Citations

Abstract Faciobrachial dystonic seizures (FBDS), paroxysmal dizziness spells, and thermal sensory attacks are highly frequent and stereotypic phenomena experienced in leucine‐rich glioma inactivated 1 (LGI1)‐antibody encephalitis. This study aims to describe the electrophysiologic mechanism underlying these pathognomonic symptoms. LGI1‐antibody encephalitis patients with active symptoms were enrolled from two separate centers in South Korea and the United States. Patients were evaluated with simultaneous magnetoencephalography (306 channels) and electroencephalography. Regional alterations in neuronal excitability represented by interictal epileptiform discharges were present in the faciobrachial area of the motor cortex, insula, and somatosensory cortex, somatotopically aligned with each of the ictal semiologies observed in patients. FBDS and other LGI1‐antibody encephalitis‐specific spells localized to cortical regions neuroanatomically corresponding to ictal semiologies: the faciobrachial homunculus (FBDS), insular cortex (paroxysmal dizziness spells), and somatosensory cortex (thermal sensory attacks). Our findings support the ictal hypothesis underlying these unique phenomena.

Functional neurological disorder (FND) is a prevalent neurologic condition, yet existing treatment approaches yield inconsistent outcomes. We propose a unifying framework that conceptualizes FND as a disorder triggered and perpetuated by individuals lacking targeted tools to reconcile the cumulative impact of intolerance of uncertainty (IU) and multidimensional allostatic overload. Expanding upon predictive coding and IU theories from neuroscience and psychology research, we argue that during times of uncertainty, individuals with FND exhibit a higher rate of prediction error but lack the energy, resources, and adaptive capacity to respond. This sustained hyperactivation of the brain and body trigger and perpetuate FND. We propose that FND treatment requires a strategic and progressively tiered behavioral approach. First, the individual with FND must be taught behavioral skills to gain immediate symptom control and shift automatic, hyperactive processes into conscious awareness. Only then, can practices from Acceptance and Commitment Therapy, Dialectical Behavioral Therapy, and Mindfulness Therapy be leveraged. These practices help explicitly identify sources of uncertainty and teach how to effectively respond to hyperactive processes with skills that optimize function, commitment to values, and well-being. This framework offers testable hypotheses and a pathway to more effective, individualized care for FND.

ABSTRACT In LGI1-linked animal models of inherited autosomal dominant lateral temporal lobe epilepsy, increased neuronal excitability is accompanied by modifications in the AMPA/NMDA receptor ratio and a large decrease in Kv 1 type potassium channels. However, the mechanism which links the absence of LGI1 to reduced expression of key neuronal ion channels is unknown. We observed multiple conserved canonical ganglioside-binding domains (GBDs) within human LGI1, mainly located in the EPTP domain. We show that GT1b is co-captured from native rat brain extracts by human LGI1 antibodies and, using SPR analysis, that recombinant full length LGI1 interacted with liposomes containing GT1b and GM1, but not GM3, lyso-lactosylceramide, phosphatidylserine or phosphatidylcholine. The ganglioside binding capacity of GBD peptide sequences exposed at the surface of LGI1 were confirmed using SPR and Langmuir film balance. Our data suggest that LGI1 interacts with gangliosides and may be involved in organizing lipid membrane platforms accommodating functional protein complexes. The loss of LGI1 could destabilize these platforms and contribute to reduced expression of key ion channels in Lgi1 -/- mice.

Abstract Objectives We aimed to evaluate the effects of GLP-1 receptor agonists (GLP-1RA) on symptom burden and opioid use in patients with fibromyalgia using real-world data. Methods We conducted a retrospective cohort study using the TriNetX Research Network. Patients with fibromyalgia (≥2 diagnostic encounters) were divided into two groups: those with and without ≥2 prescriptions for GLP-1RA. Propensity score matching at a 1:1 ratio for age, sex and key comorbidities, including diabetes mellitus, obesity, osteoarthritis, inflammatory arthritis, ischemic heart disease, sleep disorders, migraine and medication use, was performed. Outcomes were assessed over a five-year follow-up period. This included opioid use, diagnostic codes for pain, fatigue and disability, body mass index and haemoglobin A1C. Statistical analysis included odds ratios, risk differences and t tests. Results After propensity score matching, there were 48 025 patients in each cohort. Baseline characteristics were well matched, though BMI and Haemoglobin A1c were higher in the GLP-1RA cohort than in non-GLP-1RA users. GLP-1RA use was associated with significantly reduced odds of opioid prescription (OR 0.65), pain diagnostic codes (OR 0.79) and fatigue diagnostic codes (OR 0.68) (all P < 0.001). There was no significant difference in disability-related diagnostic codes. BMI and HbA1C remained higher in patients on GLP-1RA. Conclusion GLP-1RA use was associated with reduced opioid prescription and a reduction in the use of ICD-10 codes related to fibromyalgia, potentially reflecting lower symptom burden. Further studies using validated outcome measures are needed to confirm these findings.

The 2 main subgroups of autoimmune myasthenia gravis, a neuromuscular junction disorder associated with muscle weakness, are early- and late-onset forms, defined by onset before or after 50 years of age. Both carry acetylcholine-receptor autoantibodies but differ in sex ratios, genetics, and occurrence of disease-specific thymus inflammation. To distinguish the 2 forms by cellular immune phenotyping, we applied multimodal techniques, including deep spectral cytometric phenotyping and single-cell sequencing. Analysis of 2 independent cohorts identified immunological differences driven by 3 main lymphocyte populations. Lower frequencies of mucosa-associated invariant T cells and naive CD8 + T cells were observed in late-onset myasthenia, suggesting enhanced immune senescence. A highly differentiated, canonical NK cell population was reduced in early-onset myasthenia and negatively correlated with the degree of thymic hyperplasia. Using only the frequency of these 3 populations, correct myasthenia subgroup assignment could be predicted with 90% accuracy. These distinct immunocellular endophenotypes for early- and late-onset disease suggest differences in immunopathogenic processes. Along with demographic factors and other disease subgroup–specific features, the frequency of the identified cell subpopulations may improve clinical classification.

Persistent pain remains a major challenge in inflammatory arthritis, even when joint inflammation is well controlled. Pain and associated symptoms such as fatigue cannot be explained by peripheral inflammation alone but reflect altered central pain processing. These changes may arise through “top‐down” mechanisms, reflecting pre‐existing dysfunction in pain perception, or “bottom‐up” pathways, driven by peripheral inflammation acting on the brain. Neuroimaging has transformed understanding of these processes by providing in vivo markers of how brain function and structure are related to pain. Functional magnetic resonance imaging (MRI) demonstrates that both task‐evoked and resting‐state activity are altered in inflammatory arthritis. Connectivity changes involving the thalamus, insula, medial prefrontal cortex, and default mode and salience networks correlate with pain, fatigue, and affective symptoms. Notably, tumor necrosis factor α (TNF‐α) inhibitors rapidly normalize pain‐related activation, preceding improvements in joint swelling, strongly supporting a bottom‐up role for peripheral inflammation. Recent randomized controlled trial data show that baseline central nervous system pain activation predicts analgesic response to TNF‐α blockade, positioning neuroimaging as a potential tool for treatment stratification. Complementary modalities provide further insights. Proton electron tomography studies suggest altered pain responses, and novel tracers may clarify contributions of neuroinflammation. Magnetic resonance spectroscopy reveals neurochemical correlates such as increased choline and myo‐inositol linked to fatigue, although group‐level evidence for overt neuroinflammation remains limited. Structural MRI highlights gray matter changes in regions mediating sensory, cognitive, and affective processing. Together, this supports a dual top‐down and bottom‐up model of persistent pain in inflammatory arthritis, with important implications for mechanism‐based therapies targeting both immune and brain pathways. image

Objective To examine real‐world patterns in pain management among adults with systemic lupus erythematosus (SLE), we focused on the sequencing of pain modalities, polypharmacy, and demographic variation. Methods We conducted a retrospective analysis of electronic health records from adults with SLE treated at a single academic medical center between 2005 and 2024. We included patients who received at least one pain‐related therapy, including glucocorticoids, opioids, nonsteroidal anti‐inflammatory drugs (NSAIDs), antidepressants, anticonvulsants, muscle relaxants, and nonpharmacologic interventions. We used sequence analysis and Sankey diagrams to map treatment trajectories and compared patterns across two periods: 2005 to 2014 and 2015 to 2024. Polypharmacy was defined as receiving five or more pain‐related prescriptions within 12 months. We examined trends by age, sex, and race or ethnicity. Results Among 769 patients, initiation of glucocorticoids and opioids declined over time (58%–51% and 28%–22%, respectively), whereas NSAID use increased (19%–29%). The median number of pain prescriptions decreased, and polypharmacy prevalence dropped from 53% to 45%. In recent years, younger adults and men received more prescriptions, with 69% of men receiving five or more compared with 43% of women. Racial disparities narrowed overall in recent years but persisted in sensitivity analyses excluding glucocorticoids. Conclusion Pain management in SLE is shifting away from high‐risk therapies; however, prescribing intensity remains high and varies by demographic group. Visualizations serve as a complementary lens to traditional prescription counts, allowing representation of polypharmacy not only by volume but also by the diversity and sequencing of therapeutic classes over time.