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.

Cerebral perfusion simulation using realistically generated synthetic trees for healthy and stroke patients.

BACKGROUND AND OBJECTIVE: Cerebral vascular diseases are among the most burdensome diseases faced by society. However, investigating the pathophysiology of diseases as well as developing future treatments still relies heavily on expensive in-vivo and in-vitro studies. The generation of realistic, patient-specific models of the cerebrovascular system capable of simulating hemodynamics and perfusion promises the ability to simulate diseased states, therefore accelerating development cycles using in silico studies and opening opportunities for the individual assessment of diseased states, treatment planning, and the prediction of outcomes. By providing a patient-specific, anatomically detailed and validated model of the human cerebral vascular system, we aim to provide the basis for future in silico investigations of the cerebral physiology and pathology. METHODS: In this retrospective study, a processing pipeline for patient-specific quantification of cerebral perfusion was developed and applied to healthy individuals and a stroke patient. Major arteries are segmented from 3T MR angiography data. A synthetic tree generation algorithm titled tissue-growth based optimization (GBO)1 is used to extend vascular trees beyond the imaging resolution. To investigate the anatomical accuracy of the generated trees, morphological parameters are compared against those of 7 T MRI, 9.4 T MRI, and dissection data. Using the generated vessel model, hemodynamics and perfusion are simulated by solving one-dimensional blood flow equations combined with Darcy flow equations. RESULTS: Morphological data of three healthy individuals (mean age 47 years ± 15.9 [SD], 2 female) was analyzed. Bifurcation and physiological characteristics of the synthetically generated vessels are comparable to those of dissection data. The inability of MRI based segmentation to resolve small branches and the small volume investigated cause a mismatch in the comparison to MRI data. Cerebral perfusion was estimated for healthy individuals and a stroke patient. The simulated perfusion is compared against Arterial-Spin-Labeling MRI perfusion data. Good qualitative agreement is found between simulated and measured cerebral blood flow (CBF)2. Ischemic regions are predicted well, however ischemia severity is overestimated. CONCLUSIONS: GBO successfully generates detailed cerebral vascular models with realistic morphological parameters. Simulations based on the resulting networks predict perfusion territories and ischemic regions successfully.

Safety and efficacy of dietary supplement (gintonin-enriched fraction from ginseng) in subjective memory impairment: A randomized placebo-controlled trial.

BACKGROUND: Gintonin inhibits ß-amyloid production, increases acetylcholine level in the brain, and promotes neurogenesis. We evaluated the efficacy of gintonin-enriched fraction (GEF) in improving the cognitive performance in subjective memory impairment. METHODS: In this 8-week, randomized, assessor and participant blinded, placebo-controlled study, participants with subjective memory impairment but preserved cognitive function (Korean Mini-Mental State Examination [K-MMSE] score ≥23) were assigned to GEF 300mg/day or placebo. K-MMSE, Korean versions of the Alzheimer's disease assessment scale, color-word stroop test (K-CWST), clinical dementia rating, and Beck depression inventory-II were evaluated along with the safety profiles. The primary outcome was set as the change in the K-MMSE. RESULTS: Seventy-six participants complete the study protocol. After 8 weeks, there was no inter-group difference in the primary or secondary outcome score changes. However, GEF group showed an improvement in the K-MMSE scores (P= 0.026), and in the number of correct answers in both word reading (P= 0.008) and color reading (P= 0.005) of K-CWST, although only the improvement in the K-CWST scores were higher than the minimum clinically important difference. The frequency of adverse events was comparable between the groups and all were of mild severity. CONCLUSION: GEF is safe but might not be effective in treating subjective memory impairment within the current study setting. However, GEF showed a trend of improving the global cognition and the frontal executive function. Further large-sized studies with longer follow-up period are warranted. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at Clinical Research Information Service of Korea Centers for Disease Control and Prevention: KCT0004636.

Alterations of Functional Connectivity in Patients With Restless Legs Syndrome.

Restless legs syndrome (RLS) is a common neurological illness marked by a strong desire to move one's legs, usually in association with uncomfortable sensations. Recent studies have investigated brain networks and connectivity in RLS. The advent of network analysis has greatly improved our understanding of the brain and various neurological disorders. A few studies have investigated alterations in functional connectivity in patients with RLS. This article reviews functional connectivity studies of patients with RLS, which have identified significant alterations relative to healthy controls in several brain networks including thalamic, salience, default-mode, and small-world networks. In addition, network changes related to RLS treatment have been found, including to repetitive transcranial magnetic stimulation, transcutaneous spinal cord direct-current stimulation, and dopaminergic drugs. These findings suggest that the underlying pathogenesis of RLS includes alterations in the functional connectivity in the brain and that RLS is a network disorder.

Cognitive improvement effect of gintonin might be associated with blood-brain barrier permeability enhancement: dynamic contrast-enhanced MRI pilot study.

Along with the multiple neuroprotective effect, recent studies suggest that gintonin might increase the blood brain barrier permeability. We evaluated the effect of gintonin on the vascular permeability changes in different brain segments, using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). In this 8-week, randomized, open label pilot study, ten participants with subjective memory impairment but preserved cognitive function assigned to gintonin-enriched fraction (GEF) 300 mg/day or placebo groups. Korean versions of the Alzheimer's disease assessment scale (ADAS-K) and DCE-MRI parameters including Ktrans and Vp in different brain segments were evaluated at baseline and at 8 weeks after treatment. Nine participants completed the study protocol. No adverse events occurred during the observation period for 8 weeks in both groups. Following gintonin administration, increment trends of the brain permeability that did not reach a statistical significance were observed in the left hippocampus (Ktrans and Vp, both, p = 0.062), left thalamus and in left putamen (Ktrans, p = 0.062), and left insula and right amygdala (Vp, p = 0.062), but not in the control placebo group. The increment of the Ktrans value in the left thalamus from the baseline was highly correlated with the change of the ADAS scores (r = -0.900, p = 0.037). Gintonin might enhance the blood-brain barrier (BBB) permeability in the brain structures involved in cognitive functions. Further efficacy exploration for the synergistic effect of gintonin's BBB permeability enhancement to its other cognitive enhancing mechanisms are warranted. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0003418.

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.

HLA-B27 association of autoimmune encephalitis induced by PD-L1 inhibitor.

OBJECTIVE: While immune checkpoint inhibitors are increasingly used for various cancers, unpredictable immune-related adverse events (irAEs) such as autoimmune encephalitis is life-threatening. Here, we report an association between human leukocyte antigen (HLA) and atezolizumab-induced encephalitis. METHODS: From an institutional prospective cohort for encephalitis, we identified patients with autoimmune encephalitis after the use of atezolizumab, a PD-L1 (programmed death-ligand 1) inhibitor, from August 2016 to September 2019 and analyzed their HLA genotypes. RESULTS: A total of 290 patients received atezolizumab, and seven patients developed autoimmune encephalitis, and five of whom were enrolled for the analysis. The patients presented altered mentality, seizures, or myelitis. Three patients had the HLA-B*27:05 genotype in common (60%), which is significantly frequent given its low frequency in the general population (2.5%). After Bonferroni correction, HLA-B*27:05 was significantly associated with autoimmune encephalitis by atezolizumab (corrected P < 0.001, odds ratio 59, 95% CI = 9.0 ~ 386.9). INTERPRETATION: Here we found that three in five patients with autoimmune encephalitis associated with atezolizumab had the rare HLA-B*27:05 genotype. Further systematic analyses in larger cohorts are necessary to investigate the value of HLA screening to prevent the life-threatening adverse events.

Human leukocyte antigen associations in postural tachycardia syndrome.

Associations between human leukocyte antigen (HLA) and postural orthostatic tachycardia syndrome (POTS) have not been investigated. We included patients diagnosed with POTS and showing orthostatic heart rate increases ≥ 50 during orthostatic vital sign measurement or experiencing syncope/near-syncope while standing (prominent POTS; n = 17). DQB1*06:09 was present in seven (41%) patients, a significantly higher percentage than in healthy Koreans (7%; odds ratio [OR] 8.7, 95% confidence interval [CI] 3.1-24.3, corrected P = 3.2 × 10-4) and epilepsy controls (8%; OR 7.9, 95% CI 2.7-23.5, corrected P = 3.2 × 10-4). Six (35.3%) carried the A*33:03-B*58:01-C*03:02-DRB1*13:02-DQB1*06:09 haplotype. The results signify an autoimmune etiology in prominent POTS.

Recurrent optic neuritis and neuromyelitis optica-IgG following first and second human papillomavirus vaccinations.

Human papillomavirus (HPV) vaccine is widely used to prevent cervical cancer caused by certain types of HPV in girls and young women. Demyelinating disorders within months following HPV innoculation have been reported, but the causal link between HPV vaccination and the onset of demyelinating disorders have not been certain. We report a case of neuromyelitis optica spectrum disorder (NMOSD) that was noteworthy because optic neuritis (ON) occurred in a very close temporal association with both the first and second HPV vaccinations, which might suggest an association between HPV vaccination and the development of NMO-IgG and recurrent ON. This emphasizes the necessity for continuing surveillance for adverse events after HPV vaccination.