Effects of Oral Steroid Therapy on Prevention of Recurrence of Febrile Seizures in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome
Article information
Abstract
Purpose
This study aimed to investigate the occurrence rate of febrile seizures in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and to evaluate the effect of steroid treatment on febrile seizure recurrence.
Methods
Patients diagnosed with PFAPA syndrome at a single tertiary center between 2011 and 2023 were included. Demographic data and febrile seizure history were obtained through a retrospective review of medical records. Oral steroid treatment was administered to 56.7% (72/127) of patients based on the individual clinical course, and its effect on febrile seizure recurrence was evaluated.
Results
A total of 127 patients with PFAPA syndrome were included, and the occurrence rate of febrile seizures was 20.4% (26/127). Of the 26 patients with febrile seizures, 15 (57.7%) received steroid treatment, and the mean number of previous febrile seizure episodes was 3.5±3.5. After steroid treatment, 12 of 15 patients (80.0%) had no further febrile seizures, whereas three of 15 (20.0%) displayed an improvement with only one additional febrile seizure.
Conclusion
The occurrence of febrile seizures was higher in patients with PFAPA syndrome than in the general population. However, febrile seizure recurrence may be substantially reduced with appropriate oral steroid treatment. Therefore, accurate diagnosis of PFAPA syndrome and appropriate steroid treatment may help reduce recurrent febrile seizures.
Introduction
Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is characterized by periodic episodes of high fever (>38°C) lasting 3 to 6 days, typically recurring every 3 to 8 weeks, and accompanied by aphthous stomatitis, pharyngitis, and cervical adenitis. The syndrome was first described in 1987 by Marshall et al. [1], and the acronym PFAPA was subsequently introduced [1,2]. PFAPA is considered an autoinflammatory disease with an unclear pathophysiology. Although the exact occurrence rate of this syndrome remains uncertain, it is known to be more common in children younger than 5 years [3,4].
Similar to PFAPA syndrome, febrile seizures (FS) occur in children between 6 months and 6 years of age and are associated with fever of 38°C or higher [5]. The prevalence of FS in the general population is estimated to be 2%–5% [6]. Given the overlap in age range and the presence of high fever, FS may co-occur with PFAPA syndrome. However, the frequency of co-occurrence of these two conditions has not been clearly established.
Oral steroids, the primary treatment for PFAPA syndrome, are well known for their potent anti-inflammatory effects. After steroid administration, fever typically resolves within 2 to 24 hours in approximately 84.1% to 95% of patients with PFAPA syndrome [7]. Oral steroid therapy for PFAPA syndrome may reduce the duration and frequency of febrile episodes, thereby potentially lowering the risk of associated FS. However, research directly examining whether steroid use reduces FS recurrence in PFAPA syndrome remains limited.
Several studies from Europe, the United States, and South Korea have examined the clinical manifestations of PFAPA syndrome and have also evaluated FS as an associated symptom [8-12]. In particular, a study from Turkey found a significantly higher occurrence rate of FS in patients with PFAPA syndrome than in the general population, which the authors attributed to the higher frequency of fever episodes in PFAPA syndrome [12]. However, to our knowledge, no study has investigated changes in FS recurrence after oral steroid therapy.
Therefore, this study aimed to investigate the occurrence rate of FS in pediatric patients diagnosed with PFAPA syndrome at a tertiary children’s hospital and to compare this rate with its prevalence in the general population. In addition, this study aimed to determine whether steroid use was associated with recurrence of FS in patients with PFAPA syndrome.
Materials and Methods
1. Patients
In this cohort study, we retrospectively reviewed the electronic medical records of patients diagnosed with PFAPA syndrome at Pusan National University Children’s Hospital between May 2011 and June 2023. Patients were selected according to the Marshall criteria for PFAPA syndrome: (1) periodic fevers (>38.3°C) recurring at regular intervals of 3 to 8 weeks, typically beginning at a young age; (2) systemic symptoms in the absence of another proven upper respiratory tract infection, accompanied by at least one of the following: aphthous stomatitis, cervical lymphadenitis, or pharyngitis; (3) exclusion of cyclic neutropenia and other periodic fever syndromes based on medical history or laboratory findings; (4) asymptomatic intervals between febrile episodes; and (5) normal growth and development. Patients with significant neurological disorders or incomplete medical records were excluded.
2. Data collection and assessment of treatment outcomes
For each patient, the following data were collected: sex, age at PFAPA syndrome diagnosis, history of FS, age at FS onset, FS frequency, seizure type, follow-up duration, laboratory findings, brain magnetic resonance imaging (MRI) findings, electroencephalography (EEG) findings, and history of oral steroid treatment.
FS were defined as seizures occurring in association with fever (body temperature ≥38.0°C) in the absence of central nervous system infection or other identifiable causes. For this study, only FS occurring during PFAPA-related febrile episodes were included in the analysis. Mean FS frequency was defined as the average number of FS episodes per patient during the study period. Recurrent seizures occurring within a single febrile episode (within 24 hours) were considered one event. FS were classified as simple or complex based on focal features, seizure duration, and frequency. Complex FS were defined as seizures lasting longer than 15 minutes, occurring more than once within a 24-hour period, or showing focal features, in accordance with standard clinical criteria. Follow-up duration was defined as the interval from PFAPA diagnosis to the last clinic visit. Follow-up duration was recorded for all patients to assess long-term clinical outcomes, including recurrence of FS.
Oral steroid treatment was administered to patients with a history of FS who met at least one of the following criteria: (1) complex FS or (2) recurrent simple FS (≥2 episodes). In addition, treatment was considered for patients whose caregivers had a high level of anxiety about fever or frequently misused antibiotics despite the absence of evidence of bacterial infection.
Oral steroids were prescribed in advance after an explanation of their purpose, rationale, and method of administration, allowing caregivers to administer them immediately at fever onset. Oral prednisolone was administered at a dose of 1–2 mg/kg every 12–24 hours in one or two doses, up to a maximum of three doses. For patients whose fever remained well controlled for at least 2 to 3 weeks after a single oral steroid dose, only one dose was used. However, if fever recurred within a few days because of incompletely controlled inflammation after a single dose, two to three doses were administered at 12- to 24-hour intervals. Patients with no history of FS or with only a single episode of simple FS were not treated with oral steroids.
Data were collected for patients who received steroid treatment, including age at initiation of oral steroid treatment, treatment duration, and FS frequency before and after steroid initiation. Only one patient who experienced recurrent FS did not receive appropriate treatment because of loss to follow-up.
3. Statistical analysis
Age, frequency, duration, and laboratory findings were presented as mean±standard deviation. Categorical variables were analyzed using the chi-square test. Continuous variables were analyzed using either the Student t-test or the Mann–Whitney U test, as appropriate. A P value of less than 0.05 was considered statistically significant.
4. Ethics statement
This study was approved by the Institutional Review Board of Pusan National University Yangsan Hospital (IRB No. 55-2023-009). Written informed consent by the patients was waived due to a retrospective nature of our study.
Results
1. Demographic and laboratory findings of the overall study population
Among the 127 patients with PFAPA syndrome, 72 (56.7%) received steroid therapy, and 65 (51.2%) were male. The mean age at diagnosis was 5.0±2.6 years, and 26 patients (20.4%) had experienced FS. The mean follow-up duration was 51±32 months (range, 1 to 145). Comparison of the general characteristics of patients with PFAPA syndrome in the steroid-treated and steroid-untreated groups showed no significant differences in sex, age at diagnosis, occurrence of FS before treatment, or laboratory findings (Table 1).
Comparison of clinical and laboratory findings between steroid-untreated and steroid-treated groups in patients with PFAPA syndrome
2. Clinical findings in patients with PFAPA syndrome and FS
The clinical characteristics of the 26 patients with PFAPA syndrome who experienced FS during PFAPA-related febrile episodes are presented in Table 2. The mean FS frequency was 3.5±3.5 episodes. Of these 26 patients, 15 (57.7%) received steroid treatment (steroid-treated group). The mean FS frequency was significantly higher in the steroid-treated group than in the steroid-untreated group (4.5±3.8 vs. 1.7±1.0, P=0.039). No significant differences were observed between the groups in age at FS onset or seizure type. Brain MRI findings were normal in all patients. EEG findings were also normal in all patients in the steroid-untreated group, whereas only one patient in the steroid-treated group showed abnormal interictal epileptiform discharges (Table 2). This abnormality was no longer present on follow-up EEG.
Comparison of clinical and laboratory findings between steroid-untreated and steroid-treated groups in PFAPA syndrome patients with FS
3. Characteristics of steroid-treated patients with PFAPA syndrome and FS
Among the 15 patients in the steroid-treated group, the mean FS frequency before steroid treatment was 4.5±3.8 episodes, and the overall reduction rate in FS was 96.2% (Table 3). After steroid treatment, 12 patients experienced no further FS (group A), whereas three patients experienced one additional FS episode before achieving complete remission (group B). Patients in group B had a significantly higher FS frequency before steroid treatment than those in group A (8.7±3.2 vs. 2.7±2.4, P=0.005). Even in group B, complete remission was achieved after a mean duration of 11.8±18.3 months. No significant differences were observed between the groups in age at FS onset, age at steroid treatment initiation, or seizure type (Table 3).
Comparison of characteristics and frequency of FS between no additional FS group and only one additional FS group among steroid-treated patients with PFAPA syndrome
Discussion
The occurrence of FS in children with PFAPA syndrome was higher than that reported in the general pediatric population. Furthermore, steroid therapy was associated with reduced FS recurrence, as most treated patients experienced either no further seizures or only minimal recurrence. These findings suggest a potential association between PFAPA-related febrile episodes and increased seizure susceptibility and support a possible role for steroid therapy in reducing seizure burden.
Several studies have suggested that PFAPA syndrome and FS may share similarities in age at presentation and underlying mechanisms. Although the precise pathophysiology of PFAPA syndrome remains unclear, it is considered an autoinflammatory disorder involving dysfunction of both the innate and adaptive immune systems [13,14]. Interleukin-1 beta (IL-1β) is thought to play a major role in hyperinflammatory responses. Studies investigating cytokine changes during PFAPA febrile episodes have reported increases in proinflammatory cytokines, decreases in anti-inflammatory cytokines, and dysregulation of IL-1β secretion [13,14].
Other recent studies have explored the genetic basis of PFAPA syndrome and have suggested a familial tendency. However, the absence of a clear monogenic pattern indicates a heterogeneous, polygenic, or otherwise complex mode of inheritance [15]. Additionally, one study proposed that PFAPA onset may be influenced by environmental stress [16].
Similarly, studies of FS pathophysiology have also implicated elevated IL-1β secretion as a key factor [17-19]. One animal study described the following pathway: fever promotes production of the pyrogenic cytokine IL-1β, which acts as a seizure-promoting mediator. IL-1β activates neuroinflammatory responses in the brain and contributes to abnormal neuronal activation, leading to seizures. Elevated brain temperature alters neuronal function, including the activity of temperature-sensitive channels in hippocampal neurons. Furthermore, hyperthermia-induced hyperventilation and the resulting respiratory alkalosis increase neuronal excitability [20].
Taken together, these findings, particularly the abnormal increases in cytokines such as IL-1β, support the possibility of pathophysiological overlap between PFAPA syndrome and FS.
Low-dose steroid therapy is recommended as the first-line treatment for PFAPA syndrome, with approximately 84.1% to 95% of patients experiencing fever resolution within 2–24 hours [21]. The anti-inflammatory effects of steroids are partly attributed to inhibition of transcription factors such as nuclear factor kappa B (NF-κB), which regulates the expression of numerous genes involved in inflammation, including those encoding tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-2 [22]. Based on this mechanism, prednisolone has been widely used in PFAPA syndrome because it suppresses production of several proinflammatory and regulatory cytokines, including IL-1β, IL-6, IL-17, IL-10, TNF-α, interferon-gamma, and transforming growth factor-beta [23,24].
When the steroid-treated and steroid-untreated groups were compared, no significant difference was observed in the overall proportion of patients with a history of FS (15/72 [20.8%] vs. 11/55 [20.0%], P=0.908) (Table 1). However, the steroid-treated group had a higher FS frequency before treatment, suggesting that steroid therapy was preferentially administered to patients with more severe or recurrent seizures.
Therefore, direct comparison between the two groups may be subject to selection bias, and the observed differences in outcomes should be interpreted with caution. The reduction in FS after steroid therapy may reflect both treatment effects and underlying differences in baseline seizure susceptibility.
This study found that recurrence of FS decreased by 96.2% among patients who received low-dose steroids. Among the three patients who experienced additional FS after steroid initiation, two had their last FS approximately 1 month after treatment began, whereas the third experienced a seizure after a 3-year interval. In the latter case, it is unclear whether steroid treatment contributed to the cessation of FS; however, the other two patients may have benefited from treatment.
To date, no studies have clearly elucidated the mechanism by which steroid treatment prevents FS in children with PFAPA syndrome. Steroids are known to suppress synthesis of proinflammatory cytokines such as TNF-α, IL-1β, and IL-2 through genomic mechanisms, primarily via inhibition of transcription factors such as NF-κB. Based on this mechanism, steroids may reduce secretion of cytokines involved in FS pathogenesis and thereby exert a preventive effect [17-20,22-25].
Although excessive steroid use solely for the prevention of FS is not considered appropriate, this study suggests that appropriate steroid use in patients with PFAPA syndrome may help reduce FS frequency. Therefore, accurate diagnosis and appropriate steroid therapy may help alleviate the burden of FS in children with PFAPA syndrome who experience recurrent FS.
This study has several limitations. First, the decision to initiate steroid therapy was based on patients’ clinical characteristics, particularly FS severity and recurrence, which may have introduced selection bias. As a result, direct comparison between the steroid-treated and steroid-untreated groups is limited, and causal inferences regarding the effect of steroid therapy should be made with caution. In addition, analyses of high-risk subgroups, such as patients with recurrent or complex FS, were not performed because of the limited sample size. Therefore, the independent effect of steroid therapy in these subgroups could not be fully evaluated. Second, the retrospective design resulted in an unequal distribution of patients between the steroid-treated and steroid-untreated groups. Third, some patients may not have visited the hospital for every FS episode, and some may have been lost to long-term follow-up. In addition, the study relied on caregivers’ recollections of medical history, which may have introduced recall bias.
Despite these limitations, this study is the first to report the occurrence rate of FS in children with PFAPA syndrome in South Korea and to analyze the potential effect of steroid treatment on FS in this population. Further studies incorporating stratified or controlled analyses in high-risk subgroups, such as patients with recurrent or complex FS, are needed to better evaluate the independent effect of steroid therapy.
In conclusion, our results showed that the frequency of FS in patients with PFAPA syndrome was higher than that in the general population. Furthermore, this study suggests that steroid treatment in patients with PFAPA syndrome could help reduce FS frequency and may lead to cessation of recurrence.
Further cohort studies with larger patient populations, as well as molecular investigations including cytokine profiling, are expected to provide more definitive insights. In patients presenting with the typical clinical features of PFAPA syndrome, recurrent fever, and frequent FS, accurate diagnosis and appropriate steroid treatment may help alleviate the burden and stress associated with recurrent FS.
Notes
Conflicts of interest
Sang Ook Nam is an editorial board member of the journal, but he was not involved in peer reviewer selection, evaluation, or the decision-making process for this article. The other authors have no conflicts of interest to disclose.
Author contribution
Conceptualization: SEP and YJL. Data curation: SL, JK, SEP, KJJ, and TJL. Formal analysis: SL. Methodology: SL. Project administration: YJL. Writing-original draft: SL. Writing-review & editing: JK, SON, SEP, and YJL.