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.

Optimal models are needed to understand the pathophysiology of human cerebral aneurysms (CA). We investigated the development of experimental CA by decreasing the activity of lysyl oxidases by dietary copper deficiency from the time of gestation and then augmenting vascular stress by angiotensin II infusion in adulthood. Rats were fed copper-free, low-copper, or normal diets at different time periods from gestation to adulthood. The incidences of CAs were evaluated and autopsies performed to determine the coexistence of cardiovascular diseases. A copper-free diet from gestation was associated with high mortality rates (79.1%) resulting from rupture of ascending aorta aneurysms; a low-copper diet led to acceptable mortality rates (13.6%) and produced CAs and subarachnoid hemorrhage in 46.4% and 3.6% of animals, respectively. Higher proportions of CAs (up to 33.3%) in the rats primed for copper deficiency from gestation ruptured following angiotensin II infusion from adulthood. Gene expression array analyses of the CAs indicated that genes involving extracellular matrix and vascular remodeling were altered in this model. This model enables future research to understand the entire pathogenetic basis of CA development and rupture in association with systemic vasculopathies.

Gintonin inhibits β-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. 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. 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. 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. This clinical trial was registered at Clinical Research Information Service of Korea Centers for Disease Control and Prevention: KCT0004636.

Lee WJ, et al. Transl Clin Pharmacol. 2021 Mar;29(1):21-32. https://doi.org/10.12793/tcp.2021.29.e2

New-onset refractory status epilepticus (NORSE) is unexpected onset of refractory status epilepticus in individuals with no preexisting relevant neurologic condition. The etiologies remain largely cryptogenic; treatment is challenging after failure to control seizures despite use of multiple antiepileptic drugs and anesthetic agents. Frequent fever and other infectious prodromes, elevated proinflammatory cytokine/chemokine levels, and limbic or multifocal brain lesions indicate active inflammation in NORSE. Among identified causes, autoimmune encephalitis is the most common and accounts for more than one-third of all known NORSE cases, followed by infection-related etiologies. Although more evidence is needed, anti-cytokine therapies with tocilizumab and anakinra along with other immunotherapeutic agents used in autoimmune encephalitis can aid in alleviating or hindering the inflammatory cascade and controlling seizures.

Background/Objectives: New-onset refractory status epilepticus (NORSE) is a rare neurologic emergency that often requires immunotherapy despite an unclear etiology and poor response to standard treatments. Tocilizumab, an anti-interleukin-6 monoclonal antibody, has shown promise in case reports; however, objective early biomarkers of treatment response remain lacking. We investigated early electroencephalography (EEG) changes following tocilizumab administration in NORSE patients using both quantitative and qualitative analyses. Methods: We retrospectively analyzed six NORSE patients who received tocilizumab and underwent continuous EEG monitoring during the period of its administration, following the failure of first- and second-line immunotherapies. Clinical characteristics, treatment history, and EEG recordings were collected. EEG features were analyzed from 2 h before to 1 day after tocilizumab treatment. Quantitative EEG metrics included relative band power, spectral ratios, permutation and spectral entropy, and connectivity metrics (coherence, weighted phase lag index [wPLI]). Temporal EEG trajectories were clustered to identify distinct response patterns. Results: Changes in spectral power and band ratios were heterogeneous and not statistically significant. Among entropy metrics, spectral entropy in the theta band showed a significant reduction at 1 day post-treatment. Connectivity metrics, particularly wPLI, demonstrated a consistent decline after treatment. Clustering of subject–channel trajectories revealed distinct patterns including monotonic changes, indicating individual variation in response. Visual EEG review corroborated qualitative improvements in all cases. Conclusions: Tocilizumab was associated with measurable early EEG changes in NORSE, supported by visually noticeable EEG changes. Quantitative EEG may serve as a useful early biomarker for treatment response in NORSE and assist in monitoring the critical phase. Further validation in larger cohorts and standardized protocols is warranted to confirm these findings and refine EEG-based biomarkers.