Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

The effect of continuous positive airway pressure (CPAP) on the quality of life in patients with multiple system atrophy.

PURPOSE: To evaluate the effect of continuous positive airway pressure (CPAP) on the quality of life (QoL) in patients with multiple system atrophy (MSA) and their caregivers. METHODS: We reviewed the electronic medical records of patients with MSA treated with CPAP (n = 15). After CPAP treatment, we checked the patient global impression of change (PGI-C) scale for sleep complaints and QoL for six patients who continued to use CPAP. QoL was also assessed for five caregivers of these patients. RESULTS: A total of 15 patients (6 women) were included. The mean age was 63.6 ± 8.1 years old and the mean disease duration was 4.9 years. The mean duration of CPAP treatment was 22.1 ± 10.6 months and the average compliance was 90%. Three patients died during CPAP treatment, and two patients discontinued CPAP after tracheostomy. For six patients who continued to use CPAP, sleep complaints minimally improved. Five patients reported an improved QoL, and all five caregivers reported improved caregivers' QoL. CONCLUSION: This study showed that the use of CPAP has a beneficial effect on sleep complaints and QoL of patients with MSA and their caregivers.

Comparative efficacy of prolonged-release melatonin versus clonazepam for isolated rapid eye movement sleep behavior disorder.

PURPOSE: Clonazepam and melatonin are recommended as first-line treatments for isolated rapid eye movement (REM) sleep behavior disorder (iRBD). This study aimed to compare their efficacy and safety in REM sleep without atonia (RWA) and RBD-related symptoms. METHODS: This prospective, open-label, randomized trial included patients with video-polysomnography-confirmed iRBD. The patients were randomly assigned to receive either clonazepam 0.5 mg or prolonged-release (PR) melatonin 2 mg 30 min before bedtime for 4 weeks. The primary outcome was changes in RWA on follow-up polysomnography (PSG). Secondary endpoints were changes in other PSG parameters, clinical global improvement-impression scale (CGI-I) scores, and sleep questionnaire scores. The safety endpoint was adverse events. RESULTS: Of 40 patients with probable RBD considered, 34 were enrolled in the study and randomized. Visual scoring parameters of RWA indices were reduced, and automatic scoring parameters tended to be improved after clonazepam treatment but not after PR melatonin treatment. The proportion of N2 sleep was increased, and N3 and REM sleep were decreased only in the clonazepam group. The clonazepam group tended to answer "much or very much improvement" on the CGI-I more frequently than the PR melatonin group (p = 0.068). Daytime sleepiness and insomnia symptoms were reduced after PR melatonin but not after clonazepam. Depressive symptoms increased after clonazepam. Four of the patients (13.3%) reported mild to moderate adverse events, which were similar between the two groups. CONCLUSION: Four weeks of clonazepam, but not PR melatonin, improved RWA. RBD symptom improvement tended to be better after clonazepam than PR melatonin in exchange for increased depressive symptoms and daytime sleepiness. CLINICALTRIALS: gov identifier: NCT03255642 (first submitted August 21, 2017).

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.

Explainable Machine-Learning-Based Characterization of Abnormal Cortical Activities for Working Memory of Restless Legs Syndrome Patients.

Restless legs syndrome (RLS) is a sensorimotor disorder accompanied by a strong urge to move the legs and an unpleasant sensation in the legs, and is known to accompany prefrontal dysfunction. Here, we aimed to clarify the neural mechanism of working memory deficits associated with RLS using machine-learning-based analysis of single-trial neural activities. A convolutional neural network classifier was developed to discriminate the cortical activities between RLS patients and normal controls. A layer-wise relevance propagation was applied to the trained classifier in order to determine the critical nodes in the input layer for the output decision, i.e., the time/location of cortical activities discriminating RLS patients and normal controls during working memory tasks. Our method provided high classification accuracy (~94%) from single-trial event-related potentials, which are known to suffer from high inter-trial/inter-subject variation and low signal-to-noise ratio, after strict separation of training/test/validation data according to leave-one-subject-out cross-validation. The determined critical areas overlapped with the cortical substrates of working memory, and the neural activities in these areas were correlated with some significant clinical scores of RLS.

Working memory deficits in patients with idiopathic restless legs syndrome are associated with abnormal theta-band neural synchrony.

Cognitive impairment, particularly prefrontal function, has been reported in patients with restless legs syndrome. However, working memory performance in patients with restless legs syndrome remains uncertain. The present study aimed to examine working memory performance in patients with restless legs syndrome by investigating electroencephalography theta-band oscillations within task-relevant brain regions and the synchronization among oscillations during a working memory task. Twelve female idiopathic patients with restless legs syndrome and 12 female healthy controls participated in this study. Nineteen-channel electroencephalography data were recorded while participants performed a Sternberg working memory task. We analysed event-related theta-band activity and interregional theta-band phase synchrony during the memory retrieval phase. The spatial pattern of theta-band phase synchrony was quantified using graph theory measures, including the clustering coefficient, characteristic path length, and small-world propensity. Considerable increases in theta-band activity and theta-band phase synchrony were observed at 600-700 ms in controls and at 650-750 ms in restless legs syndrome subjects after the probe item was presented. During this period, induced theta-band activity showed lower with borderline significance in the restless legs syndrome subjects than in the controls regardless of channel location (F4,88  = 3.92, p = .06). Theta-band phase synchrony between the frontal and posterior regions was significantly reduced in the restless legs syndrome subjects. Inefficiency in both global and local networks in the restless legs syndrome subjects was revealed by the decreased small-world propensity (t22  = 2.26, p = .03). Small-world propensity was negatively correlated with restless legs syndrome severity (r = -.65, p = .02). Our findings suggest that patients with restless legs syndrome have multiple deficits in cognitive processes, including attentional allocation, evaluation of incoming stimuli, and memory manipulation of encoded information during a working memory task. Abnormal local theta-band neural synchrony and global theta-band neural synchrony may underlie the neurophysiological mechanism of the working memory dysfunction associated with restless legs syndrome.

Sleep structure and electroencephalographic spectral power of middle-aged or older adults: Normative values by age and sex in the Korean population.

The fine structure of sleep electrocortical activity reflects health and disease. The current study provides normative data for sleep structure and electroencephalography (EEG) spectral power measures derived from overnight polysomnography (PSG) and examines the effect of age and sex among Korean middle-aged and older adults with or without obstructive sleep apnea (OSA). We analysed home PSG data from 1,153 adult participants of an ongoing population-based cohort study, the Korean Genome and Epidemiology Study. Sleep stages were visually scored and spectral power was measured on a single-channel EEG (C4-A1). We computed spectral power for five frequency ranges. The EEG power was reported in relative (%) and log-transformed absolute values (µV2 ). With ageing, the proportion of N1 sleep increased, whereas N3 decreased, which is more noticeable in men than in women. The amount of N3 was relatively low in this cohort. With ageing, relative delta power decreased and alpha and sigma power increased for the whole sleep period, which was more pronounced during REM sleep in non-OSA. For men compared with women, relative theta power was lower during REM and sigma and beta were higher during N1 sleep. The differences of relative powers by age and sex in OSA were comparable to those in non-OSA. In a community-based Korean population, we present normative data of sleep structure and spectral power for middle-aged or older adults of a non-Caucasian ethnicity. The values varied with age and sex and were not influenced by sleep apnea.

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.

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.

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.

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study.

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

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.

Peripheral Blood Inflammatory Cytokines in Idiopathic REM Sleep Behavior Disorder.

BACKGROUND: Although previous research provides insight into the role of neuroinflammation in idiopathic REM sleep behavior disorder, the association of this disorder with peripheral blood inflammatory markers remains unclear. OBJECTIVE: To investigate inflammatory cytokines in plasma samples in patients with idiopathic rapid eye movement sleep behavior disorder and to explore whether these markers are associated with prodromal symptoms of α-synucleinopathies. METHODS: We collected plasma from patients with polysomnographically confirmed idiopathic rapid eye movement sleep behavior disorder without parkinsonism or dementia (n = 54) and from healthy controls (n = 56). The following cytokines were measured: interleukin-1ß, interleukin-2, interleukin-6, interleukin-10, and tumor necrosis factor-α. The idiopathic REM sleep behavior disorder patients underwent sleep, motor, cognitive, olfactory, and autonomic testing. RESULTS: The anti-inflammatory cytokine, interleukin-10, levels in the idiopathic rapid eye movement sleep behavior disorder group were significantly upregulated compared to the control group (P = 0.022), but this difference did not withstand Bonferroni correction. The other proinflammatory cytokine levels did not differ between the groups. No correlation was found between the cytokine levels and any clinical variable. CONCLUSIONS: Our data do not provide evidence supporting the role of peripheral inflammation in idiopathic rapid eye movement sleep behavior disorder. However, considering the limited statistical power because of the small sample size, further large-scale longitudinal studies with a broader spectrum of cytokines are needed to clarify this issue. © 2019 International Parkinson and Movement Disorder Society.

Anti-LGI1 encephalitis is associated with unique HLA subtypes.

OBJECTIVE: Autoimmune encephalitis (AE), represented by anti-leucine-rich glioma-inactivated 1 (anti-LGI1) and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, has increasing clinical significance based on recent discoveries of neuronal autoantibodies. However, its immunopathogenesis is not fully understood. Here, we investigated whether AE is associated with the human leukocyte antigen (HLA) subtypes. METHODS: We compared the HLA genotypes of 11 anti-LGI1 and 17 anti-NMDAR encephalitis patients to the control groups, which consisted of 210 epilepsy patients and 485 healthy Koreans. RESULTS: Anti-LGI1 encephalitis was associated with the DRB1*07:01-DQB1*02:02 haplotype (10 patients; 91%) in HLA class II genes, as well as with B*44:03 (8 patients; 73%) and C*07:06 (7 patients; 64%) in the HLA class I region. The prevalence of these alleles in anti-LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti-NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA-peptide binding prediction algorithms and computational docking underpinned the close relationship. INTERPRETATION: This finding suggests that most anti-LGI1 encephalitis develops in a population with specific HLA subtypes, providing insight into a novel disease mechanism. Ann Neurol 2017;81:183-192.

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.

Clinical manifestations and treatment outcomes of parvovirus B19 encephalitis in immunocompetent adults.

Parvovirus B19 (PVB19) has rarely been identified as a cause of encephalitis in immunocompetent adults, in whom clinical information regarding PVB19 encephalitis has remained unclear. Herein, we report the clinical presentations, laboratory and imaging findings, and treatment outcomes of five immunocompetent adults with PVB19 encephalitis. Although none of the patients showed any distinctive features of PVB19 infection, they showed various clinical manifestations, including one instance of brainstem involvement. Additionally, immunotherapy can be considered an effective approach, especially in immunocompetent adults with PVB19 encephalitis who are resistant to the initial management.

HLA-B*40:02 and DRB1*04:03 are risk factors for oxcarbazepine-induced maculopapular eruption.

OBJECTIVE: Oxcarbazepine (OXC) is a widely used antiepileptic drug for the treatment of partial seizures that was developed through structural variation of carbamazepine. Although OXC has a lower risk of cutaneous adverse drug reactions (cADRs) than carbamazepine, cADRs ranging from maculopapular eruption (MPE) to the more severe Stevens-Johnson syndrome and toxic epidermal necrolysis still limit the use of OXC in some patients. A few human leukocyte antigen (HLA)-related genetic risk factors for carbamazepine-induced cADRs have been identified. However, the HLA-related genetic risk factors associated with OXC-induced cADRs are unknown. METHODS: A total of 40 patients who experienced OXC-induced MPE and 70 patients who were tolerant to OXC treatment were included in the study. Genomic DNA was extracted from the peripheral blood of these patients, and high-resolution HLA genotyping was performed. RESULTS: The HLA-B*40:02 and HLA-DRB1*04:03 alleles were significantly associated with OXC-induced MPE compared with the OXC-tolerant group (odds ratio [OR] 4.33, p = 0.018 and OR 14.64, p = 0.003, respectively) and the general Korean population (OR 4.04, p = 0.001 and OR 3.11, p = 0.019, respectively). The HLA-B*15:01 genetic frequency was significantly lower in the OXC-MPE group compared to the OXC-tolerant group (OR 0.18, p = 0.016) and the Korean population (OR 0.22, p = 0.030). The allele frequencies of well-known HLA-related risk factors for carbamazepine-induced cADRs (HLA-B*15:02, A*31:01 and B*15:11) were not different among the three groups. SIGNIFICANCE: This study is the first to demonstrate an association of HLA-B*40:02 and HLA-DRB1*04:03 with OXC hypersensitivity using a large cohort of patients with OXC-induced MPE. These findings should be confirmed in future studies in different ethnic groups.

Prediction of mortality and functional outcome from status epilepticus and independent external validation of STESS and EMSE scores.

BACKGROUND: Two clinical scoring systems, the status epilepticus severity score (STESS) and the epidemiology-based mortality score in status epilepticus (EMSE), are used to predict mortality in patients with status epilepticus (SE). The aim of this study was to compare the outcome-prediction function of the two scoring systems regarding in-hospital mortality using a multicenter large cohort of adult patients with SE. Moreover, we studied the potential role of these two scoring systems in predicting the functional outcome in patients with SE. METHODS: The SE cohort consisted of patients from the epilepsy centers of eight academic tertiary medical centers in South Korea. The clinical and electroencephalography data for all adult patients with SE from January 2013 to December 2014 were derived from a prospective SE database. The primary outcome variable was defined as in-hospital death. The secondary outcome variable was defined as a poor functional outcome, i.e., a score of 1-3 on the Glasgow Outcome Scale, at discharge. RESULTS: Among the 120 non-hypoxic patients with SE recruited into the study, 16 (13.3%) died in the hospital and 64 (53.3%) were discharged with a poor functional outcome. The receiver-operating characteristic (ROC) curve for prediction of in-hospital death based on the STESS had an area under the curve of 0.673 with an optimal cutoff value for discrimination (best match for both sensitivity (0.56) and specificity (0.70)) that was ≥ 4 points. The two combinations of elements of the EMSE system (EMSE-ALDEg and EMSE-ECLEg) predicted not only in-hospital mortality with the best match for sensitivity (more than 0.6) and specificity (more than 0.6), but also a poor functional outcome with the best match for both sensitivity (>0.7) and specificity (>0.6). STESS did not predict a poor functional outcome (area under the ROC, 0.581; P = 0.23). CONCLUSION: Although the EMSE is a clinical scoring system that focuses on individual mortality, we did not find differences between the EMSE and STESS in the prediction of in-hospital death. The EMSE was useful in predicting poor functional outcome, as it was significantly better than STESS.