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.

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.

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.

ABSTRACT Objectives To investigate the value of cytokine, chemokine, and neurofilament light chain (NfL) concentrations in predicting relapse risk, chronic epilepsy, and functional impairment in LGI1 autoimmune encephalitis (AE). Methods Cytokines/chemokines (IL‐1‐beta, IL‐2, IL‐4, IL‐5, IL‐6, IL‐8/CXCL8, IL‐10, IL‐12p70, IL‐13, IL‐17A, GM‐CSF, TNF‐alpha, IFN‐gamma, CXCL9, CXCL10, CXCL13, BAFF) and NfL concentrations were measured in CSF and paired serum from LGI1‐AE patients evaluated at Mayo Clinic (01/2015–02/2024), using a multiplex immunoassay system (ELLA, Bio‐Techne) and correlated with clinical outcomes. A laboratory‐based cohort of LGI1‐IgG‐positive patients and control cohorts, including patients with mixed non‐inflammatory disorders (MNID), Alzheimer's disease (AD), and temporal lobe epilepsy (TLE) were analyzed. Results Forty‐four patients with LGI1‐AE were included; 29 (66%) were male, with a median age of 68.5 years (range, 8–85). Median time from symptom onset to CSF sampling was eight months (IQR, 3–17); 19/42 (45%) experienced a clinical relapse and 27% developed chronic epilepsy. Serum IL‐6, serum and CSF IL‐8/CXCL8, and IL‐17A were higher in LGI1‐IgG positive patients than MNID ( p < 0.05). TLE cytokine/chemokine profiles were similar to LGI1 AE; AD patients had lower serum IL‐6 and CSF IL‐8/CXCL8 ( p = 0.04; p = 0.01), and higher serum IL‐17A and GM‐CSF ( p = 0.004; p = 0.01) than LGI1‐AE. Higher CSF IL‐6 and IL‐8/CXCL8 in LGI1‐AE associated with clinical relapse ( p < 0.05) and higher CSF NfL associated with chronic epilepsy ( p = 0.01). Conclusion Elevations in IL‐6, IL‐8/CXCL8, and IL‐17A were identified in this LGI1‐AE cohort. CSF IL‐6, IL‐8/CXCL8, and NfL levels are potential prognostic biomarkers for risk of relapse and chronic epilepsy in LGI1‐AE.

Abstract Objective Autoimmune encephalitis is a cause of brain inflammation characterized by auto‐antibodies, which target cell surface neuronal proteins and lead to neuronal dysfunction. The most common form is associated with auto‐antibodies to leucine‐rich glioma‐inactivated 1 (LGI1) protein, the presentation of which includes frequent focal seizures. The exact cause of these auto‐antibodies remains unknown, but established predispositions include overrepresented human leukocyte antigen ( HLA ) alleles. Yet, these HLA alleles are themselves common in the healthy ancestry‐matched population. One potential etiological hypothesis is that an environmental trigger, such as the gut microbiome, interacts with a genetically predisposed individual. Methods To investigate this, we studied 42 patients with LGI1‐antibody encephalitis (LGI1‐Ab‐E) and 27 familial/environmentally matched controls, and performed metagenomic shotgun sequencing, to describe the compositional and functional differences in the gut microbiome. Results We observed that LGI1‐Ab‐E gut microbiomes exhibited a significant reduction in the ratio of Firmicutes (or Bacillota) and Bacteroidetes phyla, which is associated with the dosage of HLA susceptibility allele count in patients with LGI1‐Ab‐E. Furthermore, we identified differences in functional gene profiles in the gut microbiome that led to a reduction of neuroinflammatory protective short‐chain fatty acids (SCFAs) in LGI1‐Ab‐E patients. Significance Taken together, our results suggest that a compositional shift in the gut microbiome of LGI1‐Ab‐E associates with a neuroinflammatory state, possibly through the reduction of SCFA production. Our study highlights the potential of the gut microbiome to explain some of the complex condition and unravel etiological questions. Validation studies with greater sample sizes are recommended.

Abstract Anti-IgLON5 disease is an autoimmune encephalitis that presents with a heterogenous clinical phenotype, including sleep disorders, movement abnormalities and bulbar involvement. It is characterized by autoantibodies against IgLON5, 85% association with HLA-DQB1*05:∼ and a brainstem-dominant tauopathy. Cellular and murine models report pathogenic effects of the autoantibodies, and neurodegenerative factors suggest progressive atrophy as a common sequela. However, evidence from in vivo patient data and long-term follow-up is limited, and the degree of progression remains elusive. In this multicentre study, clinical and brain MRI data were collected from 127 patients across 12 countries to investigate the relationships between clinical presentations and the development of distinct brain atrophy patterns. Our data show that most patients develop a complex multisystem phenotype as the disease progresses; however, neuromuscular manifestations rarely emerge at later disease stages. By comparison to healthy controls, this disease presents with severe substructure-specific atrophy, especially affecting the hypothalamus, brainstem, accumbens and basal ganglia, which, in age-independent analyses, show significant ventricular enlargement and also suggest progression of brainstem atrophy over the disease course. Moreover, the focality of atrophy was functionally linked to specific symptoms, with more severe involvement of the basal ganglia in patients with movement disorders, and greater atrophy in the hippocampus and thalamus in patients with cognitive impairment. Taken together, our results provide evidence of distinct atrophy patterns in anti-IgLON5 disease, which closely mirror sites of pathophysiologic processes, including autoantibody binding and tau deposition. Our data emphasize the brainstem as the pathophysiological hub of the disease and provide normative data for the incorporation of atrophy measurements into routine clinical assessments and future treatment studies to monitor disease trajectory and evaluate future treatment strategies.

Abstract Introduction: Hyperexcitability, particularly of DRG neurons, is a key driver of persistent pain states including neuropathic pain. Contactin-associated protein-like 2 (CASPR2) is transmembrane protein known to interact and regulate the function of Kv1 channels, important determinants of neuronal excitability. Patients with autoantibodies (-Abs) against CASPR2 commonly have neuropathic pain, and these patient-Abs enhance the excitability of DRG neurons secondary to Kv1 channel disruption, leading to pain-related hypersensitivity. This is also observed after genetic ablation of CASPR2. Conversely, increasing CASPR2 levels in DRG neurons reduces excitability. Objectives: The aim of this study was to assess whether overexpressing CASPR2 could be a potential approach to treat pain. Methods: We generated a Cre-dependent mouse line to express human CASPR2 (R26 LSL:hCNTNAP2(+/+) (CASPR2 OE )) and crossed this with either Hoxb8 Cre or Nav1.8 Cre mice for CASPR2 overexpression in either all DRG neurons or to target nociceptors more selectively. Results: In both lines, CASPR2 was significantly overexpressed in DRG neurons, including at the cell membrane. In comparison to control littermates, overexpression of CASPR2 did not affect acute pain–related behaviour to mechanical or thermal stimulation or nerve injury–induced pain-related hypersensitivity. However, in both overexpression mouse lines, there were significantly reduced nocifensive responses to capsaicin. Although CASPR2 overexpression increased the contribution of α-dendrotoxin–sensitive Kv1 channels to the slowly inactivating outward current I KD , it did not affect total I KD. Conclusion: CASPR2 overexpression in DRG neurons can affect nociception, reducing pain-related behaviours to the noxious stimulant capsaicin, yet is insufficient to reduce mechanical pain–related hypersensitivity caused by nerve injury.