Clinical Features And Changes Of Inflammatory Factors Of Anti-Leucine Rich Glioma Inactivated 1 Protein Encephalitis

ObjectiveThis study aimed to summarize the clinical data of patients with anti-leucine rich glioma inactivated 1 protein(LGI1)antibody encephalitis in acute phase,analyzed the clinical manifestations and the auxiliary examination,to provide experience for early clinical diagnosis.A case-control study was conducted to investigate the changes of interleukin 6(IL-6),interleukin 10(IL-10),interleukin 17(IL-17),stromal cell derived factor 1(CXCL12),CXC motif chemokine 13(CXCL13),B cell activation factor(BAFF)and high-mobility group box protein 1(HMGB1)in serum and cerebrospinal fluid(CSF)between anti-LGI1 antibody encephalitis and the control group,correlation and regression model was used to analyze the correlation between inflammatory factors and clinical manifestations in patients with anti-LGIl antibody encephalitis.Materials and methods53 patients who were admitted to the department of neurology,Qilu Hospital of Shandong University and diagnosed with anti-LGI1 antibody encephalitis from April 2015 to November 2020 were enrolled.The clinical data of patients were collected and retrospectively analyzed to summarize the clinical features of anti-LGI1 antibody encephalitis.From 2017 to 2020,serum and CSF samples of 16 patients with acute anti-LGI1 antibody encephalitis were collected from neurology department of Qilu Hospital of Shandong University and Shandong provincial hospital,serum and CSF samples of 9 gender and age-matched patients with tension headache or cervical spondylosis were collected,the CSF and serum levels of IL-6,IL-10,IL-17,CXCL12,CXCL13,BAFF and HMGB1 of the LGI1 group and the control group were detected by ELISA method,compared the differences of cytokines/chemokines between different groups,and analyzed the correlation between specific cytokines/chemokines and clinical indicators in patients with anti-LGI1 antibody encephalitis.SPSS 26.0 statistics is used for statistical statistics and analysis,and GraphPad 5.0 is used for statistical mapping.Results1.Clinical characteristics of anti-LGI1 antibody encephalitis53 patients with anti-LGI1 antibody encephalitis included in this study had a male to female ratio of 39:14,the average age of onset was 58.43± 12.60 years(17 to 77 years),The time from first symptom to consultation was 70.89±76.39 days(1 to 330 days).The common first symptoms included epilepsy and cognitive dysfunction.The common clinical manifestations included seizures,mental and behavioral disorders,cognitive dysfunction(mainly the decline of near memory),faciobrachial dystonic seizure(FBDS)and sleep disorders,most patients are combined with hyponatremia,no malignant tumor was detected in all patients.CSF detection may be accompanied or not accompanied by increased CSF protein concentration or white cell count.Brain magnetic resonance imaging(MRI)of some patients demonstrated abnormal signals on unilateral or bilateral medial temporal lobe/hippocampus.EEG abnormalities mainly showed diffuse slow wave or non-diffuse slow wave activity increasing.Most patients were effective for immunotherapy.2.Study on the changes of inflammatory factors in patients with anti-LGI1 antibody encephalitisThe level of CXCL13 in CSF of anti-LGI1 antibody encephalitis group was significantly higher than that of the control[1.72pg/ml(2.07pg/ml)vs.0.25pg/ml(0.24pg/ml),P=0.001],the level of IL-6 in the CSF was higher than that of the control[2.06pg/ml(2.88pg/ml)vs.1.34pg/ml(1.13pg/ml),P=0.013],and the level of IL-17 in CSF was lower than that of the control[7.38pg/ml(3.75pg/ml)vs.11.04pg/ml(6.73pg/ml),P=0.013].There was no significant difference of IL-10,CXCL12,BAFF and HMGB1 levels in CSF between anti-LGI1 antibody encephalitis group and control group(P>0.05).The level of CXCL13 in serum(36.33+34.27pg/ml)was significantly higher than that of the control(10.84+5.02pg/ml)(P<0.05).There was no significant difference of IL-17,BAFF and HMGB1 in serum between anti-LGI1 antibody encephalitis group and control group(P>0.05).After stratification analysis of gender,the level of IL-6 in CSF of male anti-LGI1 antibody encephalitis group was higher than that of male control group[2.08pg/ml(2.72pg/ml)vs.1.34pg/ml(0.75pg/ml),P=0.010],the level of CXCL13 in CSF of anti-LGI1 antibody encephalitis of male group was significantly higher than that of the male control[1.72pg/ml(2.80pg/ml)vs.0.25pg/ml(0.28 pg/ml),P=0.004],the level of IL-17 in CSF of male anti-LGI1 antibody encephalitis group was lower than that of male control group[7.58pg/ml(4.23pg/ml)vs.12.96pg/ml(7.31 pg/ml),P=0.010].3.The relationship between clinical characteristics and cytokine/chemokine levels of patients with anti-LGI1 antibody encephalitis.Before treatment,anti-LGI1 antibody encephalitis patients with higher Modified Rankin Scale(MRS)scores(>2 vs.≤2)had higher level of IL-17 in CSF[8.92pg/ml(6.15pg/ml)vs.6.42pg/ml(1.54pg/ml),P=0.048].Patients with abnormal mental behavior had lower level of CXCL12 in CSF than those without such symptoms[590.00pg/ml(380.00pg/ml)vs.840.00pg/ml(785.00pg/ml),P=0.039].Patients with hyponatremia had lower level of CXCL12 in CSF than patients without hyponatremia[620.00pg/ml(370.00pg/ml)vs.960.00pg/ml(1505.00pg/ml),P=0.039].Patients with FBDS had lower lever of IL-10 in serum than patients without the symptom[0.17pg/ml(0.69pg/ml)vs.4.17pg/ml(4.92pg/ml),P=0.047].Patients with hyponatremia had significantly lower level of CXCL12 in serum than patients without hyponatremia[1340.00pg/ml(855.00pg/ml)vs.2300.00pg/ml(1630.00pg/ml),P=0.019].The serum level of BAFF in patients with temporal lobe/hippocampus abnormality was higher than that of patients without this manifestation on brain MRI[0.27pg/ml(0.15pg/ml)vs.0.09pg/ml(0.23pg/ml),P=0.047].The serum level of IL-6 in patients with CSF antibody titer<1:3.2 was lower than that of patients with CSF antibody titer>1:3.2[0.03pg/ml(0.07pg/ml)vs.0.15pg/ml(-),P=0.034].4.Correlation between clinical features and inflammatory factors in patients with anti-LGI1 antibody encephalitis.CSF IL-6 level in patients with anti-LGI1 antibody encephalitis was positively correlated with CSF white blood cells count(correlation coefficient rs=0.644,P=0.010)and CSF antibody titer(rs=0.644,P=0.024).CSF IL-17 level was positively correlated with CSF white blood cells count(rs=0.524,P=0.045).Serum IL-6 level was positively correlated with CSF antibody titer(rs=0.791,P=0.034),and was negatively correlated with Serum/CSF antibody titer(rs=0.799,P=0.031).Serum BAFF level was positively correlated with CSF antibody titer(rs=0.896,P=0.006),and was negatively correlated with Serum/CSF antibody titer(rs=0.896,P=0.011).For serum CXCL13 levels and CSF protein levels were in line with normal distribution,linear correlation analysis showed that Serum CXCL13 level was positively correlated with CSF protein level(correlation coefficient r=0.670,P=0.034).linear regression analysis showed that Serum CXCL13 level was positively correlated with CSF protein level(correlation coefficient R2=0.449,P=0.034).Conclusion1.The clinical manifestations of anti-LGI1 antibody encephalitis are diverse.The possibility of anti-LGI1 antibody encephalitis should be considered in patients with acute and subacute onset epilepsy,FBDS,mental and behavioral abnormalities,and cognitive impairment.2.Routine CSF examinations of patients with anti-LGI1 antibody encephalitis are non-specific,increased CSF leukocyte count and CSF protein concentration only appears in a small number of patients.3.In the specific antibody detection,the positive rate of antibody in serum is higher than that in CSF of patients with anti-LGI1 antibody encephalitis.It is suggested to send both serum and CSF antibodies to improve the positive rate of antibody detection.4.Brain MRI shows abnormal signal in temporal lobe/hippocampus in some patients.EEG abnormalities mostly manifest as diffuse slow wave and non-diffuse slow wave activity increasing.Epileptiform discharge was rare.Normal brain MRI and EEG could not exclude the diagnosis of anti-LGI1 antibody encephalitis.5.The majority of patients are effective in immunotherapy,most of the relapsed patients are admitted to the hospital because of epilepsy and abnormal mental behavior,it is common in the patients with premature withdrawal and rapid hormone reduction.6.CXCL13 and IL-6 may be neuroinflammatory markers in patients with acute anti-LGI1 antibody encephalitis.CSF IL-6 level was positively correlated with CSF white blood cells count and antibody titer,serum IL-6 level was positively correlated with CSF antibody titer,serum CXCL13 level was positively correlated with CSF protein concentration.