Effects of ACTH Treatment in Infantile Spasm; Insights from Electrocardiography and Echocardiography

doi:10.21203/rs.3.rs-1689795/v2

Objective

Infantile spasms (ISs) are a group of epileptic disorders, which represents the most frequent type of epilepsy in the first year of life. The most effective treatment for IS is adrenocorticotropic hormone (ACTH). We hypothesized that ACTH treatment might have cardiac adverse effects. This study aimed to evaluate the effects of ACTH treatment on the heart muscle and/or arrhythmia risk in patients with IS.

Methods

Twenty-four patients with IS and 24 healthy children (control group) participated in the study. Electroencephalography (EEG), electrocardiography (ECG), and transthoracic echocardiography were studied during treatment, and evaluations were made at 0-2-4 and 6th months of the treatment.

Results

None of the patients had significant tachycardia or bradycardia when compared with the healthy group, or during treatment. On the other hand, values of the PR, QRS, QT, tp/te, tpte/QT, and tpte/QTc values were significantly increased compared with either pretreatment values or each other, which indicated an increased arrhythmia risk in the patient group. In transthoracic echocardiographic examinations, we observed diminished diastolic dysfunctions, either with pulse wave or TDI Doppler. We found a significant difference between the groups in terms of longitudinal strain parameters.

Conclusion

Although we use low-dose and short-duration ACTH treatment in patients with IS, it may cause subclinical damage to the heart muscle and an increased risk of arrhythmia.

infantile spasm

electrocardiography

echocardiography

tissue Doppler

strain echocardiography

arrhythmia risk

Infantile spasms (ISs) are a group of epileptic disorders, which represents the most frequent type of epilepsy in the first year of life [1] The prevalence is 1–2/10,000 children at the age of 10 years with onset within 1 year of life in 90% of cases [2]. The peak is seen between 4–7 months, with a male to female ratio of 6:4 [3].

IS treatment aims to block epileptic attacks and relapses and normalize electroencephalography (EEG) anomalies, thereby avoiding neurodevelopmental delay. For this reason, ACTH is the most effective treatment for the short-term therapy of IS, with the dose spectrum ranging from 20 to 120 UI/L. Although high-dose ACTH is more effective compared with low-dose treatment, it has several adverse effects, such as irritability, hypertension, cushingoid features, and infections secondary to immunosuppression [4–5]

Although as mentioned above, low-dose ACTH is thought to cause fewer adverse effects, in this report, we hypothesized that low-dose ACTH might also lead to adverse effects on the heart muscle and electrical system.

Study group:

Infants diagnosed as having IS in the pediatric neurology department were included in this study. Twenty-four patients with IS and 24 healthy children (control group) participated in the study.

At least one 21-channel EEG recording was performed on all patients during stage 2 sleep states. Electrodes were placed using the International 10-20 System with bipolar and referential montages (including the Oz electrode). Interelectrode resistance was below 3 kΩ, and filters were set at 0.3 to 70 Hz. All patients had hypsarrhythmia on EEG according to the criteria defined by Gibbs and Gibbs [6].

Written informed consent was obtained from all parents of the children for participation in the study, which was approved by our Hospital Ethics Committee (09.2019.410).

Twelve-channel surface electrocardiography (ECG) and transthoracic echocardiography were performed on all patients before and after 2-4-6th months of the ACTH treatment. All participants were free of any cardiac abnormalities and other systemic diseases.

ACTH (Synacthen® Depot) was administered for 2 months in a total of 18 doses as low-dose treatment (0.5 mg/kg <10 kg, 1 mg/kg >10 kg).

Electrocardiographic measurement:

A 12-lead ECG with standard chest and limb leads was used to evaluate the Tp-Te interval, QTc interval, and QTd interval. The 12-lead ECG was recorded at a paper speed of 50 mm/s in the supine position. To decrease measurement errors, all ECGs were scanned and transferred to a personal computer and then used for 400% magnification using the Adobe Photoshop software. QTd was calculated as the difference between the longest and the shortest QT intervals. ECG measurements of QTc and Tp-Te intervals were performed by two cardiologists who were blinded to the patient data. Subjects with U waves on their ECGs were excluded from the study. An average value of three readings was calculated for each lead. The QT interval was measured from the beginning of the QRS complex to the end of the T wave and corrected for heart rate using the Bazett formula: cQT = QTÖRR interval. The Tp-Te interval was defined as the interval from the peak of the T wave to the end of the T wave. Measurements of the Tp-Te interval were performed from the precordial leads. The Tp-Te/QT ratio was calculated from these measurements [7] (Figure 1). Any QRS morphology with a QRS duration >120 ms, including bundle branch block or intraventricular conduction delay, was excluded.

Echocardiographic measurements

All patients underwent an echocardiographic examination at the time of diagnosis, and after 2-4-6th months of the ACTH treatment using a Philips Healthcare EPIQ 7 Ultrasound System Inc. echocardiography device equipped with 5-MHz sector transducers. Two-dimensional echocardiographic images were obtained using apical four-chamber (4C) and (2C) views, and a parasternal long axis (LAX) view.

Left ventricular functions:

Left ventricular dimensions, interventricular septal diameter (IVSD), LVPWD (left ventricular posterior wall diameter), and LVED (left ventricle end-diastole) and LVEDS (left ventricle end-systole) dimensions were measured and left ventricular ejection and shortening fractions (LVEF-SF) were calculated using the Teichholtz formula [8]. Left ventricular diastolic functions were studied using pulsed-wave (PW) echocardiography with mitral inflow Doppler velocities, early (E wave) and late (A wave) velocities, deceleration time, and IVRT were measured. Isovolumic relaxation time (IVRT) was measured using PW Doppler, in which the transducer is angulated into the apical 5-chamber or long-axis view, and the sample volume is placed within the left ventricular outflow tract (LVOT), but in proximity to the anterior mitral valve (MV) leaflet to record both inflow and outflow signals. Three cardiac cycles should be averaged when measuring transmitral velocities and IVRT.

The mitral annular early and late diastolic velocity (E' and A') was obtained using PW tissue Doppler imaging from the lateral annulus position.

Left ventricle longitudinal and circumferential strain were measured using semi-automated speckle-tracking echocardiography. Images of the apical four-chamber, two-chamber, and long-axis view were optimized at a frame rate of 60 frames/sec. Systole was defined in the apical long-axis view by the aortic valve opening and closure [9].

Statistical analysis:

Statistical analysis was performed using the SPSS Statistics for Windows version 20 software package (SPSS, Inc., Chicago, IL, USA). The independent-sample t-test, paired-sample t-test, or Mann-Whitney U test was used to compare study variables. For categorical variables, the Chi-square test was used. Correlations were evaluated using univariate and multivariate linear regression analysis. A p-value of <0.05 was accepted as statistical significance.

We evaluated the parameters before treatment, and during the 2-4-6 months of the treatment.

The baseline demographic characteristics of the patients are presented in Table 1. The mean and median ages of the patients were 16.8 months and 16.7 months, respectively (p>0.05). The patient group consisted of 12 female (50%) and 12 male (50%) subjects. The control group consisted of 11 females (45.83%) and 13 males (54.17%). No significant changes were observed between the control and patient groups in terms of demographic values, such as age, sex, weight, and BMI (p=0.997, p=0.773, p=0.975, and p=0.895).

When we compared heart rate and blood pressure before and after treatment, there was also no significance between the variables (p>0.05).

None of the patients had clinically significant arrhythmia during treatment.

On ECG, we evaluated depolarization and repolarization parameters using QRS, QTd, QTc, Tp-Te, and Tp-Te/QTc. ECG parameters were presented in Table 2. Only PR values were significantly increased, which showed a first-degree AV block in the patient group (p<0.001).

On ECG, we observed significantly increasing values during the treatment. Values of PR, QRS, QT, tp/te, tpte/QT, and tpte/QTc were significantly increased compared with both pretreatment values and each other. Significant difference was observed on the sixth month of the treatment when compared to pretreatment values by means of QRS, QT, QTc, tp-te, Tp-te/QT, Tp-te/QTc. However, no significant difference was observed between the values of the months when compared with each other (Table 3).

When we compared the M-mode echocardiographic values of the patients with the control group, we found a significant difference between LVEDD, LVESD, and EF (p<0.05).

Diastolic functions examined from the mitral valve showed that the deceleration time was significantly shorter than in the control group (p<0.05) (Table 4)

TDI values obtained from mitral lateral annuli were evaluated. Mitral A’, IVCT, IVRT, and MPI were significantly increased when compared with the control group (p<0.05) (Table 4).

In the assessment of left ventricular strain parameters of the groups, there was a significant difference between the groups (Table 4).

On transthoracic echocardiography, after evaluation of the M-mode and PW parameters, there was a significant difference between pretreatment values and the 6th month of the treatment in terms of IVSD, LVEDD, LVESD, LVPWD, SF, EF, LV MASS, pulse wave a wave, deceleration time, and IVRT (Table 5).

In the evaluation of the TDI parameters, we observed all 6th-month values, except TDI IVRT and IVCT, were significantly increased compared with pretreatment values (Table 5).

After evaluation of strain parameters, we observed a significant difference between pretreatment and 6th-month values (p<0.05) (Table 6).

We also evaluated the patients through etiology, such as genetic causes, hypoxic-ischemic, and hypoxic causes only. There was no significant difference between the pretreatment values and during the treatment (Table 7-10).

In our study, we showed that even low-dose ACTH treatment has a significant effect on either ECG or echocardiographic parameters.

In the literature, we found a few studies about this subject [10-11]. Our study is the most recent with the largest number of patients. Besides, this is the single study, evaluating the patient insights of ECG through depolarisation and repolarisation abnormalities, and strain echocardiography.

The surface ECGs of the patients in our study showed no arrhythmia. None of the patients had significant tachycardia when compared with the healthy group, or during treatment. Besides, none of the patients had significant bradycardia as an adverse effect of steroid treatment. Sharma et al. described two children who developed sinus bradycardia within a week of starting prednisolone for epileptic spasms, an abnormality that resolved when the medication was discontinued [12]

The association of bradycardia with high-dose corticosteroids was first reported in 1986 by Tvede et al. [13]. They described five adults with rheumatoid arthritis who developed sinus bradycardia approximately 4 days after receiving intravenous methylprednisolone. Duffy et al. reported 150 children with acute lymphoblastic leukemia who developed bradycardia following steroid administration. Of the 90 patients with significant bradycardia, 20 had received oral prednisone (30 mg/m²/dose twice per day) [14]. Bradycardia has been reported with adrenocorticotropic hormone treatment in 15 patients with West syndrome [15].

The pathophysiology of steroid-related arrhythmias is not clearly understood. Animal studies have shown that high-dose methylprednisolone can alter cardiovascular sensitivity to catecholamines [16]. In humans, corticosteroids may have the ability to induce sudden electrolyte shifts, resulting in cardiac arrhythmias including bradycardia [17]. Another proposed mechanism outlines that corticosteroids induce changes in sodium and water physiology, resulting in plasma volume expansion with subsequent activation of low-pressure baroreceptors and reflex bradycardia [17].

Tp-Te interval and Tp-Te/QT ratio have been evaluated as actual markers of increased dispersion of ventricular repolarization [18,19] Prolongation of Tp-Te interval was related to increased mortality in Brugada syndrome, long QT syndrome, and patients with acute myocardial infarction [19] Tp-Te can be affected by body weight and heart rate, so it has some limitations for use as a repolarization marker. On the other hand, Tp-Te/QT and Tp-Te/QTc are not affected by heart rate or body weight. As a result, Tp-Te, Tp-Te/QT, and Tp-Te/QTc are novel markers of ventricular repolarization. Recent studies showed that increased levels may be a marker of ventricular arrhythmias. Yayla et al. found increased levels of Tp-Te/QTc in a group of patients who underwent radiofrequency catheter ablation, those whose ejection fraction was lower than 50% [20]. In our study, we observed significantly increased levels of Tp-Te, Tp-Te/QT, and Tp-Te/QTc during steroid treatment

Gupta et al. claimed that the Tp-Te/QT ratio could be used as an index of arrhythmogenesis, even in the presence of short, normal, or long QT intervals, and additionally, they indicated that the Tp-Te/QT ratio was a better marker of ventricular repolarization [19].

The expected effect of steroid treatment is hypertension. Hormonal medications such as ACTH and prednisolone are known to cause elevated blood pressure and cardiomyopathy in older populations. However, blood pressure monitoring was not routinely included in early reports of ACTH used for infantile spasms and other epilepsies. Thus, the first studies of adverse effects contained no significant data pertaining to hypertension [21]. Cardiomyopathy during ACTH treatment of infantile spasms was first published in the early 1980s, which may have prompted increased monitoring of blood pressure and cardiac function during treatment [22]. Partikian et al. published a study in 2007 that focused on the adverse effects of therapies for IS. They described that children treated with ACTH had a statistically significant increase in baseline blood pressures when compared with those not treated with ACTH [23]. McGarry observed that hypertension occurred in 34/77 (44%) children during treatment with ACTH and 4/11 (36%) children during treatment with prednisolone [24].

Bobele et al. studied the echocardiographic effects of ACTH treatment, showing abnormal cardiac hypertrophy in 72% of 18 patients. There was no significant difference among the groups with respect to age, sex, or etiologic characteristics [11]. Lang et al. reported that echocardiographic examinations revealed a pattern similar to hypertrophic cardiomyopathy. Ventricular septal thickness is significantly increased in all patients and left ventricular posterior wall thickness is increased only in four patients during or shortly after treatment [25].

Kusuda et al. reported the case of an infant with an interrupted aortic arch (IAA) after a Norwood procedure with the right ventricle to a pulmonary artery (RV-PA) conduit complicated by IS. After ACTH therapy, acute circulatory failure developed due to severe stenosis of the RV-PA conduit following myocardial hypertrophy. With extracorporeal membrane oxygenation (ECMO) support and conduit clip removal using a balloon dilatation catheter, the patient survived the ACTH therapy-related myocardial hypertrophy exacerbation [26].

To evaluate diastolic dysfunction, we use tissue Doppler imaging. There are many studies based on different systemic diseases. Lateral mitral annulus E’ was significantly decreasing, whereas PW Doppler E/E’ was increased [27]. In our study, E/E’ was significantly increased compared with the control group, but despite this, the ratio was decreased during the treatment.

The myocardial performance index is a Doppler parameter that can assess both systolic and diastolic functions of the heart. Kutluk et al. observed that after ACTH treatment, there was an increase in LV MPI and a decrease in E' (10). Few studies are reporting the effects of steroids on heart muscle using tissue Doppler echocardiographic methods. Baykan et al. reported diastolic dysfunction in Cushing syndrome using TDI. In our study, we showed a significant increase in MPI levels compared with the controls. Besides, there was a significant MPI increase during the treatment [28].

Little is known about strain echocardiography results during steroid treatment, even in adult patients. Aksakal et al. found that left ventricular global longitudinal strain was increased after high-dose steroid treatment in adults [29]. Rasmussen et al. observed impaired left ventricular global longitudinal strain in illicit steroid users when compared with controls [30]. Witczak et al. showed decreased longitudinal strain under steroid treatment of children diagnosed as having mixed connective tissue disorder [31].

In our study, we observed a significant difference between pretreatment and after-treatment levels through both longitudinal and circumferential strain.

This is the first study based on ECG and advanced echocardiographic parameters in patients with IS receiving ACTH treatment. We suggest longer follow-up durations to evaluate the changes in heart muscle. Patients should be monitored with a multidisciplinary approach in terms of identifying efficacy and complications of treatment. Further studies are needed to show the adverse effects of ACTH treatment on cardiac function.

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Table 1: Demographic values of the groups

		Control n=24		Patient n=24		p*
Age		16.9±17.48		16,81±18,54		0.997
Sex	Male	13	54.17%	12	50.00%	0.773
	Female	11	45.83%	12	50.00%
Weight		9.92±2.57		9.89±2.93		0.975
BMI		0.381±0.149		0.385±0.156		0.895
Heart rate (min)		130±1.4		128±2.3		>0.05
BP sys (mm Hg)		94±1.8		93.3±1.3		>0.05
BP dias (mm Hg)		52±1.8		53±1.6		>0.05

Table 2. Surface electrocardiography parameters of the patient and control groups before treatment

	Control n=24	Patient n=24	p*
Pr	69±3.28	79.08±5.9	<0.001
QRS	81.71±8.61	80.25±6.36	0.508
QT	379.92±10.31	384.17±11.39	0.182
QTc	385.32±7.95	384.58±7.93	0.997
tpte	74.96±3.13	74.83±2.97	0.982
Tpte/qt	0.191±0.023	0.191±0.024	0.951
Tpte/QTc	0.172±0.019	0.168±0.02	0.472

Table 3: ECG parameters compared each other during treatment

	Pretreatment	2nd month	4th month	6th month	p‡
Pr	79.08±5.9	80.21±5.07	79.08±5.96	82.33±5.39	0.008
QRS	80.25±6.36	80.25±6.66	84.58±9.07	90.67±8.88	<0.001
QT	384.17±11.39	386.67±13.41	392.71±12.25	398.33±8.43	<0.001
QTc	384.58±7.93	385±7.52	398.54±5.8	392.08±9.55	<0.001
Tp-te	74.83±2.97	78.25±3.48	79.42±5.29	86.1±6.38	<0.001
Tpte/QT	0.191±0.024	0.206±0.014	0.205±0.025	0.231±0.01	<0.001
Tpte/QTc	0.168±0.02	0.174±0.018	0.224±0.013	0.247±0.02	<0.001

Table 4 Transtorasic echocardiography M-mode, Pulsed Wave, TDI, strain parameters before treatment

	Control n=24	Patient n=24	p*
IVSD	0.535±0.076	0.58±0.102	0.084
LVEDD	2.85±0.52	2.31±0.56	0.001
LVESD	1.93±0.55	1.48±0.47	0.003
LVPWD	0.622±0.126	0.563±0.096	0.074
SF	32.96±2.29	33.33±4.38	0.712
EF	66.63±2.62	69.29±4.68	0.019
LVMASS	17.53±3.47	18.13±1.69	0.447
MITRAL E	0.799±0.211	0.801±0.157	0.966
MITRAL A	0.532±0.17	0.596±0.141	0.159
DECT	95.38±32.22	72.58±29.58	0.014
IVRT	55.54±20.87	59.25±13.19	0.466
E’	12.71±5.08	10.97±2.41	0.137
A’	5.261±2.239	6.997±3.567	0.049
IVCT TDI	48.92±16.37	62.46±20.73	0.016
IVRT TDI	51.88±18.11	65.42±16.48	0.009
S TDI	8.38±2.59	11.09±11.43	0.263
ET	83.38±27.32	83.67±25.96	0.970
MPI	0.541±0.19	0.848±0.056	<0.001
l strain	-21.74±1.68	-23.63±0.87	<0.001
c strain	-23.09±2.11	-23.44±0.74	0.452

Table 5: Transthoracic echocardiography parameters compared with each other during treatment

	Pretreatment	2nd month	4th month	6th month	p‡
IVSD	0.58±0.102	0.585±0.10	0.592±0.062	0.763±0.11	<0.001
LVEDD	2.31±0.56	2.42±0.48	3.00±0.52	3.29±0.21	<0.001
LVESD	1.48±0.47	2.00±0.50	2.46±0.49	2.81±0.20	<0.001
LVPWD	0.563±0.096	0.617±0.093	0.684±0.104	0.787±0.076	<0.001
SF	33.33±4.38	33.46±2.98	35.38±3.5	36.79±2.70	0.003
EF	69.29±4.68	69.42±2.83	70.04±3.52	75.58±2.80	<0.001
LVMASS	18.13±1.69	18.64±1.79	26.63±4.03	28.66±3.79	<0.001
ME	0.801±0.157	0.789±0.163	0.76±0.132	0.828±0.249	0.680
MA	0.596±0.141	0.676±0.08	0.528±0.11	0.685±0.204	<0.001
DT	72.58±29.58	80.92±26.31	84.17±28.56	103.38±28.6	<0.001
IVRT	59.25±13.19	63±17.74	63.08±12.59	79.08±10.38	<0.001
E’	10.97±2.41	10.11±1.97	11.36±3.68	12.68±3.08	0.001
A’	7±3.57	5.79±2.36	7.92±3.28	9.63±2.83	0.001
IVCT TDI	62.46±20.73	57.54±18.81	75.75±15.88	90.50±10.41	<0.001
IVRT TDI	65.42±16.48	67.13±16.92	70.08±11.25	67.04±21.74	0.813
S TDI	11.09±11.43	8.56±2.15	10.08±2.64	13.04±1.87	0.085
ET	83.67±25.96	89.46±25.46	101.04±26.28	108.17±30.41	<0.001
MPI	0.848±0.056	0.728±0.162	0.815±0.164	0.949±0.22	<0.001
lstrain	23.63±0.87	23.12±2.14	22.65±2.58	25.57±2.26	0.008
cstrain	23.44±0.74	23.39±1.57	24.24±2.15	28.28±2.32	<0.001

E: early diastolic mitral inflow velocity, A: late diastolic mitral inflow velocity, IVRT: isovolumetric relaxation time, IVSD: interventricular septum diameter, LVPWD: left ventricle posterior wall diameter, LVESD: left ventricle end-systolic diameter, LVEDD: left ventricle end-diastolic diameter, FS: fractional shortening, EF: ejection fraction, DT: deceleration time IVCT: isovolumic contraction time, S: s wave, ET: Ejection time, MPI: Myocardial performance index, lstrain: longitudinal strain, cstrain: circumferential strain

Table 6: Strain echocardiography parameters compared over the months

Newman-Keuls	lstrain	cstrain
pre / 2nd month	0.220	0.849
pre / 4th month	0.073	0.079
pre / 6th month	<0.001	<0.001
2nd month / 4th month	0.507	0.105
2nd month / 6th month	0.001	<0.001
4th month / 6th month	<0.001	<0.001

Table 7: ECG parameters during treatment by etiology

		Genetic n=7	HIE n=7	Hypoxia n=10	p†
PR	Pretreatment	80.29±6.16	75.43±4.58	80.8±5.9	0.148
	2nd month	79.29±3.5	81.43±4.72	80±6.39	0.739
	4th month	80±6.11	75.14±4.3	81.2±5.98	0.102
	6th month	86±6.73	79.14±2.27	82±4.71	0.055
QRS	Pretreatment	79.43±4.86	77.43±4.28	82.8±7.84	0.219
	2nd month	80.86±8.32	77.57±6.88	81.7±5.25	0.455
	4th month	85.14±10.25	79.71±10.16	87.6±6.52	0.213
	6th month	91.43±10.69	88.29±10.67	91.8±6.56	0.717
QT	Pretreatment	382.86±13.8	380±5.77	388±12.29	0.355
	2nd month	388.57±14.64	382.86±9.51	388±15.49	0.688
	4th month	387.86±11.13	394.29±15.12	395±11.06	0.477
	6th month	397.86±8.09	397.86±11.5	399±6.99	0.952
QTC	Pretreatment	385.71±10.97	382.86±8.09	385±5.77	0.793
	2nd month	385±8.66	383.57±4.76	386±8.76	0.820
	4th month	400±5.77	399.29±6.07	397±5.87	0.552
	6th month	392.86±12.2	389.29±10.97	393.5±6.69	0.668
tpte	Pretreatment	73.86±3.58	75±3.21	75.4±2.46	0.586
	2nd month	77±3.61	79.57±2.94	78.2±3.74	0.401
	4th month	79.43±5.86	81.71±4.82	77.8±5.12	0.339
	6th month	84.47±8.89	84.67±6.25	88.26±4.07	0.395
tpteqt	Pretreatment	0.187±0.021	0.187±0.03	0.196±0.022	0.682
	2nd month	0.2±0.016	0.213±0.015	0.205±0.012	0.251
	4th month	0.211±0.016	0.193±0.021	0.21±0.031	0.287
	6th month	0.23±0.007	0.231±0.009	0.232±0.012	0.894
tpteqtc	Pretreatment	0.166±0.023	0.171±0.023	0.167±0.018	0.868
	2nd month	0.177±0.021	0.176±0.016	0.171±0.018	0.773
	4th month	0.231±0.009	0.223±0.014	0.219±0.014	0.171
	6th month	0.241±0.021	0.253±0.02	0.246±0.02	0.571

Table 8: Echocardiography parameters (m-mode, PW Doppler) during treatment by etiology

		Genetic n=7	HIE n=7	Hypoxia n=10	p†
IVSD	Pretreatment	0.551±0.074	0.646±0.093	0.555±0.112	0.131
	2nd month	0.629±0.111	0.593±0.093	0.549±0.093	0.274
	4th month	0.6±0.046	0.591±0.051	0.586±0.08	0.907
	6th month	0.809±0.097	0.744±0.129	0.745±0.106	0.453
LVEDD	Pretreatment	2.53±0.68	2.11±0.39	2.3±0.57	0.384
	2nd month	2.74±0.41	2.25±0.27	2.31±0.57	0.113
	4th month	3.11±0.53	2.99±0.48	2.93±0.57	0.797
	6th month	3.34±0.21	3.28±0.25	3.26±0.2	0.711
LVESD	Pretreatment	1.6±0.64	1.41±0.32	1.43±0.45	0.726
	2nd month	2.29±0.45	1.84±0.14	1.9±0.63	0.190
	4th month	2.53±0.43	2.41±0.47	2.46±0.59	0.905
	6th month	2.79±0.17	2.87±0.06	2.8±0.27	0.718
LVPWD	Pretreatment	0.583±0.095	0.557±0.085	0.552±0.112	0.811
	2nd month	0.611±0.076	0.64±0.115	0.605±0.094	0.750
	4th month	0.696±0.107	0.689±0.098	0.673±0.115	0.906
	6th month	0.78±0.064	0.801±0.065	0.782±0.095	0.849
KF	Pretreatment	33.86±3.98	31.43±3.78	34.3±4.99	0.402
	2nd month	33.14±2.61	33.14±2.97	33.9±3.45	0.841
	4th month	35.29±4.5	37.14±2.34	34.2±3.19	0.241
	6th month	36.71±3.04	37.71±2.93	36.2±2.39	0.543
EF	Pretreatment	68.71±6.32	68.57±3.78	70.2±4.26	0.740
	2nd month	68.57±1.81	70±1.53	69.6±3.98	0.637
	4th month	70.43±2.15	70±2.71	69.8±4.85	0.941
	6th month	75.86±3.02	75.57±1.62	75.4±3.47	0.951
LVMASS	Pretreatment	18.33±1.95	18.53±1.68	17.72±1.58	0.604
	2nd month	19.23±1.96	19.02±1.88	17.97±1.54	0.299
	4th month	27.66±4.68	26.86±4.47	25.75±3.45	0.641
	6th month	29.39±4.51	28.67±4.71	28.14±2.75	0.814
ME	Pretreatment	0.899±0.209	0.743±0.046	0.773±0.147	0.136
	2nd month	0.856±0.266	0.723±0.057	0.788±0.107	0.325
	4th month	0.717±0.141	0.806±0.13	0.757±0.13	0.474
	6th month	0.833±0.244	0.741±0.219	0.886±0.277	0.518
MA	Pretreatment	0.666±0.213	0.57±0.115	0.566±0.081	0.316
	2nd month	0.677±0.124	0.644±0.076	0.697±0.034	0.430
	4th month	0.523±0.05	0.539±0.151	0.523±0.119	0.955
	6th month	0.681±0.192	0.637±0.192	0.721±0.233	0.723
DT	Pretreatment	87.57±43.84	59.43±18.31	71.3±20.48	0.207
	2nd month	88.14±32.33	86.86±24.98	71.7±22.21	0.364
	4th month	100±31.54	66.29±16.56	85.6±28.16	0.080
	6th month	119±30.48	98.71±27.05	95.7±26.65	0.231
IVRT	Pretreatment	57.14±6.18	66.43±22.4	55.7±5.23	0.233
	2nd month	61.71±16.29	69.14±26.85	59.6±10.17	0.558
	4th month	67.71±10.47	61.43±20.44	61±5.48	0.532
	6th month	83.29±8.67	80.71±13.21	75±8.63	0.247

Table 9: Echocardiography parameters (tissue Doppler) during treatment by etiology

		Genetic n=7	HIE n=7	Hypoxia n=10	p†
E’	Pretreatment	12.24±2.52	10.35±2.58	10.52±2.11	0.263
	2nd month	11.06±2.07	9.65±1.17	9.77±2.28	0.334
	4th month	12.82±3.22	12.11±3.84	9.83±3.62	0.215
	6th month	13.72±3.05	13.69±3.18	11.25±2.71	0.156
A’	Pretreatment	8.13±4.67	5.73±2.39	7.1±3.45	0.470
	2nd month	7.32±3	5.3±2.12	5.06±1.63	0.120
	4th month	7.13±1.98	7.86±3.99	8.52±3.67	0.710
	6th month	8.57±2.25	10.18±3.65	9.98±2.65	0.520
IVCTTDI	Pretreatment	56±29.65	62.86±9.56	66.7±19.96	0.597
	2nd month	54.86±25.48	52.14±12.48	63.2±17.42	0.463
	4th month	76.86±7.22	77±16.53	74.1±20.54	0.918
	6th month	91.29±6.32	92.43±9.24	88.6±13.65	0.753
IVRTTDI	Pretreatment	62.29±19.53	69.43±16.52	64.8±15.39	0.729
	2nd month	65±17.4	76.71±10.83	61.9±18.61	0.195
	4th month	70.14±10.7	70.57±14.8	69.7±10.03	0.989
	6th month	66±20.2	71±23.01	65±23.76	0.857
STDI	Pretreatment	8.17±2.87	10.03±4.01	13.89±17.36	0.593
	2nd month	8.69±2.18	9.25±2.52	7.97±1.9	0.490
	4th month	10.93±1.14	10.09±4.23	9.48±2.02	0.559
	6th month	13.09±2.67	13.4±1.17	12.76±1.76	0.796
ET	Pretreatment	91.14±26.11	67.86±9.32	89.5±30.56	0.160
	2nd month	88.71±32.43	88.86±14.02	90.4±28.69	0.989
	4th month	109.14±30.71	95±20.86	99.6±27.65	0.608
	6th month	112.29±29.7	104.71±33.74	107.7±31.51	0.904
MPI	Pretreatment	0.827±0.059	0.873±0.042	0.846±0.061	0.322
	2nd month	0.723±0.154	0.679±0.197	0.765±0.147	0.574
	4th month	0.813±0.177	0.716±0.157	0.887±0.133	0.101
	6th month	0.993±0.125	0.873±0.308	0.972±0.208	0.563

Table 10: Echocardiography parameters (strain) during treatment by etiology

		Genetic n=7	HIE n=7	Hypoxia n=10	p†
lstrain	Pretreatment	23.51±0.94	23.84±1.18	23.55±0.59	0.746
	2nd month	22.69±1.72	23.7±2.51	23.03±2.25	0.682
	4th month	21.91±1.83	24.31±2.9	22.01±2.49	0.128
	6th month	25.37±2.54	26.77±2.24	24.86±1.92	0.228
cstrain	Pretreatment	23.83±0.55	23.54±0.59	23.09±0.84	0.113
	2nd month	23.4±1.93	23.11±1.28	23.57±1.63	0.852
	4th month	24.11±2.44	24.07±2.17	24.44±2.14	0.932
	6th month	25.57±2.87	26.99±1.66	26.28±2.32	0.507

No competing interests reported.

Effects of ACTH Treatment in Infantile Spasm; Insights from Electrocardiography and Echocardiography

Status:

Version 2

Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Material-method

Results

Discussion

Conclusion

References

Tables

Additional Declarations

Status:

Version 2