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Sleep Disorders in Leucine-Rich Glioma-Inactivated Protein 1 and Contactin Protein-Like 2 Antibody-Associated Diseases.

ABSTRACT: Objective: Sleep disorders are common in voltage-gated potassium channel complex antibody (VGKC-Ab) diseases. The aim was to investigate the sleep disturbances and polysomnography (PSG) characteristics in patients with VGKC-Ab-associated diseases. Methods: Twenty-seven patients with leucine-rich glioma-inactivated protein 1 antibody (LGI1-Ab) encephalitis, seven patients with contactin protein-like 2 antibody (Caspr2-Ab)-associated diseases, and 14 healthy controls with at least one PSG or actigraphy recording were recruited at Peking Union Medical College Hospital from January 2014 to July 2019. Results: Sleep disorders including insomnia, hypersomnia, rapid eye movement (REM) sleep behavior disorder (RBD), periodic limb movements in sleep (PLMS), agrypnia excitata, and obstructive sleep apnea syndrome were observed. Twenty-one PSG recordings from patients with LGI1-Ab encephalitis demonstrated a decrease in total sleep time (TST) (median 365.5, range 184.5-495.5 min), sleep efficiency (70.0%, 47-92%), N3 sleep (9.7%, 0-32.9%), and REM sleep (9.9%, 0.4-27.9%). Of five patients with Caspr2-Ab-associated diseases, TST was found to be 329.5 (167.0-377.5 min), and sleep efficiency was found to be 61.7% (34.6-71.7%). The percentage for N3 and REM sleep was found to be 15.0% (0-34.6%) and 12.7% (0-22.2%), respectively. Both RBD and PLMS were observed more frequently in patients with LGI1-Ab encephalitis. We identified status dissociatus (SD) in five (23.8%) patients with LGI1-Ab encephalitis and two (40%) patients with Caspr2-Ab diseases. The former is more likely to have simple limb movements rather than complex movements, which mimic the contents of their dreams. Continuous insomnia was more common in patients with Caspr2-Ab diseases than patients with LGI1-Ab encephalitis. Patients reported clinical and PSG improvements following immunotherapy. Conclusion: Sleep disorders in patients with VGKC-Ab-associated diseases include decreased TST and poor sleep efficiency. Our studies provide evidence of SD in patients with LGI1-Ab encephalitis.

SUBMITTER: Lin N

PROVIDER: S-EPMC7406672 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Sleep Disorders in Leucine-Rich Glioma-Inactivated Protein 1 and Contactin Protein-Like 2 Antibody-Associated Diseases.

Lin Nan N Hao Honglin H Guan Hongzhi H Sun Heyang H Liu Qing Q Lu Qiang Q Jin Liri L Ren Haitao H Huang Yan Y

Frontiers in neurology 20200730

<b>Objective:</b> Sleep disorders are common in voltage-gated potassium channel complex antibody (VGKC-Ab) diseases. The aim was to investigate the sleep disturbances and polysomnography (PSG) characteristics in patients with VGKC-Ab-associated diseases. <b>Methods:</b> Twenty-seven patients with leucine-rich glioma-inactivated protein 1 antibody (LGI1-Ab) encephalitis, seven patients with contactin protein-like 2 antibody (Caspr2-Ab)-associated diseases, and 14 healthy controls with at least on ...[more]

PMID: 32849186

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Project description:ImportanceAlthough acquired autoimmune neuromyotonia (NMT) is associated with voltage-gated potassium channel (VGKC)-complex antibodies, to date there has been no systematic study of autoantibodies to the specific antigens leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein 2 (CASPR2), and contactin 2 together with the full clinical syndrome, particularly pain and autonomic and central nervous system involvement.ObjectivesTo study the full spectrum of clinical features and serum autoantibodies in patients with NMT, including the effects of pain on quality of life.Design, setting, and participantsA cohort study of clinical features and serologic testing in 38 patients with electrophysiologically-confirmed NMT, reviewed clinically between February 2007 and August 2009, in the Universities of Sydney and Kagoshima and followed up across 2 to 4 years. Association of NMT with quality of life was researched in an independent, patient-led, online pain survey conducted from April 2012 to May 2012. Serologic analyses were performed in 2012, and final data analysis was performed in 2016.Main outcomes and measuresClinical data and scores on the modified Rankin Scale (mRS), which measures disability on a range of 0 to 6, with 0 indicating normal and 6 indicating death, before and after treatments were combined with CASPR2, LGI1, and contactin 2 antibody status.ResultsAmong the 38-person NMT cohort, 25 (65.8%) were male and the median (range) age was 55 (12-85) years. Twenty-three (60.5%) were Japanese and 15 (39.5%) were of white race/ethnicity. Symptomatic treatments (mainly antiepileptic drugs) were used in most patients with mild disease (12 patients with mRS <3), whereas immunotherapies were successful in most patients with mRS scores greater than 2. Autoantibodies to VGKC-complex antigens (17 patients [45%]), bound to CASPR2 (5 [13%]), contactin 2 (5 patients, 1 with CASPR2 [13%]), LGI1 (2 [5%]), or both LGI1 and CASPR2 (6 [16%]). The last group of 6 patients had high mRS scores (mean [SD], 3.8 [1.7]), thymoma (4 patients), pain (5 patients), autonomic (6 patients) and sleep (5 patients) disturbance, suggesting Morvan syndrome. The 56 responders to the independent patient-led survey reported pain that could be severe, anatomically widespread, and that often resulted in unemployment, domestic problems, and poor quality of life.Conclusions and relevanceThe cohort study detailed underrecognized aspects of the clinical and serologic spectrum of NMT. The heterogeneity of clinical features and of specific antibodies limit associations, but the common existence of thymoma, pain, and autonomic and central nervous system features, often with both LGI1 and CASPR2 antibodies, should be better recognized to more completely address the range of comorbidities and consequences of the disease regarding quality of life.

Project description:Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

Project description:ObjectiveTo characterize seizure semiology and the utility of antiepileptic drug (AED) therapy in leucine-rich glioma inactivated-1 ( LGI1-Ab) autoimmune epilepsy (AE).MethodsPatients with voltage-gated potassium channel complex (VGKCc) titers higher than 0.02 nmol/L who were evaluated between May 2008 and June 2016 at the 3 Mayo Clinic sites (Arizona, Florida, or Minnesota) were identified. We then performed a retrospective review of those who were LGI1-Ab positive and were treated for seizures.ResultsA total of 1,095 patients with VGKCc titers higher than 0.02 nmol/L were identified, in which 77 were LGI1 positive. Of these, 56 patients with seizures were included in the analysis. Mean age at symptom onset was 62.9 years; 66% (n = 37) were male. The most common seizure semiology was focal faciobrachial dystonic seizures with preserved awareness (FBDS) (n = 35, 63%), followed by focal with impaired awareness (FIA) (n = 29, 52%), generalized tonic-clonic (GTCs) (n = 28, 50%), and focal non-motor seizures with preserved awareness (n = 28, 50%). The majority had more than one seizure type (n = 49, 88%; median = 2.5). Thirty-eight patients (68%) became seizure free: 29 (76%) with immunotherapy, 3 (5%) with AEDs alone, 2 (3%) with AEDs before any immunotherapy, and 4 (7%) with AEDs after immunotherapy. Levetiracetam (n = 47, 84%) and valproic acid (n = 21, 38%) were the most commonly used AEDs, but neither were associated with seizure freedom. Sodium channel blocking (NCB) AEDs were associated with seizure freedom in 4 patients compared to none treated with non-NCB AEDs. Regardless of class, AEDs prior to or apart from immunotherapy were associated with seizure freedom in only five patients (9%). In patients with FBDS, seizure freedom was more often associated with immunotherapy than AEDs (20/30 vs. 3/34, p = 0.001).SignificanceAlthough FBDS are the most characteristic seizure type seen in LGI1-Ab AE, other seizure types including FIA and GTCs also occur. Immunotherapy was the treatment most frequently associated with seizure freedom in LGI1-Ab AE. In general, AEDs seemed to confer a very low chance for seizure freedom, although AEDs with NCB-blocking properties were associated with seizure freedom in a limited number. Levetiracetam in particular appears to be ineffective in this patient population.

Project description:PurposeBrain 18F-fluorodeoxyglucose positron emission tomography (FDG PET) is a sensitive technique for assisting in the diagnosis of patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. However, the common pattern of this disorder assessed by FDG PET remains unknown. The present study aimed to explore the glucose metabolic patterns of this disorder based on PET voxel analysis.MethodsThis retrospective study enrolled 25 patients with anti-LGI1 encephalitis, who were admitted in Beijing Tiantan Hospital between September 2014 and July 2019. The glucose metabolic pattern was compared between the included patients and 44 age- and gender-matched healthy controls using Statistical Parametric Mapping. Then, the correlation between the metabolic pattern and scaled activities of daily living (ADLs) of the patients was assessed.ResultsThe median time from symptom onset to PET scans was 9 w (range:2-53w). The groupwise analysis revealed that patients with anti-LGI1 encephalitis had left hippocampal hypermetabolism and hypometabolism in almost all neocortical regions. The individual-level results showed most patients presented a decreased metabolism in neocortical regions, as well as an increase in metabolism in the hippocampus and basal ganglia. Furthermore, the metabolic gradient between hippocampus and neocortical regions was positively associated with the ADLs (frontal lobe, r=0.529, P=0.008; parietal lobe, r=0.474, P=0.019; occipital lobe, r=0.413, P=0.045; temporal lobe, r=0.490, P=0.015), respectively. In addition, the patients with facio-brachial dystonic seizures (FBDS) presented bilateral putamen hypermetabolism, when compared to patients without FBDS and healthy controls.ConclusionSubcortical hypermetabolism associated with cortical hypometabolism presented with a common metabolic pattern in patients with anti-LGI1 encephalitis in the present study. The resolution of the metabolic gradient of the hippocampal hypermetabolism and neocortical hypometabolism may bring about improved clinical neurologic disability.

Project description:BackgroundAberrant DNA methylation occurs commonly during pathogenesis of neuroimmunological diseases and is of clinical value in various encephalitis subtypes. However, knowledge of the impact of DNA methylation changes on pathogenesis of leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis remains limited.MethodsA total of 44 cytokines and 10 immune checkpoint moleculars (ICMs) in the serum of patients with LGI1 encephalitis and healthy donors (HDs) were measured to evaluate the association of them with clinical parameters. Genome-wide DNA methylation profiles were performed in peripheral blood mononuclear cell (PBMC) from LGI1 encephalitis patients and HDs using reduced representation bisulfite sequencing (RRBS) and validated for the methylation status by pyrosequencing. MicroRNA profiles were acquired in serum exosome by small RNA sequencing. Targeted cytokines expression was assessed at the presence or absence of miR-2467-5p in PBMCs and the culture media, and the binding of miR-2467-5p and its targeted genes was validated by luciferase assay.ResultsThere existed significant difference in 22 cytokines/chemokines and 6 ICMs between LGI1 encephalitis patients and HDs. Decreased PDCD1 with increased ICAM1 could predict unfavorable prognosis in one-year follow-up for LGI1 encephalitis patients. Fifteen of cytokines/chemokines and ICMs presented DNA-methylated changes in the promoter and gene body using RRBS in which five were verified as methylation status by pyrosequencing, and the methylation level of CSF3, CCL2, and ICAM1 was conversely associated with their expression in PBMCs. By combining RRBS data with exosome-derived microRNA sequencing, we found that hypomethylated-driven hsa-miR-2467-5p presented elevated expression in serum exosomes and PBMCs in LGI1 encephalitis. Mechanically, miR-2467-5p significantly induced reduced expression of CSF3 and PDCD1 by binding with their 3`UTR while enhanced CCL15 expression, but not significantly correlated with peripheral blood CD19 + B cell proportion of LGI1 encephalitis patients.ConclusionsOur results provided convincing evidence for DNA methylation changes, microRNA profiles in serum exosome for LGI1 encephalitis, and we also identified several novel cytokines related to clinical features in which some represented epigenetic modification of methylated-driven pattern and microRNA modulation. Our study contributed to develop treatment for epigenetic pathogenesis in LGI1 encephalitis.

Dataset Information

Sleep Disorders in Leucine-Rich Glioma-Inactivated Protein 1 and Contactin Protein-Like 2 Antibody-Associated Diseases.

Publications

Sleep Disorders in Leucine-Rich Glioma-Inactivated Protein 1 and Contactin Protein-Like 2 Antibody-Associated Diseases.

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