Elevated <scp>LGI</scp>1‐IgG <scp>CSF</scp> index predicts worse neurological outcome

Gadoth, Avi; Ζεκερίδου, Αναστασία; Klein, Christopher J.; Thoreson, Colton J.; Majed, Masoud; Dubey, Divyanshu; Flanagan, Eoin P.; McKeon, Andrew; Jenkins, Sarah M.; Lennon, Vanda A.; Pittock, Sean J.

doi:10.1002/acn3.561

Cited by 37 publications

(45 citation statements)

References 18 publications

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“…Of interest, it has recently been observed that intrathecal LGI1 antibody synthesis correlates with a poorer prognosis. 16 However, the lack of CSF LGI1 antibodies in some of our patients with striking intrathecal SHM may suggest that DIRS provides a more sensitive measure of B-cell activity.…”

Section: Discussionmentioning

confidence: 72%

Intrathecal B-cell activation in LGI1 antibody encephalitis

Lehmann‐Horn

Irani

Wang

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo 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. MethodsPaired 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. ResultsSerum 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. ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

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Section: Discussionmentioning

confidence: 72%

Intrathecal B-cell activation in LGI1 antibody encephalitis

Lehmann‐Horn

Irani

Wang

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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“…Although immunotherapy is fast and efficient in some LGI1 encephalitis patients, other cases are characterized by a long and continuously progressing disease process, including memory deficits, apathy, and difficulties with spatial orientation . Recent studies indicated that a high CSF index and specific IgG isotypes might be predictive of refractory symptoms and cognitive impairment . In a patient with a long‐lasting progressive LGI1 encephalitis (AIE060), our screen detected LGI1 antibodies of IgG1, IgG2, and IgG4 subtype in CSF ASCs and MBCs.…”

Section: Discussionmentioning

confidence: 88%

“…4 Recent studies indicated that a high CSF index and specific IgG isotypes might be predictive of refractory symptoms and cognitive impairment. 9,44 In a patient with a long-lasting progressive LGI1 encephalitis (AIE060), our screen detected LGI1 antibodies of IgG1, IgG2, and IgG4 subtype in CSF ASCs and MBCs. In contrast, in Patient AIE054, we found exclusively antibodies of IgG2 isotype in ASCs.…”

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confidence: 95%

“…Epileptic activity could be detected in frontal cortex as well as hippocampus of patients, and magnetic resonance imaging (MRI) studies revealed marked atrophy and impaired microstructural integrity of the hippocampus, correlating with cognitive impairment . LGI1 antibodies are present in serum and cerebrospinal fluid (CSF) of patients, and a recent study suggested that an increased LGI1‐IgG CSF index correlates with worse outcome . Like many other autoimmune disorders, LGI1 encephalitis is associated with a defined genetic predisposition …”

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confidence: 99%

“…8 LGI1 antibodies are present in serum and cerebrospinal fluid (CSF) of patients, and a recent study suggested that an increased LGI1-IgG CSF index correlates with worse outcome. 9 Like many other autoimmune disorders, LGI1 encephalitis is associated with a defined genetic predisposition. [10][11][12][13] LGI1 is secreted by neurons as a 60kDa protein containing leucine-rich repeat (LRR) and epitempin (EPTP) repeat domains.…”

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confidence: 99%

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Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Kornau

Kreye

Stumpf

et al. 2020

Annals of Neurology

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Objective Leucine‐rich glioma‐inactivated 1 (LGI1) encephalitis is the second most common antibody‐mediated encephalopathy, but insight into the intrathecal B‐cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. Methods We cloned, expressed, and tested antibodies from 90 antibody‐secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Results Eighty‐four percent of the ASCs and 21% of the memory B cells encoded LGI1‐reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non–ADAM22‐competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Interpretation Our data show that the patients’ intrathecal B‐cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N‐methyl‐D‐aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405–418

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Efficacy of immunotherapy and prognosis in anti‐LGI1 encephalitis patients: A meta‐analysis

Kong

Gong

et al. 2023

Ann Clin Transl Neurol

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ObjectiveTo assess the efficacy and safety of immunotherapy for LGI1 antibody encephalitis, and consider the predictors of poor outcomes following immunotherapy.MethodsWe searched PubMed and Embase for articles reporting the immunotherapy data of anti‐LGI1 encephalitis patients. The proportions of patients with poor outcomes (modified Rankin Scale [mRS] score > 2) at 3 months, 12 months, and the last follow‐up, as well as the odds ratio [OR] of predictors were pooled.ResultsThe review included 162 articles with 1066 patients. The proportion of patients with poor functional outcomes was 21% at 3 months, 14% at 12 months, and 14% at the last follow‐up after receiving immunotherapy. The proportion of patients with reported relapse was 16.6%. The mean duration from onset to the first relapse was 15.6 months. Predictors significantly associated with poor outcomes were age (increase of 1 year), the presence of cognitive impairment, and CSF LGI1 antibody positive. We did not find a statistically significant association between the worst mRS score in the acute phase, the presence of faciobrachial dystonic seizures (FBDS), days from symptom onset to immunotherapy, second‐line treatment, maintenance immunotherapy, or follow‐up time and outcomes.InterpretationAlthough most patients respond to immunotherapy, a minority of patients still have poor outcomes. Advanced age, cognitive impairment, and CSF LGI1 antibody positive are associated with an increased risk of poor outcomes. However, due to the insufficiency of the data, these conclusions need to be interpreted with caution.

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Elevated LGI1‐IgG CSF index predicts worse neurological outcome

Cited by 37 publications

References 18 publications

Intrathecal B-cell activation in LGI1 antibody encephalitis

Intrathecal B-cell activation in LGI1 antibody encephalitis

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Efficacy of immunotherapy and prognosis in anti‐LGI1 encephalitis patients: A meta‐analysis

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