Clinical Characteristics Analysis Of Late-onset Anti-N-methyl-D-aspartate Receptor Encephalitis

Background and objectiveIn 2005,Vitaliani et al.reported that patients with ovarian teratoma had mental symptoms,seizures,central hypoventilation and other neurological symptoms,considering that the patient’s symptoms were paraneoplastic syndrome(PNS)caused by ovarian teratoma.In 2007,Dalmau et al.found that cerebrospinal fluid(CSF)or serum antibodies in these patients bind specifically to the N-methyl-D-aspartate receptor(NMDAR)on the postsynaptic membrane of hippocampal neurons,demonstrating the presence of NMDAR antigens and defining the concept of anti-NMDAR encephalitis for the first time.China’s first case of anti-NMDAR encephalitis was reported by Xu Chunling of Capital Medical University in 2010.The anti-NMDAR encephalitis is an autoantibody-mediated autoimmune disease.The anti-NMDAR antibody could specifically bind the NMDAR on postsynaptic membrane of neurons,mediate NMDAR internalization,reduce the density of NMDAR on postsynaptic membrane,and affect synaptic plasticity and signal transduction between neurons.Anti-NMDAR encephalitis is the most common autoimmune encephalitis(AE),most commonly in young women,ranging from 2 months to 85 years and with a median age of 21 years.Its diverse clinical manifestations could be manifested as mental symptoms,seizures,disturbance of consciousness,cognitive decline,motor disorders,autonomic nervous system dysfunction and so on.Anti-NMDAR encephalitis is more common in children and young people,elderly patients are rare.38 percent of patients with anti-NMDAR encephalitis had tumors,96 percent of which were teratomas,while those with non-teratoma tumors were mostly elderly.Moreover,it has been reported that late-onset anti-NMDAR encephalitis in patients≥45 years old have clinical characteristics different from those of early-onset patients,suggesting that elderly patients may have unique clinical characteristics.Female menopause is generally 49-50 years old.Postmenopausal hormone levels will have an impact on the immune system,which may be related to clinical characteristics of late-onset autoimmune disease.In other studies of late-onset autoimmune diseases,such as multiple sclerosis,systemic lupus erythematosus,neuromyelitis optica spectrum disorders,age criteria for late-onset patients are defined as age≥50 years.Therefore,this study set the age standard for patients with late-onset anti-NMDAR encephalitis as age≥50 years old,compared and analyzed the clinical data of patients with late-onset and early-onset anti-NMDAR encephalitis,and explained the clinical characteristics of late-onset anti-NMDAR encephalitis.Materials and MethodsThis study collected clinical data of patients diagnosed with anti-NMDAR encephalitis from January 1,2010 to May 1,2019 in the First Affiliated Hospital of Zhengzhou University(excluding patients under 18 years old).All patients met the diagnostic criteria of anti-NMDAR encephalitis:Graus and Dalmau criteria(2016)and consensus of Chinese experts in the diagnosis and treatment of autoimmune encephalitis(2017).The patients diagnosed with anti-NMDAR encephalitis were divided into late-onset group(≧50 years)and early-onset group(18-49 years)according to the age of onset.This study summarizes the clinical characteristics ofpatients in the late-onset group,and compared the differences between the late-onset group and the early-onset group in clinical manifestations,magnetic resonance imaging(MRI),cerebrospinal fluid,treatment and prognosis[evaluate the prognosis of patients with modified rankin score(mRS)at discharge,mRS=0-2 score is good prognosis,mRS>2 score is poor prognosis].ResultsA total of 110 patients with anti-NMDAR encephalitis were collected,52 in men(47%)and 58 in women(53%).110 patients were divided into two groups,18 in the late-onset group(16%)and 92 in the early-onset group(84%).Among the 18 patients with anti-NMDAR encephalitis in the late-onset group,11(61%)were male and 7(39%)were female with an age range of 50-84 years and an average age of 59.5 years.Nine cases(50%)had prodromal symptoms,mainly including headache,dizziness,fever,cough,nausea and vomiting.The common first symptoms were mental and behavioral abnormalities in 9 cases(50%)and seizures in 5 cases(28%).The main symptoms in the course of the disease were mental and behavioral abnormalities in 14 cases(78%),decreased consciousness in 13 cases(72%),autonomic dysfunction in 13 cases(72%),seizures in 9 cases(50%),dyskinesia in 9 cases(50%),and memory loss in 7 cases(39%).Seventeen patients in the late-onset group had completed the cranial magnetic resonance examination,and nine of them had inflammatory lesions of the brain parenchyma.The lesions were located in the insula lobe,frontal lobe,temporal lobe,hippocampus,thalamus,parietal lobe,occipital lobe,meninges,basal ganglia and so on.A total of 8 cases of limbic system(including temporal lobe,insula lobe,hippocampus,cingulate gyrus,etc.).All 18 patients underwent cerebrospinal fluid examination,and CSF pressure increased(>180mmH2O)in 5 patients(28%).Of the 18 patients,17(94%)had abnormal CSF test results and 14(78%)had elevated CSF leukocytes,of which 10(55%)were slightly elevated.Of the 18 patients,15(83%)had elevated proportion of CSF lymphocytes and 10(56%)had elevated CSF proteins.Cerebrospinal fluid protein electrophoresis was performed in 15 patients,of which 5(33%)had positive oligoclonal bands and 11(73%)had elevated CSF intrathecal IgG synthesis rates.Seventeen cases were tested for cerebrospinal fluid virology and were positive in 4 cases(24%).Herpes simplex virus(HSV)type I IgG was positive in 3 cases.Cerebrospinal fluid anti-NMDAR antibodies were positive in 18 patients.A total of 13 patients were tested for anti-NMDAR antibodies,of which 5(38%)were positive.All 8 patients tested were negative for serum anti-neuronal intracellular antigen antibody(anti-Hu,Ri,Yo,CV2,Ma2,Amphiphsin).Of the 18 patients,4(22%)had a tumor,including 1 left adrenal adenoma,1 lymphoma,1 meningioma,and 1 small cell carcinoma of the gallbladder.10 patients(56%)had a mRS=5 in the course of the disease.11 patients(61%)needed ICU support because of their severe condition.The median time from onset to admission was 17.5 days,the median time from onset to diagnosis was 27 days,and the median time from onset to receive immunotherapy was 27 days.17 patients received first-line immunotherapy.11 patients(65%)were combined with glucocorticoid,intravenous immunoglobulin or plasma exchange,of whom nine(82%)patients were combined with intravenous immunoglobulin and glucocorticoids.The median time of hospitalization was 28 days.12 patients(67%)had a good prognosis(mRS=0-2 at discharge)and 4 patients(22.2%)had a relapse.Comparisons between the late-onset group and the early-onset group in patients with anti-NMDAR encephalitis are as follows.The male proportion was 61%in the late-onset group and 45%in the early-onset group,and the difference was not statistically significant(P=0.198).In terms of clinical manifestations,the proportion of autonomic dysfunction in the late-onset group was higher than that in the early-onset group,and the difference was statistically significant(72%vs 45%,P=0.032).In terms of cranial magnetic resonance examination,the overall positive rate of the two groups was 50%,and the lesions were mainly located in the limbic system(66%).The cranial magnetic resonance of the late-onset group suggested that the proportion of insular lobe lesions was higher than that of the early-onset group(67%vs 27%,P=0.047).In CSF examination,the proportion of increased cerebrospinal fluid protein in late-onset group was higher than that in early-onset group(56%vs 28%,P=0.023),and proportion of elevated CSF intrathecal IgG synthesis rates in late-onset group was higher than that in early-onset group(73%vs 44%,P=0.041),besides,the positive rate of cerebrospinal fluid virology in late-onset group was higher than that in early-onset group(24%vs 5%,P=0.028).Between the two groups,there was no significant difference in the proportion of complicated tumors,but no late-onset anti-NMDAR encephalitis had a teratoma compared with all early-onset patients had a teratoma(P=0.001).Conclusion1.Late-onset anti-NMDAR encephalitis are more prone to insular lobe lesions in MRI.2.Late-onset anti-NMDAR encephalitis are more prone to inflammatory reaction in CSF.3.Late-onset anti-NMDAR encephalitis are more prone to autonomic dysfunction.4.The pathogenesis of late-onset Anti-NMDAR encephalitis may not be associated with teratoma.