Gut microbiome diversity in a febrile seizure mouse model.

Purpose: Febrile seizures at a young age can provoke late-onset temporal lobe epilepsy. Since recent evidence has suggested that the gut microbiome affects central nervous system pathology across the blood-brain barrier, we hypothesized that febrile seizures alter the composition of the gut microbiome to provoke epilepsy. Methods: Third-generation C57BL/6 mice were separated into two groups (n = 5 each), and hot air was applied to only one group to cause febrile seizures. After two weeks of heat challenge, the fecal pellets acquired from each group were analyzed. Results: The gut microbiota of fecal pellets from each group revealed five taxa at the genus level and eight taxa at the species level that were significantly different in proportion between the groups. Conclusion: Although there was no significant difference in the overall diversity of the gut microbiota between the two groups, the identified heterogeneity may imply the pathognomonic causative relevance of febrile seizures and the development of epilepsy.

Topiramate dosage optimization for effective antiseizure management via population pharmacokinetic modeling.

OBJECTIVE: Despite the suggested topiramate serum level of 5-20 mg/L, numerous institutions have observed substantial drug response at lower levels. We aim to investigate the correlation between topiramate serum levels, drug responsiveness, and adverse events to establish a more accurate and tailored therapeutic range. METHODS: We retrospectively analyzed clinical data collected between January 2017 and January 2022 at Seoul National University Hospital. Drug responses to topiramate were categorized as "insufficient" or "sufficient" by reduction in seizure frequency ≥ 50%. A population pharmacokinetic model estimated serum levels from spot measurements. ROC curve analysis determined the optimal cutoff values. RESULTS: A total of 389 epilepsy patients were reviewed having a mean dose of 178.4 ± 117.9 mg/day and the serum level, 3.9 ± 2.8 mg/L. Only 5.6% samples exhibited insufficient response, with a mean serum level of 3.6 ± 2.5 mg/L while 94.4% demonstrated sufficient response, with a mean 4.0 ± 2.8 mg/L, having no statistical significance. Among the 69 reported adverse events, logistic regression analysis identified a significant association between ataxia and serum concentration (p = 0.04), with an optimal cutoff value of 6.5 mg/L. INTERPRETATION: This study proposed an optimal therapeutic concentration for topiramate based on patients' responsiveness to the drug and the incidence of adverse effects. We recommended serum levels below 6.5 mg/L to mitigate the risk of ataxia-related side effects while dose elevation was found unnecessary for suboptimal responders, as the drug's effectiveness plateaus at minimal doses.

Teratoma pathology and genomics in anti-NMDA receptor encephalitis.

INTRODUCTION: Ovarian teratoma is a common occurrence in patients with anti-NMDA receptor encephalitis (NMDARe), and its removal is crucial for a favorable prognosis. However, the initial pathogenesis of autoimmunity in the encephalitic teratoma remains unclear. In this study, we aimed to investigate the genomic landscape and microscopic findings by comparing NMDARe-associated teratomas and non-encephalitic control teratomas. MATERIALS AND METHODS: A prospective consecutive cohort of 84 patients with NMDARe was recruited from January 2014 to April 2020, and among them, patients who received teratoma removal surgery at Seoul National University Hospital were enrolled. We conducted a comparison of whole-exome sequencing data and pathologic findings between NMDARe-associated teratomas and control teratomas. RESULTS: We found 18 NMDARe-associated teratomas from 15 patients and compared them with 17 non-encephalitic control teratomas. Interestingly, the genomic analysis revealed no significant differences in mutations between encephalitic and non-encephalitic teratomas. Pathologic analysis showed no discrepancies in terms of the presence of neuronal tissue and lymphocytic infiltration between the encephalitic teratomas (n = 14) and non-encephalitic teratomas (n = 18). However, rituximab-naïve encephalitic teratomas exhibited a higher frequency of germinal center formation compared to non-encephalitic teratomas (80% vs. 16.7%, P = 0.017). Additionally, rituximab-treated encephalitic teratomas demonstrated a reduced number of CD20+ cells and germinal centers in comparison to rituximab-naïve encephalitic teratomas (P = 0.048 and 0.023, respectively). DISCUSSION: These results suggest that the initiation of immunopathogenesis in NMDARe-associated teratoma is not primarily attributed to intrinsic tumor mutations, but rather to immune factors present in the encephalitic patient group, ultimately leading to germinal center formation within the teratoma.

Anti-seizure medication prescription in epilepsy patients in South Korea: A seven-year population-based retrospective cohort study.

BACKGROUND AND OBJECTIVES: This study aimed to explore the natural history of patients with epilepsy using overall antiseizure-medication (ASM) treatment patterns on a nationwide scale in South Korea. METHODS: We investigated a retrospective longitudinal cohort of patients with epilepsy in South Korea using nationwide data from the Korean National Health Information Database of the Health Insurance and Review Assessment Service between January 1st, 2009, and December 31st, 2018. Histories of each patient's ASM prescription were followed for up to 7 years from the index date, the first observed date of ICD-10 epilepsy diagnosis codes with at least one ASM prescription. RESULTS: Of 82,390 incident patients analyzed, ten thousand and fifty-nine were followed up to seven years, and nearly 60% of them discontinued the ASM(s). The proportion of patients with possible drug-resistant epilepsy (DRE), who experience three or more types of ASMs, gradually increased, reaching approximately 8.8% of the total number of patients in the seventh year (6.45% for adults, 21.8% for children). The duration of progression for half of the patients with possible DRE was 1.29 years for children, 1.79 years for adults, and 1.62 years for mixed-age patients. However, even in the sixth year, 72 cases progressed to possible DRE, and 6 cases with possible DRE discontinued ASMs in the next year, showing a dynamic process. DISCUSSION: Our population-based study showed the dynamic changes of anti-seizure medication prescription in epilepsy patients with real-world data, which slowly stabilizes over years after the first diagnosis of epilepsy.

Trends in sleep duration in Korea: The Korean time use survey.

OBJECTIVES: An accurate assessment of sleep duration is important in that it can be one of the indicators of a country's overall health and well-being. The global trend in sleep duration is controversial according to study types. We investigated trends in sleep duration in South Korea with a time diary method. METHODS: Data from the Korean Time Use Survey (KTUS) in 2004, 2009, 2014, and 2019, were analyzed. The KTUS is a nationwide, cross-sectional survey that measures daily time use patterns of individuals and has been performed every five years by Statistics Korea. For this survey, all participants were asked to record their activities for 2 continuous days in 10-min intervals. RESULTS: Among the 168,682 people who completed the survey in 2004 through 2019, the final analytical sample consisted of 91,998 individuals. Over 15 years, the sleep duration of the Korean population increased from 411.1 min (SD 22.5) in 2004 to 434.5 min (SD 26.1) in 2019 (p for trend <0.001). This increase was observed for all age groups. Over the study period, while bedtime showed no significant change, wake time was generally delayed for all age groups. The increase in sleep duration in the Korean population was largely due to catch-up sleep on Saturdays, which was substantially prolonged with belated wake times. CONCLUSION: Our nationwide time use survey data showed that sleep duration in South Korea has increased over the past 15 years but still has room for improvement in terms of weekday sleep duration.

Clinicoradiologic data of familial cerebral cavernous malformation with age-related disease burden.

OBJECTIVE: Familial cerebral cavernous malformation (FCCM) is an autosomal dominant disease induced by loss-of-function mutations in three CCM genes, KRIT1, CCM2, and PDCD10. However, previous studies paid little attention to analyzing the radiologic features and age-related disease burden according to the genes. Therefore, we retrospectively reviewed the genetic tests of our center's clinical FCCM patients. METHOD: This study investigated clinical FCCM patients with multiple lesions or a family history of CCMs who underwent the FCCM gene (KRTI1, CCM2, and PDCD10) panel test. The clinical, genetic, and radiologic features were analyzed. RESULT: Among the patients (n = 34) undergoing the FCCM gene test, twenty-seven patients had CCM confirmed by brain MRI, and twenty-one patients were considered to have FCCM (cohort 1). In cohort 1, thirteen patients had mutations in the FCCM gene, but eight did not. Cohort 2 comprised cohort 1 and four family members with the same mutation as the probands. Six novel variants in CCM genes were detected (KRIT1 c.22_26del, c.815dup, c.1094_1098del, c.1147-2A>G, c.2124dup, and PDCD10 c.150 + 1dup). Cohort 1 demonstrated that brainstem lesions were mostly associated with the mutation detection in CCM genes (brainstem, lateral temporal, and parietal lesions vs. lateral temporal and parietal lesions, AUC 0.928 vs. 0.779, P = 0.0389). The radiologic severity worsened according to age in the KRIT1 group compared with the Mutation not detected group (correlation coefficient 0.75 (P < 0.001) versus 0.53 (P = 0.004)). CONCLUSION: The brainstem lesion could be the radiologic marker for FCCM with the mutation detected. The age-related disease burden regarding FCCM according to genetic information was demonstrated.

Nanopore 16S sequencing enhances the detection of bacterial meningitis after neurosurgery.

OBJECTIVE: Nosocomial bacterial meningitis is one of the major complications after neurosurgery. We performed nanopore 16S amplicon sequencing from cerebrospinal fluid (CSF) to evaluate bacterial meningitis in patients who underwent neurosurgery. METHODS: Among the patients who visited the neurosurgery department of Seoul National University Hospital between July 2017 and June 2020, those with clinically suspected bacterial meningitis were included. 16S rDNA PCR was performed from the CSF, and nanopore sequencing was performed for up to 3 h. The reads were aligned to the BLAST database. In each case, the culture and the 16S rRNA gene amplicon analysis were simultaneously performed and compared with each other, and we retrospectively reviewed the medical records. Genuine infection was determined by the identical results between conventional culture study and the sequencing, or clinically determined in cases with inconsistent results between the two methods. RESULTS: Of the 285 samples obtained from 178 patients who had 16S rDNA PCR, 41 samples (14.4%) were diagnosed with genuine infection. A total of 56.1% (23/41) of the samples with genuine infection showed a false-negative culture test. In particular, 16S amplicon sequencing was useful in evaluating patients at the initial tests who had infection with intraventricular hemorrhage (Culture false-negative rate = 100%), subarachnoid hemorrhage (Culture false-negative rate = 77.8%), and systemic cancer (Culture false-negative rate = 100%), which are risk factors for central fever. Moreover, 16S amplicon sequencing could suggest the possibility of persistent bacterial meningitis in empirical antibiotic use. CONCLUSION: CSF nanopore 16S sequencing was more effective than conventional CSF culture studies in postoperative bacterial meningitis and may contribute to evidence-based decisions for antibiotic maintenance and discontinuation.

Anakinra treatment for refractory cerebral autoinflammatory responses.

Refractory cerebral autoinflammatory-autoimmune diseases are often associated with dysregulated innate immunity and are targeted by anakinra, an interleukin-1 receptor antagonist. We analyzed the therapeutic effect of anakinra in refractory cerebral autoinflammatory response (CAIR) at a single institution from January 2017 to May 2021. In total, 12 patients with various etiologies were sympathetically treated with anakinra (100 mg/day subcutaneously). Four patients showed good responses, and among these patients, three patients had pathologically demonstrated CAIR. The other eight patients were nonresponsive. No patient had a serious adverse effect. Thus, anakinra may be a therapeutic option for refractory cerebral autoinflammatory diseases.

Predictors of critical illness among young males with chest pain, abdominal pain, or headaches in the Republic of Korea Army.

Purpose: Chest pain, abdominal pain, and headache are common symptoms associated with critical illness. Here, we aimed to evaluate predictors associated with critical illness in young males of the Republic of Korea Army. Methods: We retrospectively reviewed previously healthy young males with chest pain, abdominal pain, or headaches who visited Armed Forces Seoul District Hospital between January 2019 and December 2020. Critical illness was defined as a condition that required hospitalization, a procedure or surgery, or referral to a tertiary hospital. The symptoms and signs of critical illness were evaluated. Results: Of the 762 enrolled patients, a critical illness was diagnosed in 45 patients (5.9%). Among chest pain signs, palpitation (odds ratio [OR], 22.8; 95% confidence interval [CI], 5.08-102.4; p < 0.001), exertional dyspnea (OR, 16.3; 95% CI, 3.38-78.8; p = 0.001), duration (> 5 minutes) (OR, 7.54; 95% CI, 1.93-29.49; p = 0.004), and squeezing type (OR, 5.28; 95% CI, 1.11-25.11; p = 0.037) were significantly associated with critical illness. Among abdominal pain signs, right-lower-quadrant tenderness (OR, 11.87; 95% CI, 4.671-31.87; p < 0.001) was an alarming sign. For headaches, criticality was low (1.5%), and half of patients with critical illness were diagnosed incidentally regardless of headache. Conclusion: We identified symptoms and signs significantly associated with critical illness in young male patients. This study might serve as a reference for deciding when to transfer soldiers in the field to a rear hospital, thereby contributing to the welfare and combat power of soldiers.

Telemedicine in epilepsy and encephalitis: previous research and indication guidelines in Korea.

Telemedicine is an emerging field of medicine that has become more important during the coronavirus disease 2019 (COVID-19) pandemic era and is being studied actively in various medical fields. In neurology, the introduction of telemedicine is accelerating worldwide under the label of teleneurology. So far, few studies have been conducted on telemedicine for patients with epilepsy. In nonmetropolitan areas, video-based clinics have been demonstrated to be effective for seizure control, and smartphone-based diagnosis has also been confirmed to be accurate. Indeed, after the onset of the COVID-19 pandemic, telemedicine has been used to treat patients with epilepsy around the world. Few studies have examined the use of telemedicine for patients with autoimmune encephalitis. One showed that telephone-based evaluation is sufficient to assess the cognitive reserve of leucine-rich glioma inactivated-1-antibody encephalitis patients, thereby diagnosing their dementia. Telephone-based outpatient clinics are temporarily permitted under Korean medical law, and telemedicine can be attempted for clinically stable patients with epilepsy in Korea. In addition, patients with autoimmune encephalitis in stable or improving status may also be candidates for treatment with telemedicine. This review presents evidence for the safety and efficacy of telemedicine to treat epilepsy and encephalitis patients and discusses indication guidelines. Based on our literature review and current Korean medical law, we suggest tentative guidelines for telemedicine in the fields of epilepsy and autoimmune encephalitis.

High-Dose Diazepam Controls Severe Dyskinesia in Anti-NMDA Receptor Encephalitis.

OBJECTIVE: Because there is no standard treatment to control dyskinesia in anti-NMDA receptor (NMDAR) encephalitis, we analyzed the therapeutic efficacy of high-dose diazepam in dyskinesia associated with NMDAR encephalitis. METHODS: We reviewed patients with NMDAR encephalitis with dyskinesia who were admitted to Seoul National University Hospital between November 2012 and July 2018. High-dose diazepam was administered orally or via a nasogastric tube 3-6 times a day. We assessed the treatment effect by comparing dyskinesia severity between the first day of the highest dose of diazepam and one week after the treatment. RESULTS: Among 68 patients with NMDAR encephalitis during the study period, 33 patients were treated with enteral diazepam (ranging from 6 to 180 mg) to control dyskinesia, along with immunotherapy. The severity of dyskinesia improved from average grade 2.4 ± 0.6 to 1.1 ± 0.7 after 1 week of the highest dose of diazepam (mean severity change -1.4 ± 0.6, 95% confidence interval -1.2 to -1.6; p < 0.001). No patients had serious adverse events except for mild sedation. CONCLUSIONS: Dyskinesia in NMDAR encephalitis improved after treatment with enteral diazepam without significant side effects. This study suggests that enteral diazepam could be a treatment option for control dyskinesia in NMDAR encephalitis. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with dyskinesias associated with NMDAR encephalitis, enteral diazepam is effective and safe in dyskinesia control.

A new rapid titration protocol for lamotrigine that reduces the risk of skin rash.

OBJECTIVE: Lamotrigine is one of the most widely used antiepileptic drugs, but it has a critical issue of a skin rash if the starting dose is too high or the escalation rate is too rapid. We investigated the efficacy and safety of a novel and rapid titration protocol for lamotrigine that takes only 11 days to reach a daily dose of 200 mg. METHODS: We prospectively enrolled 33 adult patients (age 18-85) who were diagnosed with epilepsy and started lamotrigine administration for the first time at a single tertiary hospital. Our new protocol starts with a subthreshold dose of the drug and then administers a stepwise-incremental dose until reaching the full therapeutic dose within 11 days. RESULTS: Of 29 patients analyzed, only two (6.9%) experienced idiosyncratic skin rash before the first follow-up visit at 2 weeks (±3 days). In addition, a therapeutic concentration was reached in more than 75% of studied patients after 2 weeks of lamotrigine administration. SIGNIFICANCE: These findings demonstrate the value of the novel tolerance induction protocol for lamotrigine, which could widen the available application of lamotrigine in various situations. However, this study is a preliminary study limited by a small number of patients and its nonrandomized and open-label design, so the current protocol needs more rigorous clinical evaluations before the application to the real clinical setting.

Population pharmacokinetic model development and its relationship with adverse events of oxcarbazepine in adult patients with epilepsy.

This study aimed to develop a pharmacokinetic (PK) model of oxcarbazepine (OXC) and analyse the relationship between monohydroxylated derivative (MHD), an active metabolite of OXC, and the adverse events of OXC. We obtained 711 OXC samples from 618 patients with epilepsy who were enrolled in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. The plasma PK model was developed using a nonlinear mixed-effect modelling method with NONMEM (ver 7.3). A one-compartment model with a first-order absorption model and proportional residual error adequately described the MHD concentration-time profiles. The only covariate incorporated for CL/F and V/F was body weight. Of the 447 patients analysed, 28 (6.26%) had dose-related adverse events (DRAEs), which were dizziness, somnolence, headache, and diplopia. For DRAE occurrence, the cut-off values of the MHD trough and AUC were 12.27 mg/L (specificity 0.570, sensitivity 0.643) and 698.5 mg h/L (specificity, sensitivity 0.571), respectively. Multivariate analysis showed the sole dizziness symptom was significantly associated with both the MHD trough and the AUC (p = 0.013, p = 0.038, respectively). We newly developed a population PK model using sparse sampling data from patients with epilepsy, and the model better reflects the actual clinical situation.

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.

Paraneoplastic encephalitis associated with renal cell carcinoma.

Purpose: Paraneoplastic encephalitis is autoimmune encephalitis accompanied by tumors. Renal cell carcinoma (RCC) is a kidney cancer originating from various types of renal cells and rarely has been associated with paraneoplastic neurologic manifestation. We identified a case series of paraneoplastic encephalitis-associated RCC. Methods: From a prospective institutional cohort, we identified autoimmune encephalitis patients with RCC. The association between RCC and encephalitis was determined by the following criteria: (1) possible autoimmune encephalitis according to the operational autoimmune encephalitis diagnostic criteria and (2) RCC simultaneously diagnosed with neurological manifestation of encephalitis. Results: A total of three patients presented encephalitis accompanied by RCC. Two patients had clear cell RCC, and one had chromophobe RCC. All patients showed limbic encephalitis with cognitive decline, memory impairment, or seizure. Brain magnetic resonance imaging showed T2 hyperintensities at the mesial temporal lobe in two patients with clear cell RCC but no remarkable findings in one patient with chromophobe RCC. While one patient who had early surgery within one month of RCC onset had a favorable response to the treatment, the other two patients showed a partial response and a detrimental result. Conclusion: Paraneoplastic encephalitis associated with RCC presented as limbic encephalitis and was responsive to immunotherapy combined with tumor resection. As our cases identified, RCC should be considered as a cause of seronegative autoimmune encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis 8 years after serial herpes simplex virus type 1 and human herpesvirus type 7 encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is triggered by herpesvirus encephalitis. Human herpesvirus type 7 (HHV-7) is a recently described herpesvirus for which neuroinvasion has been reported rarely. We report a case of anti-NMDAR encephalitis detected 8 years after recurrent herpes encephalitis associated with herpes simplex virus type 1 and HHV-7 in an immunocompetent host. Our case suggests that anti-NMDAR encephalitis may be triggered by HHV-7 meningoencephalitis in immunocompetent adults, and patients with a history of herpesvirus encephalitis should be vigilantly monitored.

Clinical Approach to Autoimmune Epilepsy.

Autoimmune epilepsy is a newly emerging area of epilepsy. The concept of "autoimmune" as an etiology has recently been revisited thanks to advances in autoimmune encephalitis and precision medicine with immunotherapies. Autoimmune epilepsy presents with specific clinical manifestations, and various diagnostic approaches including cerebrospinal fluid analysis, neuroimaging, and autoantibody tests are essential for its differential diagnosis. The diagnosis is often indeterminate despite performing a thorough evaluation, and therefore empirical immunotherapy may be applied according to the judgment of the clinician. Autoimmune epilepsy often manifests as new-onset refractory status epilepticus (NORSE). A patient classified as NORSE should receive empirical immunotherapy as soon as possible. On the other hand, a morecautious, stepwise approach is recommended for autoimmune epilepsy that presents with episodic events. The type of autoimmune epilepsy is also an important factor to consider when choosing from among various immunotherapy options. Clinicians should additionally take the characteristics of antiepileptic drugs into account when using them as an adjuvant therapy. This expert opinion discusses the diagnostic and treatment approaches for autoimmune epilepsy from a practical point of view.