Investigation Of The Etiology Of Dizziness And Correlation Of 5-HTR6 Gene Polymorphism With Vestibular Migraine

Part Ⅰ Clinical investigation of the etiology of dizziness in neurology departmentObjective:This paper summarizes the clinical characteristics of dizziness syndrome in neurology department and clarify the classification and stratification of etiology so as to provide reference for the accurate diagnosis and treatment of current dizziness syndromeMethods:1.A total of 1532 patients with dizziness who met the inclusion criteria and exclusion criteria were enrolled and treated in the neurology department of the sixth medical center of PLA general hospital and in an outpatient department of an expert team during June 1st,2015 and May 31st,2017.According to the current internationally recognized disease diagnostic criteria,relevant guidelines and expert consensus,the selected cases were investigated,examined and diagnosed by unified clinical research questionnaire2.The obtained data were processed with SPSS 20.0 statistical software,and the clinical characteristics,etiological composition ratio as well as etiological stratification characteristics of the cases in this group were summarized.Results:1.A total of 1 532 patients were included in this study,aged 9～91 years,with an average age of 53.78±14.05 years.The ratio of male to female is 1:1.65(578 males and 954 females).Among them,there were more males than females in the<20 years old group,and female patients accounted for a large proportion in the rest groups.2.Stratified by the age of patients:the peak age of dizziness consultation was 50～59 years old,followed by 40～49 years old and 60～69 years old.Patients over 40 years old accounted for 83.55%of the patients with dizziness.The number and percentage of patients are in turn:13 cases(0.85%)in the<20 years old group,64 cases(4.18%)in the 20 to 29 years old group,175 cases(11.42%)in the 30 to 39 years old group,307 cases(20.04%)in the 40 to 49 years old group,338 cases(22.06%)in the 50 to 59 years old group,306 cases(19.97%)in the 60 to 69 years old group,208 cases(13.58%)in the 70 to 79 years old group,and 121 cases(7.90%)in the≥80 years old group3.By comparing the age distribution of patients of different genders,the overall results showed that there were differences in the age distribution of patients of different genders with dizziness(χ2=15.38,P=0.032),and the majority of the patients were males aged 60-69 and females aged 50-59.4.As a whole,this study is divided into four categories according to the classification of diseases:peripheral vestibular systemic diseases,central vestibular systemic diseases,non-vestibular systemic diseases and unexplained dizziness.(1)The peripheral vestibular diseases accounted for 38.38%:BPPV(29.05%),VN(3.98%),MD(3.26%),Sudden deafness accompanied by vertigo(1.70%),Vestibular syndrome(0.26%),Hunt syndrome(0.07%),Acoustic neuroma(0.07%);(2)The central vestibular diseases accounted for 34.14%:VM(15.60%),PCI(8.03%),Migraine with vertigo(2.15%),Cerebral hemorrhage(1.04%),Parkinson’s syndrome(0.98%),Epilepsy(0.52%),Alzheimer disease(0.52%),Multiple system atrophy(0.52%),Amyotrophic lateral sclerosis(0.46%),Subclavian artery steal syndrome(0.46%),Presyncope(0.39%),Subarachnoid hemorrhage(0.39%),Paraneoplastic nervous system syndrome(0.39%),Essential tremor(0.33%),Hereditary ataxia(0.33%),Central nervous system demyelinating disease(0.33%),Corpus callosum syndrome(0.26%),Brain metastases(0.20%),Creutzfeldt-Jacob disease(0.13%),Polycranial neuritis occurred(0.13%),Syringomyelia(0.13%),Brain stem encephalitis(0.13%),Ependymoma(0.13%),Wernike encephalopathy(0.13%),PCNSL(0.13%),Craniocervical junction malformation(0.13%),Benign cranial high pressure(0.07%),Fatal familial insomnia(0.07%),and Basilar artery dilatation(0.07%);(3)Non-vestibular systemic dizziness accounted for 24.48%:PPPD(17.82%),cardiovascular dizziness(3.46%),drug-derived(1.50%),CO poisoning(0.26%),anemia(0.20%),and other causes(1.24%);(4)Unexplained dizziness accounted for 3.00%.5.Etiological analysis by age stratification:except for the group≥80 years old,BPPV was the first cause of dizziness in all the other groups,while PCI was the first cause of dizziness in the group over 80 years old.There are different characteristics in the proportion of causes of dizziness in different age groups.The number of etiological cases in different age groups was as following:In the<20 years old group,there were 7 cases of BPPV,4 cases of migraine with vertigo,1 case of VM,and 1 case of unknown etiology;In the 20～29 year old group,there were 16 cases of BPPV,13 cases of PPPD,12 cases of migraine with vertigo,and 8 cases of VM;In the group of 30～39 years old,there were 38 cases of BPPV,34 cases of PPPD,23 cases of VM,19 cases of MD;In the group from 40 to 49 years old,there were 70 cases of BPPV,64 cases of PPPD,60 cases of VM,and 24 cases of MD and VN in joint fourth place.There were 92 cases of BPPV,80 cases of PPPD,67 cases of VM and 12 cases of PCI;In the 50～59 years old group,there were 108 cases of BPPV,53 cases of PPPD,38 cases of VM,and 27 cases of PCI;In the 70～79 year old group,there were 80 cases of BPPV,35 cases of PCI,26 cases of PPPD and 23 cases of VM;In the group over 80 years old,there were 43 cases of PCI,34 cases of BPPV,21 cases of cardiovascular dizziness,and 19 cases of VM.The number of patients with BPPV,PPPD,VM,PCI,cardiovascular disease,drug-derived disease,MD and PDS showed an increasing trend with the increase of age.Among them,PDS,sudden deafness with vertigo and cardiovascular dizziness are relatively rare before the age of 50,while MD and migraine with vertigo are relatively rare after the age of 60.6.The etiology was analyzed by gender stratification:the gender composition ratio differences of BPPV,PPPD,VM,PCI,cardiovascular dizziness and migraine with vertigo were all statistically significant(χ2=5.334,P=0.019;χ2=17.073,P<0.001;χ2=4.857,P=0.029;χ2=42.463,P<0.001;χ2=18.727,P<0.001;χ2=3.916,P=0.043).The dizziness caused by BPPV,PPPD,VM and migraine with vertigo was on the high side in women,while the dizziness caused by PCI and cardiovascular disease was on the high side in men.7.The top six common causes(BPPV,PPPD,VM,PCI,VN,cardiovascular dizziness)were analyzed by age stratification,and the age distribution of different causes was found to have their own characteristics.BPPV occurred in all age groups.In each group under 80 years old,BPPV was always the first cause of dizziness,and its peak age was between 60 and 69 years old,and 50 and 59 years old.PPPD occurred in all patients over 20 years old,and was the second cause of dizziness in all groups between 20 and 69 years old.VM occurs in all age groups,ranking the third in the cause of dizziness in each age group of 30-69 years old,and ranking the fourth in patients over 70 years old.The peak age of PPPD and VM was 50～59 years old and 40～49 years old.PCI and cardiovascular dizziness were found in patients over 30 years old and over 40 years old,respectively,and the number of patients visited the clinic tended to increase with age,ranking first and third among the causes of dizziness respectively in the≥80 years old group.VN mainly occurred between the ages of 20 to 69 years old,ranking fourth in the age group of 20 to 49 years old,rising to fifth in the two age groups of 50 to 69 years old,and its peak age was in the age group of 40 to 49 years old.8.Number of visits:385 patients(25.13%)received the first visit,92 patients(6.01%)received 2 to 3 visits,1055 patients(68.86%)received more than 3 visits,and the number of first visits:multiple visits=1:2.98.9.Previous medical diagnosis and self-diagnosis:cerebral insufficiency/vertebrobasilar artery insufficiency(22.06%),cervical spondylosis/cervical vertigo(18.02%),vascular stenosis/plaque(11.95%),unclear(15.21%),others(32.77%).Conclusion:1.Peripheral vestibular diseases is the most common cause of dizziness,among which BPPV is the first cause of overall dizziness.Central vestibular disorders were the second most common cause,and VM and PCI ranked the third and fourth overall.PPPD belongs to non-vestibular dizziness and ranks the second among the overall causes.Its high incidence and low diagnosis rate require urgent attention.2.A considerable number of CNS difficult and rare diseases are characterized by dizziness as the first symptom and complicated diseases.Therefore,it is necessary to strengthen understanding,summarize and discriminate.3.The peak age of dizziness consultation was 50～59 years old,followed by 40～49 years old and 60～69 years old.Men aged 60 to 69 and women aged 50 to 59 years old were the main incidence of dizziness.The proportion of cause of dizziness has its own characteristics in each age group.Except for the group over 80 years old,BPPV was the first cause of dizziness in other groups,while PCI was the first cause of dizziness in the group over 80 years old.4.Dizziness is dominated by women.The gender difference of six causes of dizziness was prominent.BPPV,PPPD,VM and migraine with vertigo were mainly female,while PCI and cardiovascular disease dizziness were mostly male.5.Dizziness is one of the important symptoms in outpatient department of neurology repeatedly.It is common for doctors and patients to misunderstand"cerebral insufficiency" and "cervical vertigo".Part Ⅱ correlation of 5-HTR6 gene polymorphism with vestibular migraineObjective:To investigate the level of 5-HT in patients with vestibular migraine,evaluate the status of vestibular function,and explore the correlation of 5-HTR6 gene polymorphism with VM,so as to provide theoretical basis for the study of genetic polymorphism of VM.Methods:1.A total of 92 VM patients who met the inclusion and exclusion criteria in neurology department of our hospital during January 1st,2016 and January 1st,2018 were enrolled as the observation group,and 100 healthy people receiving physical examinations during the same period were enrolled as the control group,and general clinical information of the two groups were collected2.Methods:(1)Detect levels of 5-HT:The level of 5-HT in plasma were determined by high performance liquid chromatography(Gilson,France).(2)Detect the vestibular function test indexes:caloric test(<0.025Hz),head-shaking test(1～2Hz),and vestibular autorotation test(2～6Hz).(3)Selection of research sites:The full sequence of the 5-HTR6 gene was found using the US NCBI website platform(http://www.ncbi.nlm.nih.gov/).Then,through Haploview software,the pairwise labeling method was used for screening.Finally,in the labeling SNPs screening software Tagger,one of 5-HTR6 genes were selected.Polymorphic loci:rs770963777(C/T).(4)DNA extraction:Extraction was performed according to the instructions of the whole blood genomic DNA extraction Kit(BioTeke Corporation).(5)Determination of DNA concentration:The DNA concentration was determined by using ultramicro nucleic acid analyzer.(6)Single Nucleotide Polymorphism(SNP)Genotyping:Thermo Fisher Scientific’s TaqMan Single nucleotide polymorphism(SNP)Genotyping kit was used for genotyping and the results were obtained.3.Statistical methods:SPSS20.0 statistical software was used for statistical analysis of the data.Results:1.Comparisons of 5-HT level between the two groups:The observation group had a lower level of 5-HT than the control group(t=3.831,P=0.037),and the difference was statistically significant(P<0.05).2.Comparison of the vestibular function test between the two groups:The abnormality rates of the caloric test,head-shaking test,and vestibular autorotation test were evidently higher in the observation group than those in the control group(χ2=30.231,P=0.000;χ2=80.920,P=0.000;χ2=22.381,P=0.000),and the difference was statistically significant(P<0.01).3.Genetic balance test:The actual frequency and theoretical frequency of three genotypes of 5-HTR6 polymorphisms in VM group and control group were tested.The results showed that χ2=0.29,P=0.86 in VM group and χ2=1.49,P=0.48 in control group.The distribution frequencies of 5-HTR6 rs770963777 genotypes in VM group and control group were in accordance with Hardy-Weinberg equilibrium law(P>0.05).4.Comparison of the genotype distribution frequency:The distribution frequencies of genotype CC,CT,and TT in the observation group were 63.04%,31.52%,and 5.44%,respectively,and those in the control group were 45.00%,48.00%,and 7.00%,respectively.The distribution frequency of CC genotype in VM group was significantly higher than that in control group(χ2=6.340,P=0.042),and the difference was statistically significant(P<0.05).5.Comparison of the allele distribution frequency:The distribution frequencies of C and T alleles in the observation group were 78.80%and 21.20%,respectively,and those in the control group were 69.00%and 31.00%,respectively.The distribution frequency of C allele in the VM group was significantly higher than that in the control group(χ2=4.752,P=0.029),and the difference was statistically significant(P<0.05).Conclusion:1.Low level of 5-HT is correlated with VM occurrence,which may be an effective indicator for VM clinical diagnosis,drug response monitoring,and disease prognosis and progression observation2.VM patients have both central and peripheral vestibular dysfunction,and combined with different frequency vestibular function examination technology can improve the clinical detection rate of VM3.The polymorphism of rs770963777 in 5-HTR6 gene was associated with the occurrence of VM.The CC genotype significantly increased the risk of developing VM.