Recognition of cardiogenic syncope caused by acute myocarditis masquerading as febrile seizures (FS) in children can be difficult in the emergency department (ED) before a cardiac work-up. We aimed to identify clinical and laboratory characteristics of children with seizure-like activity and fever caused by myocarditis that would enable their condition to be distinguished from benign FS.
We identified seven children who visited the ED for paroxysmal seizure-like activity with fever and were diagnosed with acute myocarditis between 2012 and 2015, as well as 204 children who were diagnosed with benign FS during the same period. A detailed retrospective review of the medical charts of both groups was conducted.
Age at onset of seizure-like activity was much higher in the myocarditis group than in the FS group (4.4±1.9 years vs. 2.4±1.1 years,
Prodromal symptoms and initial laboratory results were significantly different between the myocarditis and FS groups. A good clinical history and laboratory findings can be helpful for differentiating cardiogenic syncope from benign FS.
Among the pediatric population, acute myocarditis is an uncommon but fatal disease. The actual incidence of myocarditis is unknown but is probably underestimated. Most estimates are based on autopsy studies and range from 0.1% to 5.6% in children and adults [
The most common clinical findings in a case series included tachypnea, intercostal retractions, tachycardia, and grunting, and those symptoms led to 71% of children being misdiagnosed as having either sepsis or pneumonia/asthma [
We experienced seven children with acute myocarditis presenting with seizure-like activity and mild to high fever, which was initially considered as possible FS, who were evaluated at the pediatric neurology department before cardiac examination. To the best of our knowledge, there has been no study of the differences in clinical and laboratory findings between children with acute myocarditis with seizure-like activities and FS until now. This study aimed to identify the initial clinical and laboratory characteristics of children with seizure-like activity and fever caused by acute myocarditis that could be differentiated from those of benign FS, except by regular cardiac work-ups such as electrocardiogram (ECG) and echocardiogram.
We retrospectively reviewed the medical charts of children who were diagnosed with acute myocarditis and presented a seizure-like activity with mild to high fever as the main complaint, between 2012 and 2015 in a single tertiary care hospital. In considering of the complex FS, we included not only generalized onset seizure but also focal onset seizure such as LOC/impaired awareness. In order to evaluate the children who could suspect the possible FS as well as typical FS, the range of body temperature was more than or 37.7°C. Of 24 children with myocarditis, seven patients (29.2%) visited our ED presenting with seizure-like activity as the main initial symptom. Myocarditis was diagnosed by attending pediatric cardiologists if he/she had clinical symptoms compatible with myocarditis and showed at least one of the following: elevated cardiac enzymes (creatine kinase [CK], CK-MB isoenzyme, or troponin-I [>0.1 ng/mL]), cardiomegaly (cardiothoracic ratio >0.5) on chest radiograph, or impaired heart contractility on echocardiography (ejection fraction <55%). Exclusion criterion was underlying congenital heart disease, coronary artery anomalies, cardiomyopathy, collagen vascular disease, infection/inflammation originating from the central nervous system (CNS), or heart surgery. Patients older than 6 years were also excluded for comparison with benign FS. These seven children with myocarditis with seizure-like activity and fever were enrolled to the myocarditis-group. They were initially considered as having FS and reported to our neurologist.
During the same period, children who were diagnosed with benign FS were enrolled to the FS-group. Patients with FS were defined by seizures that occurred between the age of 6 and 60 months with a body temperature of ≥38°C, which were not caused by CNS infection or any metabolic imbalance [
Patients’ demographic profiles, clinical presentations, medical history, vital signs, physical examination findings, and laboratory studies were collected and compared between the myocarditis- and FS-group.
Ethics permission for this study was granted (number: 05-2019-107) by the Institutional Review Board of Pusan National University Yangsan Hospital and fully informed written consent was obtained from each participant.
The SPSS version 19.0 software package (IBM Co., Armonk, NY, USA) was used for statistical analysis of raw scores. The two-tailed chi-square or Fisher’s exact test was used for analysis of categorical data, and the Student’s t-test for continuous variables with normal distribution. The Mann-Whitney U test was used for continuous variables without normal distribution. In addition to univariate non-parametric statistical tests, Fisher’s exact test and the Wilcoxon signed rank test were used to evaluate significant differences in categorical and continuous variables, respectively. In all analyses,
The myocarditis- and FS-group included seven and 204 children, respectively. Out of 204 FS, the patients of simple FS and complex FS were 152 (74.5%) and 52 (25.5%). There was no significant difference in gender ratio (boy:girl, 2.7:1 vs. 1.6:1) and mean age (2.3±1.2 years vs. 2.6±1.1 years) between simple and complex FS-group (data not shown). There were two boys (28.6%) in the myocarditis-group, and 140 boys (68.6%) in the FS-group (
Prodromal symptoms before onset of seizure were statistically different between the two groups (
Initial laboratory findings were significantly different between children in the myocarditis- and FS-groups (
In the myocarditis-group, the mean cardiothoracic ratio on chest X-ray was 0.52±0.24 (
This study investigated a series of seven children, finally diagnosed with acute myocarditis presenting with seizure-like activity (generalized tonic-clonic seizure or LOC/impaired awareness) and fever, who were initially suspected of having benign FS. Children in the myocarditis-group were significantly older and had a lower degree of fever than those in the FS-group. Although the type, duration, and frequency of seizure were similar between the two groups, the prodromal symptoms/signs were very different. The most common preceding symptom/sign was gastrointestinal problems, including nausea/vomiting and abdominal pain, in the myocarditis-group, and symptoms of common cold in the FS-group. We found that the initial laboratory results in ED were remarkably different between the two groups, even though further cardiac evaluation was not performed. Serum levels of AST, ALT, LDH, bilirubin, creatinine, uric acid, CK, and potassium were higher in the myocarditis-group compared to those in the FS-group. If children have specific prodromal symptoms and considerable elevation in the laboratory findings described, we should consider the possibility of seizure-like activities caused by acute myocarditis, even though these seizure-like activities with fever can look similar to those in benign FS.
As high as 20% to 30% of epileptic seizures may have been misdiagnosed [
Although many clinicians recognize that resting tachycardia is a common finding of myocarditis due to compensation for congestive heart failure [
Cardiomegaly and/or pulmonary edema are common in patients with myocarditis, but are infrequent in myocarditis complicated with CAVB. Suboptimal heart rate may lead to poor cardiac output before the development of congestive heart failure and cardiomegaly [
Modest elevations in liver enzyme levels are found in patients suffering from passive hepatic congestion [
Patients with myocarditis may have only nonspecific complaints. Newborns, infants, toddlers, and preschool children may have a history of respiratory or gastrointestinal infection, anorexia, abdominal pain, poor appetite, vomiting or lethargy, seizure-like activity, sinus tachycardia out of proportion to fever, or syncope, whereas cardiac symptoms may be not prominent [
Of the varied presentations of myocarditis, CAVB was believed to be an isolated feature, with rapid and full recovery if it was diagnosed early and treated with emergency pacemaker implantation [
This study has some limitations. First, the study is based on a retrospective investigation of medical records. Second, we acknowledge that there is a large difference in the number of patients between the two groups to make a comparison with the statistical analysis. This is because myocarditis is very rare, and our study enrolled only the children presenting with seizure-like activities and fever among of them. We did try to use the additional non-parametric statistical methods (Fisher’s exact test and Wilcoxon signed rank test) to increase the reliability of statistical analysis. Third, our study aimed to investigate the clinical and laboratory characteristics of the children with myocarditis, whose initial diagnosis could be mistaken for typical or possible FS. Therefore, not all of our myocarditis patients meet typical FS. Finally, these patients were collected at a single tertiary center and the findings may not be completely representative of the general population. Further population-based studies with a larger number of patients are needed.
In summary, children presenting with fever and Stokes-Adams seizure in our study were not diagnosed as having myocarditis at the initial physician encounter, which highlights the need for clinicians to maintain high level of alertness for myocarditis, even in the absence of clinical findings of congestive heart failure. Prodromal symptoms and initial laboratory results revealed significant differences between the myocarditis- and FS-groups. We suggest that an ECG should be considered as a screening test in all episodes of suspicious benign FS in children, especially in those with significant elevations in laboratory findings, including AST, ALT, LDH, uric acid, and CK.
No potential conflict of interest relevant to this article was reported.
Conceptualization: SON, JAP, SYB, YMK, and YJL. Data curation: SHJ, HDL, JAP, HK, and YJL. Formal analysis: SHJ, JK, and YMK. Methodology: SON, SYB, HDL, and YJL. Project administration: YJL. Visualization: HK and JK. Writing-original draft: SHJ and AK. Writing-review & editing: AK and YJL.
This study was supported by a 2018 research grant from Pusan National University Yangsan Hospital. We would like to thank Editage (
Comparison of prodromal symptoms between patients with myocarditis and febrile seizure. N/V, nausea/vomiting; FS, febrile
seizure a
Comparison of laboratory studies between patients with myocarditis and febrile seizure (FS). (A) Aspartate aminotransferase (AST), (B) alanine aminotransferase (ALT), (C) lactate dehydrogenase (LDH), (D) creatine, (E) uric acid, and (F) creatine kinase (CK).
Comparison of clinical and seizure profiles between patients with acute myocarditis and febrile seizure
Variable | Myocarditis (n=7) | Febrile seizure (n=204) | |
---|---|---|---|
Sex, male:female | 2:5 | 140:64 | 0.070 |
Previous febrile seizure | 0 | 69 (33.8) | 0.061 |
Age (yr) | 4.4±1.9 (0.7–6.0) | 2.4±1.1 (0.8–5.0) | 0.033 |
Body temperature (°C) | 37.9±0.2 (37.7–38.2) | 38.7±0.6 (38.0–40.0) | <0.001 |
<37.8°C | 3 (42.9) | 0 | <0.001 |
≥37.8°C | 4 (57.1) | 204 (100.0) | |
Seizure type | 0.425 | ||
Generalized tonic-clonic | 5 (71.4) | 181 (88.7) | |
Focal onset (impaired awareness) | 2 (28.6) | 23 (11.3) | |
Seizure frequency (/day) | 2.1±1.5 (1.0–4.0) | 1.1±0.3 (1.0–2.0) | 0.124 |
Seizure duration (min) | 1.9±1.8 (0.5–5.0) | 2.7±3.6 (0.2–20.0) | 0.570 |
Values are presented as number (%) or mean±standard deviation (range).
Demographic profiles and clinical presentation of patients with acute myocarditis with seizure-like activities
No. | Sex | Age (yr) | BT (°C) | BP (mm Hg) | HR (/min) | Seizure type | Seizure frequency (/day) | Seizure duration (min) | CTR (CXR) | ECG |
---|---|---|---|---|---|---|---|---|---|---|
1 | M | 0.7 | 37.9 | 80/50 | 100 | FIA | 1 | 5 | 0.55 | CAVB |
2 | F | 3.3 | 38.2 | 85/55 | 120 | GTC | 1 | <1 | 0.52 | ST |
3 | F | 4.5 | 38.1 | 90/55 | 95 | GTC | 4 | <1 | 0.52 | ST |
4 | F | 4.8 | 37.7 | 90/60 | 80 | GTC | 1 | 3 | 0.50 | CAVB |
5 | F | 5.6 | 38.0 | 90/60 | 65 | GTC | 3 | <1 | 0.50 | CAVB |
6 | M | 5.9 | 37.7 | 90/65 | 65 | GTC | 3 | 1 | 0.53 | CAVB |
7 | F | 6.0 | 37.7 | 85/50 | 70 | FIA | 1 | 3 | 0.55 | CAVB |
BT, body temperature; BP, blood pressure; HR, heart rate; CTR, cardio-thoracic ratio; CXR, chest X-ray; ECG, electrocardiography; FIA, focal onset impaired awareness; CAVB, complete atrioventricular block; GTC, generalized tonic-clonic; ST, sinus tachycardia.
Comparison of laboratory results between patients with acute myocarditis and febrile seizures
Laboratory findings | Myocarditis (n=7) | FS (n=204) | |
---|---|---|---|
Leukocyte (×103/µL) | 13.2±8.8 (5.3–31.8) | 13.5±6.9 (2.5–44.7) | 0.897 |
Hemoglobin (g/dL) | 12.0±1.5 (9.4–14.1) | 11.9±1.0 (9.1–13.7) | 0.797 |
Platelet (×103/µL) | 258.7±184.3 (34.0–608.0) | 271.0±79.4 (110.0–428.0) | 0.866 |
ESR (mm/hr) | 29.2±40.6 (2.0–117) | 14.2±13.0 (2.0–56.0) | 0.368 |
CRP (mg/dL) | 5.4±5.4 (1.8–17.3) | 1.5±1.8 (0.0–8.0) | 0.097 |
AST (IU/L) | 322.7±126.3 (177.0–510.0) | 37.0±12.8 (24.0–116.0) | 0.001 |
ALT (IU/L) | 149.8±64.0 (79.0–269.0) | 17.1±12.2 (8.0–93.0) | 0.002 |
LDH (IU/L) | 1,608.4±972.2 (751.0–3,682.0) | 570.2±104.8 (396.0–909.0) | 0.030 |
TB (mg/dL) | 0.7±0.3 (0.3–1.3) | 0.3±0.2 (0.1–1.2) | 0.026 |
DB (mg/dL) | 0.3±0.1 (0.1–0.5) | 0.1±0.1 (0.0–0.4) | 0.008 |
BUN (mg/dL) | 20.2±9.5 (8.7–39.5) | 12.2±3.6 (7.1–23.3) | 0.069 |
Cr (mg/dL) | 0.9±0.3 (0.5–1.5) | 0.4±0.1 (0.2–0.7) | 0.011 |
Uric acid (mg/dL) | 8.2±3.0 (5.2–14.5) | 4.0±0.9 (2.1–6.6) | 0.009 |
Na (mmol/L) | 134.5±3.6 (129.0–141.0) | 136.0±2.6 (129.0–142.0) | 0.051 |
K (mmol/L) | 4.8±0.4 (4.1–5.2) | 4.2±0.4 (3.5–5.2) | 0.001 |
Glucose (mg/dL) | 146.8±46.5 (10.05–231.0) | 112.5±20.9 (78.0–179.0) | 0.099 |
CK (U/L) | 587.3±252.4 (319.0–1,032.0) | 193.5±210.9 (48.0–993.0) | <0.001 |
Values are presented as number (%) or mean±standard deviation (range).
FS, febrile seizure; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; TB, total bilirubin; DB, direct bilirubin; BUN, blood urea nitrogen; CK, creatine kinase.