Clinic And MRI Study Of Enterovirus71 Hand Foot Mouth Disease With Long-term Followup Study

Hand foot mouth disease(HFMD)is an acute infectious disease caused by the enterovirus,and charactized by rash and hepes on hand,foot,mouth and other parts as Clinical manifestations.Total more than 20 kinds of enteroviruses can cause HFMD.The most common Pthogents are(Coxasckievirus A16,CVA16)and(Enterovirus 71,EV71).Children under 5 years old are more vulnerable to be infected.Disease course usually lasts for a few days or up to one week;most of infected children can recover completely without sequelae.However,a few of them infected by EV71,may complicated with central nervous system complications,such as aseptic meningitis,brainstem encephalitis(BE),small encephalitis,poliomyelitis.The most severe and dangerous complication was BE.There were serveral outbreaks or pandemy of HFMD in many countries and regions all over the world.The first outbroke in mainland of China was in 2008,National monitoring report of 2008 said,totally there were 488,955 cases,including 1165 severe/critical cases and 126 cases of death.Report of 2009 said,totally there were 1155525 cases,including 353 cases of death.While compared with 2008,the incidence increased by 35%and mortality increased by 80%.In 2010 another pandemic outbreak of HMFD,reporting 1,774,669 cases,905 cases of death.While compared with 2009,the incidence increased by 52.81%and mortality increased by 54.89%.Report of 2012 said,totally there were 2,168,737 cases,including 567 cases of death.Report of 2014 said,totally there were 2,778,861 cases,including 501cases of death.Severe cases and deaths mainly were caused by EV71,and combined with central nervous system complications.The most severe and dangerous complication is BE.Because BE destroyied the regulating center of respiratory circulation in the brainstem,causing neurogenic pulmonary edema and respiratory and circulatory dysfunction etc.Therefore,early diagnosis EV71 HFMD related BE and overall assessment are extremely important.Although there were many reports on this disease,regard limited in sample size and imperfect inspection program failed to unite depth analysis of clinical manifestations and MRI compared.There were no MRI classification and quantitative research of major lesions of BE,which could improve diagnosis of the disease,clinical assessment,treatment and lower mortality is extremely important.Eacher year,large number of children with severe type of EV71 HFMD discharged,and they returned to their family and backed to school.However,whether they have neurological sequelae or decrease of cognitive function,there were on such research from reported from mainland China.China's Taiwan scholars carried out long-term follow-up study of children with severe type EV71 HFMD,found a few can have neurological sequelae and long-term cognitive defect.However,few studies on this aspect from mainland China,so it is extremely necessary to conduct a long-term clinical and radiological study on EV71 HFMD with BE complication,in order to work out whether there are delayed neurological development and cognitition defect.This can provide valuable information for early clinical treatment of sick children.Chapter 1:Clinic and MRI Associated Study of EV71 Hand Foot Mouth Disease related Brainstem EcephalitisObjective:to achieve early diagnosis of EV71 HFMD related brainstem encephalitis(BE),and deepen understanding of the central nervous system(CNS)damage,so a study to assess the disease from clinical and radiology aspects was designed and conducted,in order to improve the diagnostic level and clinic application value.Method:Clinical data and neuroimaging of 91 pediatric patients with EV71 HFMD related BE were retrospectively analyzed,were hospitalized in PICU(Peadiatric Intensive Care Unit)of Shenzhen Children's Hospital(Shenzhen,Guangdong,China)between March 1st,20110 to October 31st,2012,and were analyzed retrospectively.Clinical scoring method:1 point for each of the following symptoms:startle,muscle tremor,ocular paralysis,dysphagia,facial paralysis.MRI scoring method:1 point for one involved region(Pons,medulla oblongata,midbrain,cerebellar dentate nucleus,thalamus),1 point for hemarrage and malcia lesion.Hemarrage was juded according to MRI signal.Two experienced pediatric radiologists analyzed the image data and gave a score.Aaverage scores were calculated.Statistical methods independent sample T-test was adoptted to test MRI results,positive and negative groups,MRI study time between enhanced group and non-enhanced group.Enhanced rate was the ratio between enhance caes number and all case number during the same period.Result:1.EV71 HFMD related BE often occured in young children,average age was 2.6(�1.9)years,and was more comman in male.Average temperature on the day of admission was(37.72�0.92)?.The main clinical manifestations were fever,rash on hand,foot,mouth,and buttocks,herpes,or angina herpes.Early manifestations of nervous system involvement were startle,tremors(n=65,71%),cranial nerve(?????????????cranial nerves involvement),altered mental status ranking from drowsiness,confusion,drowsiness,coma light to coma,often accompanied by respiratory and circulatory dysfunction such as shortness of breath,tachycardia.2.MRI findings:main lesion of EV71 related BE located at the posterior junction region between the pons and medulla oblongata,a vertically-shaped lesions;it may also extend up and down,involving in the medulla oblongata,midbrain,thalamus,cerebellum dentate nucleus,and even spinal cord.MRI showed the lesions were iso-or hypointensity on T1WI and ignal,iso-or hyperintensity on T2WI.3.The MRI enhancement of main lesion of EV71 related BE was founded in ther early phase of the disease course,during the first 4th to 10th day.During perk enhancement rate time between the 6th to 8th day,enhancement rate reached 75%,whild average enhacement rate was 48%.Additionally,enhanced MRI can reveal the lesion missed by plain MRI scan.4,MRI score and clinical scoreMRI score:0 points in 21 cases,1 points 13 in cases,2 points in 26 cases,21 cases of 3 points,4 points in 10 cases,Clinical score:3 points and 19 cases,4 points and 15 cases,5 points and 25 cases,6 points and 22 cases,7 in 10 cases.Spearman correlation analysis of MRI score and clinical score,r=0.753,p=0.0057.The result indicated that the greater involvement of brain,the severer clinical manifestations.Conclusion:1.EV71 HFMD related BE oftern occurred in young children(2.6�1.9)years;male to female ratio was 1.46.2.Early manifestation of nervous system involvements included startle,remors,and cranial nerve involvement(46%).3.The main lesion of EV71 related BE located at the posterior junction region between the pons and medulla oblongata,with the extent of disease exacerbations can be increased.MRI showed the lesions were iso-or hypointensity on T1WI and ignal,iso-or hyperintensity on T2WI.4.The value of enhanced MRI was that it can reveal the lesion missed by plain MRI scan.5.Spearman correlation analysis of MRI score and clinical score,r=0.753,p=0.0057.The result indicated that the greater involvement of brain,the more severe clinical manifestations,which provide valuable information for clinic diagnosis and treatment manage.Chapter 2:MRI Classification of EV71 Hand Foot Mouth Disease related Brainstem EcephalitisObjective:Previous study revealed that the main lesion of EV71 HFMD related BE located at the posterior junction region between the pons and medulla oblongata.How to enhance the MRI detection rate of this lesion,and to improve thecomprehensive understanding?In order to improve radiology diagnosis level of EV71 HFMD related BE.Methods:Clinical data and neuroimaging of 91 pediatric patients with EV71 HFMD related BE,were hospitalized in PICU(Peadiatric Intensive Care Unit)of Shenzhen Children's Hospital(Shenzhen,Guangdong,China)between March 1st,2010 to October 31st,were retrospectively analyzed.31 patients were randomly called back for clinical assessment and MRI scan during December 2013 to August 2014.MRI stages:acute stage wasdefined as from the first day to the 14th day of the course.Convalescence stage,after the 14 day till discharged day.Postmortem stage.two special cases,perform MRI scan after death after the parents signed written consent brain MRI.Long-tern follow-up study,the average follow-up period was 34.2 months(25 to 48 months)from onset to follow-up MRI study.MRI signal classification method:MRI signal alteration on T1WI,T2WI and post contrast T1WI were evaluated for the classification of acute stage,recovery stage MRI fings.MRI signal alteration on T1WI,T2WI and FLAIR were evaluated for the classification of Long-term follow-up MRI studyResult:1.EV71 HFMD related BE located at the posterior junction region between the pons and medulla oblongata.2.MRI classification:Acute stage:76 cases were classified in 6 types.Type?�? MRI results were positive,and type Type? were negative in 20 caese.Type? Hypointensive on T1WI,hyperintensive on T2WI,without enhancement,25 cases,the most common type.Type? Iso-or Hypointensive on T1WI,iso-or hyperintensive on T2WI,with mild or moderate enhancement,15 cases,the second most common type.Type? No abnormanlity on T1WI and T2WI,with mild or moderate enhancement,10 cases.Type? Isopointensive on T1WI,hypointensive on T2WI,with mild or moderate enhancement,4cases.Type? whole brainstem involved,hypointensive on T1WI,hyperintensive on T2WI,without enhancement,4 cases.There was neurogenic pumlmonary edema in these cases.Type? negative on MRI,20 cases.Convalescence stage,13 cases,3 types.Type A,hypointensive on T1WI,hyperintensive on T2WI,without enhancement,4 cases.Type B,negative on MRI,9 cases.Postmortem stage,the whole brainstem involved,presenting as sewlling,hemorrhage and edema.Long-term follow-up study:31 cases were classified in 3 types.Type I hypointensive on T1WI,hyperintensive on T2WI and FLAIR,indicating as gliosis,Type II hypointensive on T1WI and FLAIR,hyperintensive on T2WI,indicating malacia,2 cases.These 2 patients had severe respiratory dysfunction,irregular breathing or apnea at night.Type ?,MRI negative in 26 cases with good prognosis.Conclusion:1.EV71 HFMD related BE located at the posterior junction region between the pons and medulla oblongata.2.There were three stages,acute stage,convalescence stage,postmortem stage and Long-term follow-up stage.There were 6 types in actue stage,2 types in convalescence stage.In postmortem stage,the whole brainstem involved,presenting as sewlling,hemorrhage and edema.In long-term follow-up stage,the primary lesion could be gliosis or malacia.3.MRI Classification of EV71 HFMD related BE could help to deepen the understanding of the disease and improve radiology diagnosis level,lower the misdiagnosis.Chapter 3:MRI signal intensity study of EV71 Hand Foot Mouth Disease related Brainstem EcephalitisObjective:Based on the MRI classification of EV71 HFMD related BE,by using the Medflovan software to analyze the MRI signal intensity of primary lesion in brainstem,to achive the quantitative analysis and explore the discipline,for better clinical evaluation and treatment of the disease.Methods:Based on MRI classification on Charpter 2,the most common type of EV 71 HFMD related BE in acute stage,and all cases in convalesece stage,and healthy controls were introduced into the study.There were three groups,Group 1,25 cases of Type ? at acute stage,Group 2 at covalesence stage 13 cases,Group 3 healthy controls 25 cases.MRI signal intensity analysis:1 MRI image analysis and image export.2 Medflovan softwere analyze,1)Trace Contour Region;2)Segmentation of brainstem encephalitis;3)Plot Histograms of MRI signal.Statistical analysis:average T1 and T2 signal intensity of ROI in each case from 3 groups were recorded.Using One Way Anova test difference among the three groups,if P<0.05,the difference was considered as having statistical significance.SPSS version 21.0(IBM,Chicago,Illinois)were used analyzed.Result:1.T1 signal intensity:Group 1 average intensity was 47.98(�4.88):Group 2 average intensity was 53.66(�3.06),Group 3 average intensity was 65.15(�3.67).T2 signal intensity:Group 1 average intensity was 90.54(�9.19):Group 2 average intensity was 85.13(�32.64),Group 3 average intensity was 55.29(�3.42).Stastistical analysis:For T1 signal intensity,there were significant differences between group 1 and group 2,group 2 and group 3,group 1 and group 3,all with statistical meaning.For T2 signal intensity,there are significant differences between group 2 and group 3,group 1 and group 3,all with statistical meaning.Conclusion:1.T1 signal intensity,there were significant differences among 3 groups with statistical meaning.For T2 signal intensity,there were significant differences between group 2 and group 3,group 1 and group 3,all with statistical meaning.2.For T1 signal intensity,the mean value gradually increased from acute to convalescent stage group,to healthy control group.T2 mean value intensity gradually decreased from acute to convalescent stage group,to healthy control group.By monitoring dynamic changes of T1 and T2 signal intensity can provide information about the development of the disease.Chapter 4:Long-term follow-up study of EV71 Hand Foot Mouth Disease related Brainstem Ecephalitis in children.Objective:Each year a large number of severe/critical EV71 HFMD related BE children were discharged,backed to the family return to school.However,whether there was neurological sequelae of these children,cognitive function defector were still unknown.These could be both medical problem and social issues,and worthy of further study.This chapter conducted long-term follow-up study of EV71 HFMD related BE in children,including clinic and MRI study,intelligence assessments,to achive comprehensive understanding of the patients' situation and prognosis of children with cognitive function.Method:31 patients were randomly called back for clinical assessment,MRI scan,and intelligence assessments during December 2013 to August 2014.By adopting Mei-Chih Huang classification methods:(1)encephalitis phase(? Stage):(2)of the autonomic nervous dysfunction phase(?a period):(3)pulmonary edema phase(?b period):Intelligence test:children aged 4 to 6 years old,used Wechsler children intelligence tests(Chinese Version),elder than 6 years,used Wechsler Intelligence Scale for Children(fourth edition).Statistical analysis,the data was normal distribution with homogeneity of variance count data,comparision of three groups were maded by using variance analysis,for comparison between groups using disaggregated data x2 test,P<0.05 was considered statistically significant.In this study,SPSS21.0 was used for statistical analysis.Method:Of 31 patients,initial study showed that 31 cases' MRI were positive,followup study showed that 5 caes' MRI were positive(with neurogical sequela).The neurogical sequel included:right upper limb muscle strength grade IV,respiratory dysfunction,irregular breathing or apnea at night,can not sneeze,fuzzy sound.Verbal IQ scores:? phase 93.1�12.7,?a phase 86.5�21.4,IIIbphase82.3�9.5 Full scale IQ scores:? phase 98.6� 10.6,?a phase 4 91.3� 17,?b phase 85.2�8IQ<85 point n(%),? phase 2(21%),?a phase 3(38%),?b phase 3(43%)Conclusion:1.The clinical symptoms of the disease in children with EV71 HFMD related BE more severe,the higher the chances of long-term neurological sequelae,the higher the positive rate of MRI.2.Those brain stem lesions were not completely absorbed,which revealed by longterm follow-up study,had cognitive impairment or neurological sequelae.3.more severe clinical severity,lower scores of language and full scale IQ scores,higher percentage of IQ<85 points,but the difference was not statistically significant(P>IQ 0.05)...