Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug-resistant epilepsy.

OBJECTIVE: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes. METHODS: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients. INTERPRETATION: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.

Magnetic Resonance Imaging Characteristics of LGI1-Antibody and CASPR2-Antibody Encephalitis.

Importance: Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy. Objective: To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD). Design, Setting, and Participants: This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023. Main Outcomes and Measures: MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features. Results: Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala. Conclusions and Relevance: In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.

Fatigue predicts quality of life after leucine-rich glioma-inactivated 1-antibody encephalitis.

Patient-reported quality-of-life (QoL) and carer impacts are not reported after leucine-rich glioma-inactivated 1-antibody encephalitis (LGI1-Ab-E). From 60 patients, 85% (51 out of 60) showed one abnormal score across QoL assessments and 11 multimodal validated questionnaires. Compared to the premorbid state, QoL significantly deteriorated (p < 0.001) and, at a median of 41 months, fatigue was its most important predictor (p = 0.025). In total, 51% (26 out of 51) of carers reported significant burden. An abbreviated five-item battery explained most variance in QoL. Wide-ranging impacts post-LGI1-Ab-E include decreased QoL and high caregiver strain. We identify a rapid method to capture QoL in routine clinic or clinical trial settings.

Criminality in patients with autoimmune encephalitis: A case series.

BACKGROUND AND PURPOSE: Despite it being an immunotherapy-responsive neurological syndrome, patients with autoimmune encephalitis (AE) frequently exhibit residual neurobehavioural features. Here, we report criminal behaviours as a serious and novel postencephalitic association. METHODS: This retrospective cohort study included 301 AE patients. Five of who committed crimes underwent direct assessments and records review alongside autoantibody studies. RESULTS: Five of 301 patients (1.7%) with AE exhibited criminal behaviours, which included viewing child pornography (n = 3), repeated shoplifting, and conspiracy to commit murder. All five were adult males, with LGI1 autoantibodies (n = 3), CASPR2 autoantibodies, or seronegative AE. None had evidence of premorbid antisocial personality traits or psychiatric disorders. Criminal behaviours began a median of 18 months (range = 15 months-12 years) after encephalitis onset. At the time of crimes, two patients were immunotherapy-naïve, three had been administered late immunotherapies (at 5 weeks-4 months), many neurobehavioural features persisted, and new obsessive behaviours had appeared. However, cognition, seizure, and disability measures had improved, alongside reduced autoantibody levels. CONCLUSIONS: Criminal behaviours are a rare, novel, and stigmatizing residual neurobehavioural phenotype in AE, with significant social and legal implications. With caution towards overattribution, we suggest they occur as part of a postencephalitis limbic neurobehavioural syndrome.

Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.

Clinical diagnosis of LGI1 antibody encephalitis in an 83-year-old woman.

An 83-year-old woman was referred to hospital with a 2-week history of short-lived episodic unpleasant sensations in her head and running down her body. This was accompanied by new short-term memory impairment and arm spasms. Initial investigations including blood tests and brain imaging did not reveal the diagnosis. The patient developed an increasing frequency of abnormal movements of her face and arm. These were clinically recognised as faciobrachial dystonic seizures (FBDS). FBDS are pathognomonic of an autoimmune encephalitis caused by an antibody directed against leucine-rich glioma-inactivated 1 (LGI1). The clinical diagnosis resulted in treatment with immunotherapy, leading to cessation of seizures and rapid cognitive recovery. Later, the predicted serology was confirmed. This reversible and under-recognised cause of cognitive impairment, typically affecting elderly patients, can be diagnosed clinically to enable early and effective treatment.

Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2.

Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities ('double-negative') are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit.

Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms.

Autoantibodies against leucine-rich glioma inactivated 1 (LGI1) are found in patients with limbic encephalitis and focal seizures. Here, we generate patient-derived monoclonal antibodies (mAbs) against LGI1. We explore their sequences and binding characteristics, plus their pathogenic potential using transfected HEK293T cells, rodent neuronal preparations, and behavioural and electrophysiological assessments in vivo after mAb injections into the rodent hippocampus. In live cell-based assays, LGI1 epitope recognition was examined with patient sera (n = 31), CSFs (n = 11), longitudinal serum samples (n = 15), and using mAbs (n = 14) generated from peripheral B cells of two patients. All sera and 9/11 CSFs bound both the leucine-rich repeat (LRR) and the epitempin repeat (EPTP) domains of LGI1, with stable ratios of LRR:EPTP antibody levels over time. By contrast, the mAbs derived from both patients recognized either the LRR or EPTP domain. mAbs against both domain specificities showed varied binding strengths, and marked genetic heterogeneity, with high mutation frequencies. LRR-specific mAbs recognized LGI1 docked to its interaction partners, ADAM22 and ADAM23, bound to rodent brain sections, and induced internalization of the LGI1-ADAM22/23 complex in both HEK293T cells and live hippocampal neurons. By contrast, few EPTP-specific mAbs bound to rodent brain sections or ADAM22/23-docked LGI1, but all inhibited the docking of LGI1 to ADAM22/23. After intrahippocampal injection, and by contrast to the LRR-directed mAbs, the EPTP-directed mAbs showed far less avid binding to brain tissue and were consistently detected in the serum. Post-injection, both domain-specific mAbs abrogated long-term potentiation induction, and LRR-directed antibodies with higher binding strengths induced memory impairment. Taken together, two largely dichotomous populations of LGI1 mAbs with distinct domain binding characteristics exist in the affinity matured peripheral autoantigen-specific memory pools of individuals, both of which have pathogenic potential. In human autoantibody-mediated diseases, the detailed characterization of patient mAbs provides a valuable method to dissect the molecular mechanisms within polyclonal populations.

Intrathecal B-cell activation in LGI1 antibody encephalitis.

OBJECTIVE: To study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis. METHODS: Paired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB. RESULTS: Serum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls. CONCLUSIONS: Our results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

Seronegative antibody-mediated neurology after immune checkpoint inhibitors.

Checkpoint inhibitor medications have revolutionized oncology practice, but frequently induce immune-related adverse events. During autoimmune neurology practice over 20 months, we prospectively identified four patients with likely antibody-mediated neurological diseases after checkpoint inhibitors: longitudinally extensive transverse myelitis, Guillain-Barré syndrome, and myasthenia gravis. All patients shared three characteristics: symptoms commenced 4 weeks after drug administration, responses to conventional immunotherapies were excellent, and autoantibodies traditionally associated with their syndrome were absent. However, serum immunoglobulins from the myelitis and Guillain-Barré syndrome patients showed novel patterns of tissue reactivity. Vigilance is required for antibody-mediated neurology after checkpoint inhibitor administration. This phenomenon may inform the immunobiology of antibody-mediated diseases.

A practical guide to the use of anti-epileptic drugs by neurosurgeons.

Initiation of anti-epileptic drugs is increasingly relevant to daily neurosurgical practice. Intracranial pathologies ranging from brain tumours to subarachnoid haemorrhage and traumatic brain injury are commonly associated with the subsequent development of seizures. The scope and range of anti-epileptic drugs available has increased dramatically in recent years and understanding the evidence base behind this class of drugs in addition to their interaction/side effect profiles is essential. In this review we aim to generate a practical guide for neurosurgeons regarding the use of different anti-epileptic medications in common neurosurgical conditions, including considerations for their use in pregnancy.