Dynamic Contrast-enhanced MRI Quantification of Altered Vascular Permeability in Autoimmune Encephalitis.

Background Blood-brain barrier (BBB) permeability change is a possible pathologic mechanism of autoimmune encephalitis. Purpose To evaluate the change in BBB permeability in patients with autoimmune encephalitis as compared with healthy controls by using dynamic contrast-enhanced (DCE) MRI and to explore its predictive value for treatment response in patients. Materials and Methods This single-center retrospective study included consecutive patients with probable or possible autoimmune encephalitis and healthy controls who underwent DCE MRI between April 2020 and May 2021. Automatic volumetric segmentation was performed on three-dimensional T1-weighted images, and volume transfer constant (Ktrans) values were calculated at encephalitis-associated brain regions. Ktrans values were compared between the patients and controls, with adjustment for age and sex with use of a nonparametric approach. The Wilcoxon rank sum test was performed to compare Ktrans values of the good (improvement in modified Rankin Scale [mRS] score of at least two points or achievement of an mRS score of ≤2) and poor (improvement in mRS score of less than two points and achievement of an mRS score >2) treatment response groups among the patients. Results Thirty-eight patients with autoimmune encephalitis (median age, 38 years [IQR, 29-59 years]; 20 [53%] female) and 17 controls (median age, 71 years [IQR, 63-77 years]; 12 [71%] female) were included. All brain regions showed higher Ktrans values in patients as compared with controls (P < .001). The median difference in Ktrans between the patients and controls was largest in the right parahippocampal gyrus (25.1 × 10-4 min-1 [95% CI: 17.6, 43.4]). Among patients, the poor treatment response group had higher baseline Ktrans values in both cerebellar cortices (P = .03), the left cerebellar cortex (P = .02), right cerebellar cortex (P = .045), left cerebral cortex (P = .045), and left postcentral gyrus (P = .03) than the good treatment response group. Conclusion DCE MRI demonstrated that BBB permeability was increased in all brain regions in patients with autoimmune encephalitis as compared with controls, and baseline Ktrans values were higher in patients with poor treatment response in the cerebellar cortex, left cerebral cortex, and left postcentral gyrus as compared with the good response group. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Filippi and Rocca in this issue.

MOG antibody-associated encephalitis in adult: clinical phenotypes and outcomes.

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 0‒2) 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.

Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes.

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.

Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis.

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P < 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P < 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P < 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.

CaV α2δ Autoimmune Encephalitis: A Novel Antibody and its Characteristics.

OBJECTIVE: Discovery of a novel antibody would enable diagnosis and early treatment of autoimmune encephalitis. The aim was to discover a novel antibody targeting a synaptic receptor and characterize the pathogenic mechanism. METHOD: We screened for unknown antibodies in serum and cerebrospinal fluid samples from autoimmune encephalitis patients. Samples with reactivity to rat brain sections and no reactivity to conventional antibody tests underwent further processing for antibody discovery, using immunoprecipitation to primary neuronal cells, mass-spectrometry analysis, an antigen-binding assay on an antigen-overexpressing cell line, and an electrophysiological assay with cultured hippocampal neurons. RESULTS: Two patients had a novel antibody against CaV α2δ (voltage-gated calcium channel alpha-2/delta subunit). The patient samples stained neuropils of the hippocampus, basal ganglia, and cortex in rat brain sections and bound to a CaV α2δ-overexpressing cell line. Knockdown of CaV α2δ expression in cultured neurons turned off the immunoreactivity of the antibody from the patients to the neurons. The patients were associated with preceding meningitis or neuroendocrine carcinoma and responded to immunotherapy. In cultured neurons, the antibody reduced neurotransmitter release from presynaptic nerve terminals by interfering with tight coupling of calcium channels and exocytosis. INTERPRETATION: Here, we discovered a novel autoimmune encephalitis associated with anti-CaV α2δ antibody. Further analysis of the antibody in autoimmune encephalitis might promote early diagnosis and treatment. ANN NEUROL 2021;89:740-752.

Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy.

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.

Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.

Biological roles for UFM1, a ubiquitin-like protein, are largely unknown, and therefore we screened for targets of ufmylation. Here we show that ufmylation of the nuclear receptor coactivator ASC1 is a key step for ERα transactivation in response to 17ß-estradiol (E2). In the absence of E2, the UFM1-specific protease UfSP2 was bound to ASC1, which maintains ASC1 in a nonufmylated state. In the presence of E2, ERα bound ASC1 and displaced UfSP2, leading to ASC1 ufmylation. Polyufmylation of ASC1 enhanced association of p300, SRC1, and ASC1 at promoters of ERα target genes. ASC1 overexpression or UfSP2 knockdown promoted ERα-mediated tumor formation in vivo, which could be abrogated by treatment with the anti-breast cancer drug tamoxifen. In contrast, expression of ufmylation-deficient ASC1 mutant or knockdown of the UFM1-activating E1 enzyme UBA5 prevented tumor growth. These findings establish a role for ASC1 ufmylation in breast cancer development by promoting ERα transactivation.

Absolute quantification of tumor-infiltrating immune cells in high-grade glioma identifies prognostic and radiomics values.

PURPOSE: To understand the tumor immune microenvironment precisely, it is important to secure the quantified data of tumor-infiltrating immune cells, since the immune cells are true working unit. We analyzed unit immune cell number per unit volume of core tumor tissue of high-grade gliomas (HGG) to correlate their immune microenvironment characteristics with clinical prognosis and radiomic signatures. METHODS: The number of tumor-infiltrating immune cells from 64 HGG core tissue were analyzed using flow cytometry and standardized. After sorting out patient groups according to diverse immune characteristics, the groups were tested if they have any clinical prognostic relevance and specific radiomic signature relationships. Sparse partial least square with discriminant analysis using multimodal magnetic resonance images was employed for all radiomic classifications. RESULTS: The median number of CD45 + cells per one gram of HGG core tissue counted 865,770 cells which was equivalent to 8.0% of total cells including tumor cells. There was heterogeneity in the distribution of immune cell subpopulations among patients. Overall survival was significantly better in T cell-deficient group than T cell-enriched group (p = 0.019), and T8 dominant group than T4 dominant group (p = 0.023). The number of tumor-associated macrophages (TAM) and M2-TAM was significantly decreased in isocitrate dehydrogenase mutated HGG. Radiomic signature classification showed good performance in predicting immune phenotypes especially with features extracted from apparent diffusion coefficient maps. CONCLUSIONS: Absolute quantification of tumor-infiltrating immune cells confirmed the heterogeneity of immune microenvironment in HGG which harbors prognostic impact. This immune microenvironment could be predicted by radiomic signatures non-invasively.

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Tofacitinib treatment for refractory autoimmune encephalitis.

To treat intractable cases of autoimmune encephalitis, the need for novel immunotherapy that penetrates the blood-brain barrier (BBB) is increasing. Tofacitinib is a Janus kinase (JAK) inhibitor used to treat refractory immune-mediated diseases that effectively penetrates the BBB. Accordingly, tofacitinib could be a new option for patients with refractory autoimmune encephalitis. Patients treated with tofacitinib were selected from Seoul National University Hospital cohort for autoimmune encephalitis from April 2019 until July 2020. We retrospectively analyzed the efficacy of tofacitinib in patients with autoimmune encephalitis who showed insufficient responses to multimodal conventional immunotherapies. Tofacitinib was administered orally at a dose of 5 mg twice daily. A total of eight patients were treated with tofacitinib; two had good responses (clinical global impression-improvement score [CGI-I] = 1 or 2), three had partial responses (CGI-I = 3), and three showed no significant improvements (CGI-I = 4) in response to tofacitinib. The two good responders showed the improvement of chronic autoimmune meningoencephalitis and the cessation of the new-onset refractory status epilepticus in anti-myelin oligodendrocyte glycoprotein (MOG)-associated disorder, which was previously intractable to anesthetics and the other immunotherapies. No patients had serious side effects. Our findings suggest the potential of tofacitinib as a therapeutic option for central nervous system autoimmune diseases.

Differentiation between glioblastoma and primary CNS lymphoma: application of DCE-MRI parameters based on arterial input function obtained from DSC-MRI.

OBJECTIVE: This study aimed to evaluate whether arterial input functions (AIFs) obtained from dynamic susceptibility contrast (DSC)-MRI (AIFDSC) improve the reliability and diagnostic accuracy of dynamic contrast-enhanced (DCE)-derived pharmacokinetic (PK) parameters for differentiating glioblastoma from primary CNS lymphoma (PCNSL) compared with AIFs derived from DCE-MRI (AIFDCE). METHODS: This retrospective study included 172 patients with glioblastoma (n = 147) and PCNSL (n = 25). All patients had undergone preoperative DSC- and DCE-MRI. The volume transfer constant (Ktrans), volume of the vascular plasma space (vp), and volume of the extravascular extracellular space (ve) were acquired using AIFDSC and AIFDCE. The relative cerebral blood volume (rCBV) was obtained from DSC-MRI. Intraclass correlation coefficients (ICC) and ROC curves were used to assess the reliability and diagnostic accuracy of individual parameters. RESULTS: The mean Ktrans, vp, and ve values revealed better ICCs with AIFDSC than with AIFDCE (Ktrans, 0.911 vs 0.355; vp, 0.766 vs 0.503; ve, 0.758 vs 0.657, respectively). For differentiating all glioblastomas from PCNSL, the mean rCBV (AUC = 0.856) was more accurate than the AIFDSC-driven mean Ktrans, which had the largest AUC (0.711) among the DCE-derived parameters (p = 0.02). However, for glioblastomas with low rCBV (≤ 75th percentile of PCNSL; n = 30), the AIFDSC-driven mean Ktrans and vp were more accurate than rCBV (AUC: Ktrans, 0.807 vs rCBV, 0.515, p = 0.004; vp, 0.715 vs rCBV, p = 0.045). CONCLUSION: DCE-derived PK parameters using the AIFDSC showed improved reliability and diagnostic accuracy for differentiating glioblastoma with low rCBV from PCNSL. KEY POINTS: • An accurate differential diagnosis of glioblastoma and PCNSL is crucial because of different therapeutic strategies. • In contrast to the rCBV from DSC-MRI, another perfusion imaging technique, the DCE parameters for the differential diagnosis have been limited because of the low reliability of AIFs from DCE-MRI. • When we analyzed DCE-MRI data using AIFs from DSC-MRI (AIFDSC), AIFDSC-driven DCE parameters showed improved reliability and better diagnostic accuracy than rCBV for differentiating glioblastoma with low rCBV from PCNSL.

Tolerability of lacosamide rapid dose titration: A randomized, multicenter, prospective, open-label study.

OBJECTIVE: Currently recommended dosing of lacosamide often necessitates long titration periods. However, the use of a regimen consisting of initial loading dose of 200 mg followed by a maintenance dose of 200 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 400 mg/day within 1 week, and the conventional weekly titration protocol (reaching the target dose of 400 mg/day in three weeks). The ≥50% responder rate and steady-state plasma concentration of lacosamide were also analyzed. Adverse events were assessed at 1 week and 5 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 400 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.

Development of the clinical assessment scale in autoimmune encephalitis.

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.

Validation and optimization of a web-based nomogram for predicting survival of patients with newly diagnosed glioblastoma.

PURPOSE: To optimize and validate a current (NRG [a newly constituted National Clinical Trials Network group through National Surgical Adjuvant Breast and Bowel Project [NSABP], the Radiation Therapy Oncology Group [RTOG] and the Gynecologic Oncology Group (GOG)]) nomogram for glioblastoma patients as part of continuous validation. METHODS: We identified patients newly diagnosed with glioblastoma who were treated with temozolomide-based chemoradiotherapy between 2006 and 2016 at three large-volume hospitals. The extent of resection was determined via postoperative MRI. The discrimination and calibration abilities of the prediction algorithm were assessed; if additional factors were identified as independent prognostic factors, updated models were developed using the data from two hospitals and were externally validated using the third hospital. Models were internally validated using cross-validation and bootstrapping. RESULTS: A total of 837 patients met the eligibility criteria. The median overall survival (OS) was 20.0 (95% CI 18.5-21.5) months. The original nomogram was able to estimate the 6­, 12-, and 24-month OS probabilities, but it slightly underestimated the OS values. In multivariable Cox regression analysis, MRI-defined total resection had a greater impact on OS than that shown by the original nomogram, and two additional factors-IDH1 mutation and tumor contacting subventricular zone-were newly identified as independent prognostic values. An updated nomogram incorporating these new variables outperformed the original nomogram (C-index at 6, 12, 24, and 36 months: 0.728, 0.688, 0.688, and 0.685, respectively) and was well calibrated. External validation using an independent cohort showed C­indices of 0.787, 0.751, 0.719, and 0.702 at 6, 12, 24, and 36 months, respectively, and was well calibrated. CONCLUSION: An updated and validated nomogram incorporating the contemporary parameters can estimate individual survival outcomes in patients with glioblastoma with better accuracy.

Usefulness of saliva for perampanel therapeutic drug monitoring.

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.

Prognostication of anaplastic astrocytoma patients: application of contrast leakage information of dynamic susceptibility contrast-enhanced MRI and dynamic contrast-enhanced MRI.

PURPOSE: To examine the applicability of contrast leakage information from dynamic susceptibility contrast-enhanced (DSC) MRI and dynamic contrast-enhanced (DCE) MRI to determine which one is the most valuable surrogate imaging biomarker for predicting disease progression in anaplastic astrocytoma (AA) patients. MATERIALS AND METHODS: This study was approved by the institutional review board (IRB), which waived informed consent. A total of seventy-three AA patients who had undergone preoperative DCE and DSC MRI and received standard treatment, including partial resection or biopsy followed by radiation therapy, were included in this retrospective study. Based on Response Assessment in Neuro-Oncology (RANO), patients were sorted into progression (n = 21) and non-progression (n = 52) groups. Tumor boundaries were defined as high-signal intensity (SI) lesions on fluid-attenuated inversion recovery (FLAIR) imaging, where we analyzed mean pharmacokinetic parameters (Ktrans, Vp, and Ve) from DCE MRI and contrast leakage information (mean extraction fraction (EF)) from DSC MRI. RESULTS: Mean Ve and mean EF were significantly higher in patients with progression-free survival (PFS) < 18 months than in those with PFS ≥ 18 months. For distinguishing the group with PFS < 18 months, AUC values were calculated using the mean Ve value (AUC = 0.716). The Kaplan-Meier survival analysis revealed that mean Ve value was significantly correlated with PFS. In Cox proportional-hazards regression, only the mean Ve value was found to be significantly associated with PFS. CONCLUSION: We found that the mean Ve value based on high-SI tumor lesions on FLAIR imaging was capable of predicting outcomes of AA patients as a potential surrogate imaging biomarker. KEY POINTS: • Mean Ve(2.152 ± 1.857 vs. 1.173 ± 1.408) was significantly higher in anaplastic astrocytoma patients with PFS < 18 months that in those with PFS ≥ 18 months (p = 0.02). • Cox proportional-hazards regression showed that only mean Ve(p = 0.034) was significantly associated with PFS, regardless of IDH mutation status, in anaplastic astrocytoma patients.

Treatment of epilepsy in adults: Expert opinion in South Korea.

OBJECTIVE: The aim of this study was to gather the expert opinions of Korean epileptologists regarding the treatment of adult patients with epilepsy. METHODS: A total of 42 neurologists who specialized in epilepsy were surveyed. They completed an online questionnaire describing multiple patient scenarios. Using these scenarios, they evaluated treatment strategies and gave their preference for specific antiepileptic drugs (AEDs) used to treat genetically mediated generalized epilepsy and focal epilepsy. RESULTS: Initial AED monotherapy, followed by a second form of alternative monotherapy or an add-on combination therapy, was the preferred treatment strategy. The experts reached consensus for 87.2% of the items. The most commonly selected AEDs for the initial monotherapy for patients with generalized epilepsy were levetiracetam or valproate. For those with focal epilepsy, levetiracetam, oxcarbazepine, or lamotrigine were the most popular selections. Ethosuximide was the treatment of choice only for patients with generalized epilepsy with prominent absence seizures. Levetiracetam was preferred as an add-on therapy for both generalized and focal epilepsy. For special populations of patients, such as elderly adults or those with comorbid diseases, levetiracetam or lamotrigine was selected as the treatment of choice. CONCLUSION: Most of the survey results were in accordance with the US expert opinion survey published in 2016. This survey can assist clinicians in making clinical decisions when treating individual adult patients with epilepsy.

Altered Vascular Permeability in Migraine-associated Brain Regions: Evaluation with Dynamic Contrast-enhanced MRI.

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.

Rapid diagnosis of bacterial meningitis by nanopore 16S amplicon sequencing: A pilot study.

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 3 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 10 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.