Study On The Efficacy's Related Factors And The Correlation Between Cessation Of Spasms And Improvement Of Electroencephalogram In Infantile Spasms After ACTH Treatment

Infantile spasms(IS),one of the most common age-dependent epileptic encephalopathy in infancy。The average disease incidence was one in 3225 live born, With 60%being boys。Onset peaks in the first year of life,especially between 4 and 8 months。IS is characterized by a triad composed of clusters of spasms,a interictal electroencephalogram(EEG) pattern,called hypsarrhythmia and an arrest or regression of psychomotor development。More than 80%spasms is in clusters which is easily observed by parents。some times,the seizure may be very mild which are not always identified by parents as abnormal,until the symptoms of an arrest or regression of psychomotor development were very obvious,and resulting in the delay of seeing a doctor。IS has been classified into cryptogenic and symptomatic forms according to the classification of Epilepsy and Epileptic syndromes of the International League Against Epilepsy(ILAE)。IS is very difficult to cure,the prognosis is generally poor,the mortality can be as high as 20%。If these patients are not given the treatment in time,more than 90%of them will show varying degrees of regression of psychomotor development,with 50 %～60%of them subsequently developing other seizure types,and among the above,40%～60%developing the Lennox-Gastaut syndrome or other generalized seizure types,10%～32%developing focal seizure types。Most of them are belong to refractory epilepsy,and more difficult to cure。If these patients are given the treatment in time,the prognosis of IS will be obviously improved and these patients's psychomotor development can even hope to approach the normal。Untill now,there is no unite medical treat scheme to improve the prognosis,especially the intelligence for IS。IS is resistant to most conventional antiepileptic drugs(AEDs) therapy,Since Sorel et al reported that adrenocorticotropic hormone treatment successfully stopped spasms of patients with IS and improved their EEGs in 1958,Adrenocorticotropic hormone (ACTH) has been as first-line drug for IS in many countries。Nearly a half century of the use of ACTH and numerous studies of ACTH with different dosages and durations were conducted,Until now,there is still no agreement about dose,duration of treatment and the efficacy related factors using ACTH for IS are still uncertain。In the past,IS efficacy evaluation criterion was defined as the complete cessation of spasms。But the frequency of spasms counted by the parents or caregivers during the ACTH treatment is often seriously underestimated。Studies show the cessation of spasms can't prevent arrest of psychomotor development in some patients,So it is not objective and not beneficial to give accurate prediction to the efficacy according to the situation of the spasms control。Hypsarrhythmia persistence has been shown to correlate with cognitive deterioration。Some studies indicated that as long as the hypsarrhythmia exists,the brain cannot process information normally,and hypsarrhythmia persistence may have a negative influence on the developing brain and result in delay or deterioration of psychomotor development。the longer hypsarrhythmia persistence,the worse the prognosis of patients with IS。In order to increase the efficacy of ACTH treatment and look for a objective and reasonable efficacy evaluation criterion,In this study,we will study the efficacy related factors after ACTH and at the same time,we will evaluate the correlation between cessation of spasms and disappearance of hypsarrhythmia in infantile spasms after ACTH to definite a more reasonable efficacy evaluation criterion。Date and Methods1 Clinical DateFrom January 2000 to June 2007,155 infants who met IS diagnostic criteria of the ILAE were treated with ACTH in Shenzhen Children's Hospital,The inclusion criteria for this study:①Age from 0 to 12 monthes;②Before ACTH treatment,if antiepileptic drugs were ineffective within 2 weeks,ACTH was given and those drug dosages were not changed during ACTH treatment;③Patients had never been treated with ACTH or prednisolone;④CT scan of the head was made in Shenzhen Children's Hospital before treatment:⑤EEG pattern before treatment included hypsarrhythmia or modified hypsarrhythmia,a repeat video-EEG was performed after ACTH treatment in this hospital;⑥Before treatment,complete blood cell count, urinalysis,serum electrolytes,blood glucose,and metabolic studies including serum amino acids,urine amino acids and organic acids were measured,removed concomitance infection,liver and renal disfunction and immunodeficiency。81 were excluded because of they did not meet the above criteria for this study,The remaining 74 infants formed the study group with 47 boys and 24 girls;Age at onset of spasms under 3 months was in 18 patients,over 3 months was in 56 patients,treatment lag (the interval between onset of spasms and initiation of ACTH treatment) under 2 months was in 36 patients,over 2 months was in 38 patients;Age at initiation of ACTH therapy under 3 months was in 7 patients,over 3 months was in 67 patients; Having family history of epilepsy was in 10 patients,having no family history of epilepsy was in 64 patients;The symptomatic group was 49 patients and cryptogenic group was 25 patients。 2 Apparatus and method①EEG Apparatus and methodEEG Apparatus:BMSI 6000 128-channel video-EEGMethod:All video-EEGs of 3～6 hours duration including both wakefulness and sleep were recorded,synchronized with video monitoring of clinical spasms。The 19 scalp record electrodeswere applied according to the international 10-20 system referenced to the ears,one channel electrocardiogram was included。Digitally recorded EEG traces were reviewed on EEG work station or printed on papers for the subsequent analysis。All video-EEG studies were interpreted by two investigators,who were blind to the treatment assignment。The diagnostic criteria of hypsarrhythmia was based on the description by《Clinical epileptology》。②Head imaging instrument and MethodHead imaging instrument:HiSpeed Nx/ i double-deck spiral CT (American general electricity company)。Method:Routine head axial surface plain scan,thickness is 7mm,gap is 7mm, scan parameter is 120Kv,300mAs。All CT were interpreted by two investigators,who were blinded to the treatment assignment。3 Standard treatment protocolACTH:natural ACTH manufactured by First Shanghai Biochemistry Pharmaceutical limited company(25IU/ampoule 2ml)。Treatment protocol:ACTH was dissolved into 200～250ml of 5%glucose, then the mixed liquor was injected intravenously guttae in the morning at nine clock lasting more than 8 hour once a day,the daily dosage was 20～25IU for two weeks, Then it was stopped and prednisone was given orally,the daily dosage was 1.5～2mg/kg/d.then it was tapered to zero in 2～4 weeks。The ACTH treatment was completed during hospitalization,The parents or caregivers observed the patients throughout the treatment period and counted the number of spasms attacks。4 Efficacy evaluation criteriaThe treatment efficacy was evaluated at the time of 4 weeks after completion of ACTH treatment。Patients with cessation of spasms and the disappearance of hypsrrhythmia were considered as responders,Those patients with the cessation of spasms without complete disappearance of hypsrrhythmia or the continuation of spasms with a disappearance of hypsrrhythmia or both existence after 4 weeks of ACTH treatment were considered as non- responders。5 Statistic analysisThe data analysis was analyzed by SPSS 13.0。When the variable was continuous,then it was described by X±S;when the variable was count data,then X~2 test was conducted;The factors that may influence the treatment effect were statisticed by multivariate unconditional logistic regression model;The association between the improvement of hypsrrhythmia electroencephalogram and cessation of spasms was evaluated by contingency table X~2 test。P＜0.05 was considered statistically significant。Results1 EEG results of 74 patient with IS before and after ACTH treatmentEEG results of 74 patient with IS before ACTH treatment:Typical hypsarrhythmia was observed in 26 patients,modified hypsarrhythmia was observed in 48 patients; EEG results of 74 patient with IS after ACTH treatment:there were 47 patients whose hypsarrhythmia in EEG were disappeared,On the other hand,there were 27 patients whose hypsarrhythmia in EEG weren't disappeared,and Typical hypsarrhythmia was in 8 patients,modified hypsarrhythmia was in 19 patients。 2 Head CT results of 74 patient with IS before ACTH treatmentHead CT results of 74 patient with IS before ACTH treatment:Porencephaly was observed in 3(4.0%) patients,Callosal agenesis was observed in 1(1.4%) patients, Ventriculomegaly in 3(4.0%)patients,Intracranial hemorrhage in 3(4.0%)patients, Hypoxic-ischemic encephalopathy in 7(9.5%) patients,Tuberous sclerosis in 4(5.4 %) patients,Encephalatrophy in 4(5.4%) patients,Encephalomalacia in 7(9.5 %) patients,Macrogyria in 3(4.0%) patients,Brain parenchyma calcification spot in 5(6.8%) patients,Schizencephaly in 1(1.4%) patients,Exterior hydrocephaly in 4(5.4%) patients,No abnormality seen in 29(39.2%) patients。3 Clinical EffectThe overall responding rate with both spasms free and the disappearance of hypsrrhythmia was 56.8%。Responding rate in cryptogenic groups was 76%,in symptomatic groups was 46.9%,X~2=5.696,P=0.017;Responding rate in the group whose treatment lag under 2 months was 75.0%,in over 2 months group was 39.5%, X~2=9.506,P=0.002;It was 33.3%in the group whose age at onset of spasms was under 3 months,it was 64.3%in over 3 months age group,X~2=5.317,P=0.021; There were statistically significant differences about the efficacy of ACTH in groups of different etiology,age at onset of spasms and treatment lag(P was 0.017,0.002, 0.021 respectively)。In the group of age at initiation of ACTH treatment under 3 months was 42.9%,over 3 months was 58.2%,X~2=0.144,P=0.705;Responding rate in boys group was 57.4%,in girls group was 55.6%,X~2=0.025,P=0.874; Responding rate in group having family epilepsy history was 40.0%,having no familyepilepsy history group was 59.4%,X~2=1.323,P=0.250;There was no significant differentces in groups of different age at initiation ACTH treatment,the gender as well as family epilepsy history(P was 0.705,0.250,0.874 respectively). The rate of cessation of spasms was 74.3%and the rate of the disappearance of hypsarrhythmia in EEG was 63.5%after ACTH treatment。 4 Multivariate Unconditional Logistic Regression Analysis.The 6 factors(etiology,the treatment lag,age at onset,age at ACTH treatment, family epilepsy history and gender) were all put into multivariate unconditional logistic regression model,When the treatment lag and the etiology were entered into the equation of the model in turn,they were proved to be significantly different(P was 0.029,0.004 respectively)。The odds ratio was 4.564,3.542 respectively;95 %CI was 1.623～12.840,1.131～11.094 respectively。But age at onset,age at ACTH treatment,family epilepsy history and gender were proved not to be significantly different(P＞0.05)。5 Correlation Study between Cessation of Spasms and Improvement of Hypsrrhythmia in ElectroencephalogramThere were some correlation between cessation of spasms and improvement of hypsrrhythmia electroencephalogram in infantile spasms after ACTH treatment,X2 =15.264,P=0.000。r was 0.44。there are positive correlation between cessation of spasms and disappearance of hypsrrhythmia in electroencephalogram in infantile spasms after ACTH treatment,But the relationship is not very close。In the group whose hypsarrhythmia in EEG was disappeared,the cessation of spasms occurred in 89.4%patients。On the other hand,In the group of spasm cessation,the disappearance of hypsarrhythmia in EEG occurred in 76.4%patients after ACTH treatment。6 Etiology Analysis in Symptomatic GroupAbout etiologies of the symptomatic group,the prenatal factors was 61.2%(30/49), perinatal factors was 24.5%(12/49),postnatal factors was 14.3%(7/49)。Conclusions1 The total responding rate of IS after ACTH treatment is 56.8%,with both cessation of clinical spasms and disappearance of hypsarrhythmia in EEG,which proved that clinical spasms and hypsarrhythmia in EEG had been improved greatly。which is proved that low-dose(20～25IU/d) short-duration(2 weeks) ACTH treatment protocol is effective。2 From this study,we can conclude that the efficacy related factors of IS after ACTH treatment is heavily dependent on etiology and treatment lago But gender,age at onset,age at initiation ACTH treatment and family epilepsy history had not association with the efficacy after ACTH treatment。The efficacy in these patients who was in cryptogenic group or in treatment lag under 2 monthsis significantly better than in those who was in symptomatic group or in treatment lag over 2 months group。3 From this study,we can conclude that prenatal and perinatal factors are more important in the IS etiology,which reveal that it is important to prevent these factors to cut down the morbidity of IS。4 This study shows that the cessation of spasms can't reflect the situation of the disappearance of hypsarrhythmia absolutely,Changes in EEG such as resolution of of hypsarrhythmia,as well as the cessation of spasms should be considered as one of the most important indicators of efficacy in IS after ACTH treatment。...