RESULTS: A new scale consisting of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness) was developed. Each item was assigned a value of up to 3 points. The total score could therefore range from 0 to 27. We named the scale the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The new scale showed excellent interobserver (intraclass correlation coefficient [ICC] = 0.97) and intraobserver (ICC = 0.96) reliability for total scores, was highly correlated with modified Rankin scale (r = 0.86, p < 0.001), and had acceptable internal consistency (Cronbach α = 0.88). Additionally, in the validation cohort, the scale showed high interobserver reliability (ICC = 0.99) and internal consistency (Cronbach α = 0.92). INTERPRETATION: CASE is a novel clinical scale for AE with a high level of clinimetric properties. It would be suitable for application in clinical practice and might help overcome the limitations of current outcome scales for AE. ANN NEUROL 2019;85:352-358.
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Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Enfermedades Autoinmunes del Sistema Nervioso/psicología , Encefalitis/fisiopatología , Encefalitis/psicología , Adolescente , Adulto , Anciano , Agresión/psicología , Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Encefalitis Antirreceptor N-Metil-D-Aspartato/fisiopatología , Encefalitis Antirreceptor N-Metil-D-Aspartato/psicología , Ataxia/etiología , Ataxia/fisiopatología , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/fisiopatología , Enfermedades Autoinmunes/psicología , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Deluciones/psicología , Discinesias/etiología , Discinesias/fisiopatología , Distonía/etiología , Distonía/fisiopatología , Encefalitis/complicaciones , Encefalomielitis Aguda Diseminada/complicaciones , Encefalomielitis Aguda Diseminada/fisiopatología , Encefalomielitis Aguda Diseminada/psicología , Femenino , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/fisiopatología , Alucinaciones/psicología , Humanos , Trastornos del Lenguaje/etiología , Trastornos del Lenguaje/fisiopatología , Encefalitis Límbica/complicaciones , Encefalitis Límbica/fisiopatología , Encefalitis Límbica/psicología , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/fisiopatología , Persona de Mediana Edad , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , Reproducibilidad de los Resultados , Convulsiones/etiología , Convulsiones/fisiopatología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) helps optimize drug management for patients with epilepsy. Salivary testing is both noninvasive and easy, and has several other advantages. Due to technical advances, salivary TDM has become feasible for several drugs, including AEDs, and its value has been investigated. Until recently, saliva TDM of perampanel (PER) had not been reported. The purpose of our study was to confirm whether saliva is a biological substitute for plasma in PER TDM. METHODS: Adult patients diagnosed with epilepsy who received PER from August 2018 to March 2019 at Seoul National University Hospital were enrolled. Total and free PER were measured in simultaneously obtained plasma and saliva samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatographic (HPLC). We examined the correlations between saliva and plasma PER concentrations and whether the use of concomitant medications classified as cytochrome P450 (CYP)3A4 inducers affected the correlations. RESULTS: Thirty patients were enrolled, aged 16 to 60; 10 (33%) were women. Patients received 2 to 12 mg (mean, 6 mg) of PER. The average total and free concentrations of PER were 343.02 (46.6-818.0) and 1.53 (0.51-2.92) ng/mL in plasma and 9.74 (2.21-33.0) and 2.83 (1.01-6.8) ng/mL in saliva, respectively. A linear relationship was observed between the total PER concentrations in saliva and the total and free PER concentrations in plasma (both P < .001; r = .678 and r = .619, respectively). The change in the PER concentration caused by the CYP3A4 inducer did not affect the correlation between saliva and plasma concentrations (all P < .001). SIGNIFICANCE: The PER concentration in saliva was correlated with that in plasma. This correlation was not affected by CYP3A4 inducers. Our results demonstrate for the first time that PER is measurable in saliva and suggest the potential for the clinical application of the saliva PER TDM matrix.
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Anticonvulsivantes/metabolismo , Monitoreo de Drogas/métodos , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Piridonas/metabolismo , Saliva/metabolismo , Adolescente , Adulto , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Cromatografía Liquida/métodos , Epilepsia/sangre , Femenino , Humanos , Masculino , Espectrometría de Masas/métodos , Persona de Mediana Edad , Nitrilos , Piridonas/sangre , Piridonas/uso terapéutico , Adulto JovenRESUMEN
Background Recent studies showed the possible association between inflammation-induced blood-brain barrier (BBB) structural changes followed by greater permeability of the BBB and chronic pain. Thus, measurement of BBB breakdown would be a valuable aid in the diagnosis in migraine. Dynamic contrast material-enhanced (DCE) MRI can determine perfusion and permeability properties related to the BBB. Purpose To evaluate the relationship between permeability of the BBB in migraine-associated brain regions by using DCE MRI. Materials and Methods In this prospective study, from September 2016 to December 2017, 56 study participants underwent DCE MRI after gadobutrol administration and were classified into migraine (n = 35) and healthy control (n = 21) groups. Automatic volumetric segmentation was performed on the pre-contrast-enhanced T1-weighted images by using FreeSurfer, and migraine-associated brain region masks were extracted by using the software NordicICE. The corresponding maps for pharmacokinetic parameters Ktrans (the volume transfer constant) and Vp (the fractional plasma volume) were coregistered with the region-of-interest masks, and their mean values of corresponding total volume of interest were calculated. For comparison analyses, the Mann-Whitney tests were used. Receiver operating characteristic curve analysis and Spearman rank correlation tests were used to identify correlations between clinical characteristics and the aforementioned perfusion parameters. Results Mean age was younger in the migraine group (mean ± standard deviation, 57 years ± 12) than in the healthy control group (mean, 71 years ± 8) (P < .001). In the migraine group, the mean value of Vp in the left amygdala (median, 0.27 mL/100 g) was lower than that in the healthy control group (median, 0.39 mL/100 g) (P = .04). The mean value of Vp in the left amygdala was correlated with the intensity of headache attack in participants with migraine (correlation coefficient, -0.34; P = .04). Conclusion Lower fractional plasma volume in the left amygdala was observed in participants with migraine than in healthy participants. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Carroll and Ginat in this issue.
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Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/fisiopatología , Permeabilidad Capilar/fisiología , Medios de Contraste , Aumento de la Imagen/métodos , Imagen por Resonancia Magnética/métodos , Trastornos Migrañosos/fisiopatología , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organometálicos , Estudios ProspectivosRESUMEN
Early administration of antibiotics is crucial in the management of bacterial meningitis. Rapid pathogen identification helps to make a definite diagnosis of bacterial meningitis and enables tailored antibiotic treatment. We investigated if the 16S amplicon sequencing performed by MinION, a nanopore sequencer, was capable of rapid pathogen identification in bacterial meningitis. Six retrospective cases of confirmed bacterial meningitis and two prospective cases were included. The initial cerebrospinal fluid (CSF) samples of these patients were used for the experiments. DNA was extracted from the CSF, and PCR was performed on the 16S ribosomal DNA (16S rDNA). Sequencing libraries were prepared using the PCR products, and MinION sequencing was performed for up to 3â¯h. The reads were aligned to the bacterial database, and the results were compared to the conventional culture studies. Pathogenic bacteria were successfully detected from the CSF by 16S sequencing in all retrospective cases. 16S amplicon sequencing was more sensitive than conventional diagnostic tests and worked properly even in antibiotics-treated samples. MinION sequencing significantly reduced the turnaround time, and even 10â¯min of sequencing was sufficient for pathogen detection in certain cases. Protocol adjustment could further increase the sensitivity and reduce the turnaround time for MinION sequencing. Finally, the prospective application of MinION 16S sequencing was successful. Nanopore 16S amplicon sequencing is capable of rapid bacterial identification from the CSF of the bacterial meningitis patients. It may have many advantages over conventional diagnostic tests and should therefore be applied in a larger number of patients in the future.
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Meningitis Bacterianas/diagnóstico , Meningitis Bacterianas/microbiología , Técnicas de Diagnóstico Molecular , Nanoporos , Adulto , Anciano , Anciano de 80 o más Años , Bacterias/clasificación , Bacterias/genética , ADN Bacteriano/genética , Femenino , Humanos , Masculino , Meningitis Bacterianas/líquido cefalorraquídeo , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular/instrumentación , Proyectos Piloto , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , ARN Ribosómico 16S/genética , Estudios Retrospectivos , Sensibilidad y Especificidad , Análisis de Secuencia de ADN , Factores de TiempoRESUMEN
We used deep sequencing of the 16S rRNA gene from sputum to identify Haemophilus influenza in a patient with community-acquired pneumonia. This method may be more effective than conventional diagnostic tests in pneumonia patients because of its speed and sensitivity.
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Infecciones por Haemophilus/diagnóstico , Infecciones por Haemophilus/microbiología , Haemophilus influenzae/genética , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/microbiología , ARN Ribosómico 16S/genética , Esputo/microbiología , Anciano , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Biomarcadores , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/microbiología , Infecciones por Haemophilus/tratamiento farmacológico , Haemophilus influenzae/clasificación , Haemophilus influenzae/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Neumonía Bacteriana/tratamiento farmacológico , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: While brain asymmetry has been a fascinating issue in neuroscience, the critical mechanism remains to be elucidated. Based on some index cases with asymmetric 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) uptake in leucine-rich glioma-inactivated 1 (LGI1)-antibody encephalitis, we hypothesized LGI1 expression could be asymmetrically distributed in the human brain. METHODS: We enrolled 13 patients who were diagnosed with LGI1-antibody encephalitis between June 2012 and January 2018 at Seoul National University Hospital. Their pretreatment 18F-FDG-PET images were analyzed to find asymmetry between the left and right hemispheres. Guided by these observations, expression of LGI1 in the human hippocampus and the globus pallidus of both cerebral hemispheres was studied in nine post-mortem human brains. RESULTS: Eleven of the 13 LGI1-antibody encephalitis patients (84.6%) showed asymmetrical FDG high uptake in the hippocampus: nine (81.8%) on the left hippocampus and two (18.2%) on the right. In the basal ganglia, seven patients (53.8%) showed asymmetry: four (57.1%) on the left and three (42.9%) on the right. The asymmetry was not evident in the laterality of faciobrachial dystonic seizures, brain MRI, and EEG. When the expression of LGI1 protein was analyzed in nine post-mortem human brains by western blotting, LGI1 expression was higher on eight left globus pallidus samples (88.89%, P = 0.019) and on four left hippocampal samples (44.44%, P = 0.652), compared to their right hemisphere samples. CONCLUSIONS: Imaging parameters from patients with LGI1-antibody encephalitis and studies of LGI1 protein expression suggest that LGI1 is asymmetrically distributed in the human brain. These observations have implications for our understanding of human brain development.
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Autoanticuerpos/sangre , Encéfalo/metabolismo , Encefalitis/inmunología , Encefalitis/patología , Proteínas/metabolismo , Anciano , Encéfalo/diagnóstico por imagen , Electroencefalografía , Encefalitis/diagnóstico por imagen , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Tomografía de Emisión de Positrones , Proteínas/genética , Estudios Retrospectivos , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: Autoimmune encephalitis (AE), represented by anti-leucine-rich glioma-inactivated 1 (anti-LGI1) and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, has increasing clinical significance based on recent discoveries of neuronal autoantibodies. However, its immunopathogenesis is not fully understood. Here, we investigated whether AE is associated with the human leukocyte antigen (HLA) subtypes. METHODS: We compared the HLA genotypes of 11 anti-LGI1 and 17 anti-NMDAR encephalitis patients to the control groups, which consisted of 210 epilepsy patients and 485 healthy Koreans. RESULTS: Anti-LGI1 encephalitis was associated with the DRB1*07:01-DQB1*02:02 haplotype (10 patients; 91%) in HLA class II genes, as well as with B*44:03 (8 patients; 73%) and C*07:06 (7 patients; 64%) in the HLA class I region. The prevalence of these alleles in anti-LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti-NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA-peptide binding prediction algorithms and computational docking underpinned the close relationship. INTERPRETATION: This finding suggests that most anti-LGI1 encephalitis develops in a population with specific HLA subtypes, providing insight into a novel disease mechanism. Ann Neurol 2017;81:183-192.