Clinical Characteristics and Prognostic Analysis of Anti-LGI 1 Receptor Encephalitis in Northeast China

Background: To investigate the clinical characteristics and prognosis of Anti-LGI1 receptor encephalitis. Methods: This retrospective study enrolled forty -one patients with anti LGI1 receptor encephalitis diagnosed for the rst time in the Department of Neurology, the rst hospital of Jilin University from June 2015 to November 2019. Results: There are twenty-two males and nineteen females, with a median age of fty-four years. The rst symptom of male patients showed cognitive impairment in nine (40.91%) cases,facial muscle dystonia in six (27.27%) cases.Of the female patients,seven (36.84%)patients had facial-arm dystonia-like seizures,six (31.58%) patients had cognitive impairment.seven (18.42%) patients had abnormal tumor markers,but no tumor was found in all patients.Thirty patients (73.17%) had hyponatremia with a minimum of 115.4 mmol/L.Except for one patient,eighteen (45.00%) patients had normal cerebrospinal uid indicators,twenty-two (55.00%) patients had abnormal cerebrospinal uid indicators,Eleventh (50.00%) patients had elevated protein,and nine (40.91%) patients had elevated IgG,six (27.27%) patientys of white blood cells increased,and four (18.18%) patients of increased pressure. Except for four patients,twenty-two (59.46%) patients had abnormal signals of hippocampus and temporal lobe,seventeen (77.27%) of them had bilateral abnormal signals of hippocampus,ve(22.73%)cases had unilateral abnormal signals of hippocampus;Eleventh(29.73%)had lacunar Cerebral infarction and ischemic focus;Two(5.41%)cases of frontal and insular abnormal signals;one(2.70%)case of temporal and occipital abnormal signals;one(2.70%) case of white matter lesions. Except for one patient,the EEG showed twenty-seven(67.50%)cases of slow waves and focal discharges,(six(22.22%)

showed twenty-seven(67.50%)cases of slow waves and focal discharges,(six(22.22%) of which were lefttemporal spiked slow waves,and ve (18.52%) were of right-temporal spikes Slow wave,four (14.81%) cases with double temporal sharpened slow wave,six (22.22%) cases with frontotemporal sharpened slow wave, one (3.70%) case with frontal sharpened slow wave,one(3.70%)case with Three-phase waves; In addition,four(10.00%)cases of fast activity increased;three (7.50%) cases of background α generalization). Patients received rst-line immunotherapy except six patients who gave up treatment.
Conclusions: Anti-LGI1 receptor encephalitis is more common in middle-aged and older people. In male,the rst manifestation is cognitive impairment, and the female is more common with the facial-arm dystonia-like seizures,and rarely can be manifested as discharge sensation, hallucinations and autonomic symptoms.lumbar puncture pressure increased more than decreased;protein was signi cantly higher than leukocytes;EEG showed slow waves and focal discharges were more common, and abnormal background and normal EEG can occur.MRI shows that hippocampus and temporal lobe abnormal signal have the highest proportion.There is no signi cant difference in the prognosis of hormones, globulin,or both.

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Anti-LGI1 antibody-associated borderline encephalitis was previously thought to be an anti-voltage-gated potassium channel (VGKC) antibody against VGKC two related proteins, LGI1 and CASPR2 autoantibodies, LGI1 neurons Secreted proteins are mainly expressed in the hippocampus and temporal cortex, LGI 1 is secreted in the synapse, and is associated with two synaptic proteins of the catabolic factor and metalloproteinase domain (ADAM) family-presynaptic ADAM 23 and post-synaptic ADAM 22 interaction. Faciobrachial dystonic seizure (FBDS) is a speci c symptom of anti-LGI1 antibody-related borderline encephalitis, manifested as frequent, transient dystonia-like involuntary movements on one arm and face and even lower limbs. The seizure time is short, generally only a few seconds, frequent seizures can reach dozens of times a day, may be accompanied by bilateral dystonia-like seizures, changes in consciousness, etc. Studies have shown that about 50% of patients exhibit these symptoms. This study was approved by the local Ethics Committee. Written informed consent was obtained from each participant.

Data collection Laboratory examination
All the samples collected were serum and cerebrospinal uid samples from our hospital at the rst attack and sent to Beijing Union Medical College Hospital for anti-neuronal antibody testing. It was con rmed that patients with serum and/or cerebrospinal uid anti-LGI antibodies were positive.

General data collection
Retrospective analysis June 2015-November 2019 The clinical data of forty-one patients with the rst diagnosis of anti-LGI 1 receptor encephalitis admitted to the Department of Neurology, the First Hospital of Jilin University. The clinical characteristics, laboratory examinations, imaging and electroencephalogram performance of patients were collected to evaluate the treatment effect and prognosis.

Radiological examinations
Except for four patients with unknown MRI data, twenty-two(59.46%) patients had abnormal signals of hippocampus and temporal lobe, seventeen(77.27%) of them had bilateral abnormal signals of hippocampus, ve(22.73%) cases had unilateral abnormal signals of hippocampus ; Eleventh (29.73%) had lacunar Cerebral infarction and ischemic focus; Two (5.41%) cases of frontal and insular abnormal signals; on (2.70%)e case of temporal and occipital abnormal signals; one (2.70%) case of white matter lesions. ( Table 1) EEG examinations Except for one patient who did not have EEG, the EEG showed twenty-seven(67.50%) cases of slow waves and focal discharges, (six(22.22%) of which were left-temporal spiked slow waves, and ve (18.52%) were of right-temporal spikes Slow wave, four(14.81%) cases with double temporal sharpened slow wave, six (22.22%) cases with frontotemporal sharpened slow wave, one(3.70%) case with frontal sharpened slow wave, one(3.70%) case with Three-phase waves ; In addition, four(10.00%) cases of fast activity increased ; three (7.50%) cases of background α generalization; one (2.50%) case of sharp wave delivery; four (10.00%)cases of normal EEG. ( Table 1) Laboratory tests Except for three unknown cases in the detection of tumor markers, seven(18.42%) patients had abnormal tumor markers, but no tumor was found in all patients. Thirty patients (73.17%) had hyponatremia with a minimum of 115.4 mmol/L during the rst laboratory test on admission. Except for one patient with unclear lumbar puncture data, eighteen(45.00%) patients had normal cerebrospinal uid indicators, twenty -two(55.00%) patients had abnormal cerebrospinal uid indicators, Eleventh (50.00%) patients with abnormal indicators had elevated protein, and nine(40.91%) patients had elevated IgG, six (27.27%)patientys of white blood cells increased, and four (18.18%)patients of increased pressure. (  Table 1) Treatment and prognosis All patients received rst-line immunotherapy except six patients who gave up treatment. Fifteen (42.86%) patients had globulin and hormones, eleventh (31.43%) patients with hormones, and nine (23.68%) patients with globulins. After treatment, they all improved and were discharged from the hospital, but there was still a relapse. ( Table 1)

Discussion
In 2010, Lai et al. [1] reported for the rst time that anti-LGI 1 antibody-related encephalitis and anti-CASPR 2 antibody-related encephalitis were related to voltage-gated potassium channels. The rst report was reported in 2013 from China [2]. Since then, the number of con rmed cases of anti-LGI 1 antibodyrelated encephalitis has also increased year by year, which may be related to the expansion of the known neuronal autoantibody spectrum and the gradual adoption of antibody testing. In recent years, the immunopathogenic mechanism of LGI1 antibody is still to be studied, and there are reports that it may be related to human leukocyte differentiation antigen (HLA) subtypes [3]. It has also been reported that patients with anti-LGI 1 encephalitis are more likely to develop autoimmune diseases than patients with other types of encephalitis, and found that autoimmune diseases do not affect the clinical process [4].
LGI-1 antibody encephalitis is most common in elderly men with a signi cant male predominance, and the disease is often a subacute attack, usually developing into complete encephalitis without treatment during the attack. The main clinical manifestations are FBDS, memory loss, hyponatremia, and good immunotherapy effect [5]. Other rare symptoms include autonomic dysfunction, including excessive sweating, bradycardia and sphincter dysfunction, and common behavior/personality changes, including irritability, obsessive-compulsive disorder, emotionalization, and insomnia [6]. FBDS and other epilepsy symptoms usually occur before cognitive impairment. This study reported forty-one cases of patients diagnosed with anti-LGI1 antibody-associated border encephalitis for the rst time in our hospital.
Reviewing the clinical data of the patients, the rst manifestation of males was cognitive impairment, and females had the highest proportion of facial arm dystonia-like attacks, followed by Seizures, abnormal mental behavior, and hallucinations (phantom vision, olfactory auditory hallucinations), dizziness, headache, nausea, vomiting, autonomic symptoms, and abnormal discharge-like sensations in the head may be rare. To further con rm this difference, we need to further increase the sample size. Frequent seizures are also common, and it has been reported [7 8] that knocking out LGI protein genes can cause autosomal dominant temporal lobe epilepsy. Therefore, effective identi cation of seizures is helpful for early diagnosis of the disease. FBDS accounts for 50%, and the symptoms of non-FBDS attacks are diverse, usually focal attacks; general tonic clonic seizures are uncommon, usually appearing late in the disease. Recognizing this type of seizure with a relatively short duration may be di cult. Reasonable use of EEG is essential. Studies have shown that most of them appear sharp slow waves.
Approximately 31.70% of patients in this study rst showed FBDS, 67.50% EEG showed slow waves, focal discharges, temporal origins were more common, and even rare three-phase waves and the whole brain low voltage; 10.00% showed fast Increased activity; 10.00% normal EEG; 2.50% manifested as sharp wave delivery; it has been reported [9] 60% of patients with head MRI showed bilateral temporal lobe high signal, 40% is abnormal signal in one hippocampus or normal, our The report is generally consistent with the above.
It has been reported in laboratory tests [10] that serum hyponatremia accounts for about 50%; patients with hyponatremia in this article account for 73.17%, with a minimum of 115.4 mmol/L, and hyponatremia is higher than previous reports. Report [11] shows that serum LGI1 antibody is easier to detect than CSF LGI1 antibody. The double positives of blood and cerebrospinal uid antibodies in this article are greater than those of pure blood positive, but there are no patients with positive cerebrospinal uid positive in forty-one patients. According to the report, the serum LGI1 antibody is easier to detect than CSF LGI1 antibody. The speci c mechanism still needs further study. CSF examination in patients with LGI1-associated encephalitis often indicates normal or only mild to moderate protein, increased cell count, and few intrathecal IgG synthesis [12]. In this study, we found that the pressure of lumbar puncture was normal for the rst admission and the pressure increased higher than pressure reduction; protein is signi cantly higher than white blood cells. In this article, forty-one patients were found to have abnormal tumor markers, but no tumor was found. This is consistent with previous reports. There was no signi cant difference in the prognosis of thirty-ve patients regardless of hormones, globulin or a combination of the two. Patients with seizures, especially FBDS combined with other types of epilepsy, when use immunotherapy,combined use of antiepileptic drugs is bene cial to patients.

Conclusions
Middle-aged and elderly patients have the above-mentioned clinical manifestations and hyponatremia.
Regardless of whether there is abnormal signal on the cranial MRI, this disease should be considered, and the examination of cerebrospinal uid LGI 1 antibody and electroencephalogram should be improved. Anti-LGI 1 encephalitis should be treated with immunotherapy in time to prevent recurrence, and attention should be paid to distinguish it from other autoimmune encephalitis. Proper identi cation of early-onset seizures is helpful for clinical diagnosis. Positive serum and/or cerebrospinal uid LGI1 antibody is the main basis for diagnosis. Immunotherapy for the disease is effective, and the overall prognosis is good, and some patients may have residual memory impairment. Abbreviations CASPR2: contactin-associated protein-like2; CSF: cerebrospinal uid; EEG: electroencephalogram; LGI1: leucine-rich glioma-inactivated 1; MRI: magnetic resonance imaging;

Declarations
Ethics approval and consent to participate The study was approved by the First Hospital of Jilin University. Written consent was obtained from each participant.

Consent for publication
Not applicable.