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.

First familial cases of P102L Gerstmann-Sträussler-Scheinker syndrome in South Korea: diffusion-weighted imaging might reflect intrafamilial phenotypic variability.

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.

Effects of perampanel on cognition and quantitative electroencephalography in patients with epilepsy.

Antiepileptic drugs are well known for their effects on cognition and electrophysiologic changes. However, perampanel is yet to be evaluated for its effects on cognitive function and electroencephalography (EEG). The purpose of the present study was to identify the effect of perampanel on neuropsychological (NP) tests and quantitative EEG (QEEG) and their relationship with the level of the drug in blood. Seventeen patients with epilepsy were enrolled in the study. Electroencephalographic recordings were obtained, and NP tests were conducted before perampanel intake and 6 months after treatment. The relative frequency band power, peak alpha frequency, and NP test scores were compared before and after drug administration. The serum concentration of perampanel was correlated with the QEEG changes. Delayed recall of the Rey Complex Figure showed significant improvement (20.03 vs. 22.94; P = 0.004) following perampanel administration. Other cognitive function tests showed no significant differences before and after drug administration. Theta frequency band power increased in all brain regions (P = 0.001-0.01), and alpha frequency power decreased in all brain regions (P = 0.006-0.03). The theta/alpha ratio, which represents background EEG slowing, increased in all brain areas (P = 0.003-0.02). The peak frequency of the alpha rhythm decreased after perampanel intake (t = 2.45, P = 0.03). Difference of relative alpha power in the central region positively correlated with the blood level of perampanel (r = 0.53, P = 0.03). Perampanel induced electrophysiological slowing, but cognitive decline was not observed. Because the controls were not compared in the study, the results of cognitive function tests should be interpreted conservatively. Background EEG slowing correlated with the serum concentration of perampanel. Our results show the effect of perampanel on cognitive function and background EEG in adult patients with epilepsy.

Increased adverse events associated with antiepileptic drugs in anti-leucine-rich glioma-inactivated protein 1 encephalitis.

Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is a rare autoimmune condition presenting mainly as altered mental state, cognitive dysfunction, and seizure. Antiepileptic drugs (AEDs) are usually initiated to control seizures despite their limited efficacy; however, accumulating clinical experience suggests a high incidence of adverse reactions to AEDs in anti-LGI1 encephalitis. We reviewed the medical records of patients who were diagnosed with anti-LGI1 encephalitis to analyze the adverse effects of AEDs in these patients. Among the 20 patients who were treated with AEDs, 10 (50%) changed their AEDs due to adverse cutaneous drug reaction. Eight of them presented with maculopapular eruption, one with drug rash with eosinophilia and systemic symptoms syndrome, and one with eczema. Causative agents mostly consisted of aromatic AEDs. Oxcarbazepine was discontinued in two additional patients due to hyponatremia. Six patients (30%) discontinued their dose of levetiracetam because of psychiatric manifestations including irritability/aggressive behavior (four patients), insomnia (one patient), and depressive mood (one patient). Clinicians should consider adverse cutaneous drug reaction, psychiatric adverse events, and hyponatremia when selecting AEDs for the treatment of anti-LGI1 encephalitis.

Eosinophilic meningoencephalitis successfully treated with glucocorticoids and intravenous immunoglobulin: a case report.

Eosinophilic meningoencephalitis is a rare inflammatory condition of the central nervous system. As a limited number of cases has been reported, debate remains on the optimal treatment. We present a case of idiopathic eosinophilic meningoencephalitis successfully treated with glucocorticoids and intravenous immunoglobulin (IVIG). After extensive evaluation to rule out other possible causes, the patient was treated with intravenous (IV) dexamethasone and showed significant improvement within a few days. However, neurologic impairment persisted, and follow-up lumbar puncture results showed only a mild decrease in pleocytosis. Even after an additional 5 days of IV methylprednisolone, cerebrospinal fluid (CSF) pleocytosis persisted, and brain magnetic resonance imaging (MRI) showed an increase in enhanced lesions, implying persistent neuroinflammation. The patient was maintained on high-dose oral prednisolone for 2 months, and additional immune-modulatory effects were treated with IVIG. Follow-up MRI at 2 months showed a significant decrease in the extent of multiple enhanced lesions and a normalized CSF profile. The patient was maintained on regular maintenance doses of IVIG for an additional 6 months without any neurologic signs or symptoms. Inflammation is the key pathophysiology underlying neurological damage in eosinophilic meningoencephalitis. A literature review revealed that corticosteroid treatment is the only anti-inflammatory treatment used in cases of idiopathic meningoencephalitis, resulting in sufficient response in most patients but only partial response or death in a few cases. This is the first case report of IVIG use in idiopathic eosinophilic meningoencephalitis, suggesting the possibility of a new treatment modality for refractory cases.

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.

Autoimmune limbic encephalitis combined with leptomeningeal metastases of non-small cell lung cancer: treatment response to osimertinib, immunoglobulin, rituximab, and tocilizumab.

When a patient with encephalopathy has an organic brain lesion, his symptom is easily and often mistakenly attributed to that brain lesion. However, a combination of different conditions is also possible. We present a case of autoimmune limbic encephalitis combined with leptomeningeal carcinomatosis. A 57-year-old female patient was transferred to our institute with a 1-month history of seizure and aggressive behavior. Subacute onset of psychosis with multifocal T2 high signal lesions suggested autoimmune encephalitis, and high-dose steroid pulse and immunoglobulin therapy were started. However, a cerebrospinal fluid study revealed metastatic adenocarcinoma of non-small cell lung cancer, of which she was in complete remission state. Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, was started targeting leptomeningeal metastases while maintaining immunotherapy of rituximab and tocilizumab. Her neurological symptoms showed improvement in response to immunotherapy which lasted approximately 1 month and then deteriorated again. We concluded that her symptoms were more attributable to autoimmune encephalitis than leptomeningeal carcinomatosis, and discontinued osimertinib.

Myelin oligodendrocyte glycoprotein antibody-associated encephalitis after severe acute respiratory syndrome coronavirus 2 infection: a case report and retrospective case reviews.

Several cases of myelin oligodendrocyte glycoprotein (MOG) antibody-associated encephalitis have been reported after coronavirus disease 2019 (COVID-19). In this case, the patient presented with focal status epilepticus with impaired awareness, auditory hallucinations, and incoherent speech after COVID-19. Brain magnetic resonance imaging revealed no specific findings. Cerebrospinal fluid results showed pleocytosis and MOG antibody testing confirmed anti-MOG antibody with live cell-based fluorescence-activated cell sorting assay. The patient was diagnosed with MOG antibody-associated autoimmune encephalitis and treated with intravenous immunoglobulin, rituximab, and tocilizumab. This case occurred presumably due to auto-antibody production following COVID-19.

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.

Postvaccinal GABA-B receptor antibody encephalitis after ChAdOx1 nCoV-19 vaccination.

Several cases of autoimmune encephalitis have been reported after ChAdOx1 nCoV-19 (AZD1222) vaccination. We encountered a male patient who presented with generalized tonic-clonic seizures, cognitive decline, and gait disturbance that occurred suddenly after the second dose of the ChAdOx1 nCoV-19 vaccine. Clinical presentation and magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) test results were compatible with limbic encephalitis. Synaptic autoantibody tests confirmed serum and CSF GABA B receptor antibodies were present. The patient was treated with immunotherapy with intravenous immunoglobulin and rituximab. This GABA-B receptor antibody encephalitis case occurred presumably due to transient autoantibody production following vaccine administration.

Clinical significance of Epstein-Barr virus polymerase chain reaction in cerebrospinal fluid.

Purpose: Epstein-Barr virus (EBV) is implicated in various neurological conditions. However, the relationship between EBV DNA in cerebrospinal fluid (CSF) and central nervous system (CNS) infection is unclear. We evaluated the clinical manifestation of patients with EBV DNA detected in CSF. Methods: We reviewed the medical records of patients admitted to Seoul National University Hospital from January 2000 to March 2021 who underwent EBV polymerase chain reaction (PCR) tests in CSF. The subjects were divided into positive and negative groups depending on the presence of EBV DNA, and further clinical information was obtained from positive patients. Results: CSF EBV PCR tests were performed in 807 patients, and 57 (7.1%) tested positive. Pleocytosis was common (81.1%) in CSF samples with EBV DNA detected, and the proportion was significantly higher than that in samples that were EBV PCR negative (44.5%, p < 0.0001). Among 57 patients with EBV DNA detected in CSF, 51 (89.5%) were diagnosed with CNS infection or inflammatory disorders. Of the 51 patients, 31 (60.8%) had possible etiologies other than EBV. Follow-up evaluation was conducted in 19 of 20 patients, and 63.2% showed a favorable outcome. Conclusion: Positive EBV PCR in CSF is mostly nonspecific and should be interpreted with caution. A comprehensive workup is needed to identify other etiologies before considering EBV as the sole culprit.

Direct brain involvement of Takayasu arteritis treated with rituximab and infliximab: a case report.

Takayasu arteritis (TAK) is a systemic vasculitis involving large arteries. Reports of direct central nervous system (CNS) involvement in TAK are extremely rare in the literature. In addition, treatment for direct involvement has not been reported. Herein, we describe a case of encephalitis in a TAK patient who presented with fever and headache at the first attack, then cognitive impairment at the second attack. The patient improved with rituximab and especially infliximab. These findings indicate the usefulness of rituximab and infliximab to treat the direct CNS manifestations in TAK.

Epstein-Barr virus-associated acute disseminated encephalomyelitis successfully treated with rituximab: a case report.

Acute disseminated encephalomyelitis (ADEM) is a monophasic central nervous system inflammatory demyelinating disorder clinically defined by multifocal neurologic symptoms with encephalopathy. Brain magnetic resonance imaging most often reveals multiple T2 hyperintense lesions consistent with demyelination. High-dose corticosteroids are the current treatment of choice, and intravenous immunoglobulin or plasmapheresis is considered in steroid-unresponsive cases. The majority of patients show favorable outcomes with full clinical recovery and complete or partial resolution of previous lesions. For patients who are refractory to multiple immunomodulatory agents, other treatments such as rituximab have been used. We present a patient who developed ADEM after Epstein-Barr virus infection who achieved full recovery with immunotherapy including rituximab.

Low-dose interleukin-2 as a novel therapeutic option for refractory paraneoplastic neurologic syndrome: a case of chronic relapsing anti-Ma2/Ta paraneoplastic myeloradiculopathy.

Paraneoplastic neurologic syndromes (PNS) caused by anti-Ma2/Ta antibodies have diverse presentations. Myeloradiculopathy is one anti-Ma2/Ta-associated PNS manifestation. We report the case of a patient with chronic relapsing anti-Ma2/Ta paraneoplastic myeloradiculopathy. The patient was successfully treated with low-dose human recombinant interleukin-2, despite having chronic relapsing symptoms and a refractory response to conventional immunotherapy.

Progressive multifocal leukoencephalopathy successfully treated with mefloquine and literature review.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection due to reactivation of John Cunningham virus (JCV). The diagnosis depends on evidence from clinical, imaging, and virologic studies. When the cerebrospinal fluid shows a negative polymerase chain reaction result, brain biopsy is required to confirm the diagnosis. PML has no standard treatment except for immune reconstitution. The anti-JCV effect of mefloquine, however, is supported by some studies, and if brain biopsy is difficult, a mefloquine trial can be considered. We describe a case of possible PML successfully treated with mefloquine.

Respiratory virus-related meningoencephalitis in adults.

Purpose: Respiratory viruses (RVs) are pathogens that can cause central nervous system (CNS) infection, but previous research has been limited to a pediatric population. In recent years, several cases of adult RV meningoencephalitis have begun to be reported. We decided to research the CNS infection of RV in the entire neuroinfection registry. Methods: We retrospectively reviewed the neurologic infection registry of Seoul National University (Seoul, Korea). Among a total of 661 patients in the registry, 10 adult patients were diagnosed with RV-related meningoencephalitis on RV multiplex polymerase chain reaction (PCR) screening test. We analyzed the clinical presentation, laboratory findings, and clinical course of the 10 patients. Results: Three patients were definite RV meningoencephalitis who had positive PCR results from cerebrospinal fluid. The other seven patients were diagnosed with probable RV meningoencephalitis if they had positive PCR results in the sputum and negative results in other extensive workup. Conclusion: RV-related meningoencephalitis should be considered a possible etiology in adult meningoencephalitis patients. To diagnose these viruses, screening test of RV PCR is recommended even in patients without upper respiratory infection symptoms.

Increasing prevalence of antimicrobial resistance in urinary tract infections of neurological patients, Seoul, South Korea, 2007-2016.

OBJECTIVES: Urinary tract infection (UTI) is a common medical complication experienced by patients with neurologic diseases. In this study, we established the microbial etiologies of UTI, and resistances to antibiotics in UTI as well as determining which appropriate empirical antibiotics should be used to treat UTI in neurological patients. DESIGNS AND METHODS: We retrospectively reviewed microbial etiologies and antimicrobial resistance among patients experiencing UTI events in the neurology ward of Seoul National University Hospital from 2007 to 2016. RESULTS: The total number of UTI events observed was 301, and Klebsiella pneumoniae was the most common pathogen observed in UTIs. But in catheter-associated UTI (CAUTI), Enterococcus species were the most prevalent pathogens. Susceptibility to commonly-prescribed antibiotics decreased over 10 years, indicating increased antibiotic resistance in pathogens associated with UTI. ESBL-producing K. pneumoniae increased significantly, while increases of MDR K. pneumoniae, ESBL-producing E. coli, and VRE were not observed. CONCLUSIONS: The worldwide trend of increasing drug-resistant pathogens should be considered, and further studies on antibiotics resistance in UTI are needed. These data will greatly assist physicians when they select antibiotics to treat UTIs in neurological patients.

Pneumonia in hospitalized neurologic patients: trends in pathogen distribution and antibiotic susceptibility.

Background: Bed-ridden state, dysphagia, altered mental state, or respiratory muscle weakness are common in neurologic patients and increase the risk of pneumonia. The major causes of pneumonia in neurologic patients may differ from those in the general population, resulting in a different pathogen distribution. We investigated the trends of pathogen distribution in culture-positive pneumonia in hospitalized neurologic patients and the related antibiotic resistance in those with hospital-acquired pneumonia (HAP). Methods: A retrospective study was performed at Seoul National University Hospital, South Korea. Patients admitted to the Department of Neurology with a positive respiratory specimen culture between 2007 and 2016 were included. Pneumonia events in patients were screened by chronologically associating the date of respiratory specimen acquisition for culture studies and the date of antibiotics administration. Subgroup analyses regarding multidrug resistance in HAP were performed in different pneumonia categories, by presence of ≥1 risk factor and by time period (first half vs. second half of study period). Microbial resistance profiles of isolates from patients with pneumonia were analyzed. Results: We identified 351 pneumonia cases in 227 patients involving 36 different pathogens. 232 cases were HAP, of which 70 cases were intensive care unit (ICU)-HAP. The leading pathogens were Stapylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Enterobacter aerogenes, which were isolated in 133 (37.9%), 72 (20.5%), 55 (15.7%), 44 (12.5%), 33 (9.4%), and 27 (7.7%) cases, respectively. Cases with HAP showed a higher proportion of P. aeruginosa and a lower proportion of S. pneumoniae (both, p < 0.05) than those with non-HAP. ICU-HAP isolates showed a higher multidrug resistance (MDR) rate than non-ICU-HAP isolates (p < 0.005) in those with ≥1 MDR risk factor. Non-susceptibility to imipenem (p < 0.0005), piperacillin-tazobactam (p < 0.001), cefepime (p < 0.005), and trimethoprim-sulfamethoxazole (p < 0.05) in Gram-negative pathogens increased over time in both ICU and non-ICU settings. Conclusions: S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, S. pneumoniae, and E. aerogenes were the leading isolates in culture-positive pneumonia in hospitalized neurologic patients. Antimicrobial resistance of Gram-negative pathogens in neurologic patients with culture-positive HAP has recently increased.