The acid-base balance homeostasis reflected by urine pH in children with infantile epileptic spasm syndrome may be associated with response to adrenocorticotropic hormone treatment: a retrospective cohort study

Introduction

Infantile epileptic spasms syndrome (IESS), an age-related developmental and epileptic encephalopathy, is characterized by the onset of epileptic spasms at the age of 1–24 months, with electroencephalogram (EEG) showing hypsarrhythmia, multifocal, or focal epileptiform discharges during the interictal period (1,2). IESS can have various etiologies. Based on imaging and genetic findings, the etiologies can be divided into six categories: structural, genetic, infectious, metabolic, immunological, and unknown (3).

Hormonal therapy [either adrenocorticotropic hormone (ACTH) or prednisolone] and vigabatrin (VGB) are the first-line therapeutic agents for IESS (4). The current consensus recommends hormonal therapy as the preferred first-line therapy for children with IESS, except for those with tuberous sclerosis complex (TSC) combined with IESS (4-6). However, the results of treatment for IESS remain unsatisfactory. The proportion of children with epileptic spasms remission after short-term ACTH treatment (2–3 weeks) ranges from 36.7% to 87% (5). A few studies on long-term outcomes showed that only a quarter of patients achieve a favorable long-term cognitive outcome, while a third of children remain seizure-free (5). However, not all factors affecting ACTH treatment response can be explained based on the existing studies. Previous studies have found that the efficacy of ACTH is influenced by diverse clinical and biological factors, including etiology, age of onset, time to first treatment, EEG features such as the presence, type, and duration of epileptiform discharges, dose of ACTH, and combination with other treatments (7-11). And further research is needed to identify biomarkers that predict ACTH efficacy.

The normal functioning of the human body depends on the maintenance of an appropriate acid-base balance (12). The primary goal of regulating body acid-base metabolism is to maintain the pH of body fluids within a tight range to provide optimal conditions for cellular function (13). Acid-base balance can significantly affect seizure susceptibility with alkaline pH being proconvulsant and acidic pH having anti-seizure effects (14,15). pH also can influence drug pharmacokinetics, including solubility, absorption and distribution, stability, and excretion. If disturbed, pH can alter drug bioavailability, causing under- or over-dosing (12,13). Changes in urine pH may reflect the state of the acid-base balance and the ability of the kidneys to regulate it. Exogenous supplementation of acidic or alkaline substances may regulate the acid-base balance and thus influence drug metabolism (12). This acid-base balance may regulate drug metabolism by acidifying or alkalizing the urine to some extent. Studies showed that urine pH plays an important role in the treatment of urinary tract infections with antibiotics. Additionally, urine pH changes may impact the activity of antibiotics (16,17).

ACTH treatment for IESS can lead to electrolyte disturbances such as hypocalcemia, hypophosphatemia, and hypokalemia (5,18). A previous study showed that higher serum calcium was significantly associated with a favorable ACTH response and positive long-term outcomes (9). On the one hand, ACTH can influence serum Ca²⁺ levels in children with IESS. On the other hand, serum Ca²⁺ levels play an important role in predicting the therapeutic efficacy of ACTH in children with IESS. Considering that the stability of the internal environment is the result of the interaction and a certain proportion of electrolytes, electrolyte disturbances (such as abnormal blood sodium and phosphate levels) are associated with epilepsy (19,20). Whether electrolyte stabilization associated with the acid-base balance correlates with the efficacy of ACTH also requires exploration.

Therefore, we conducted this study to explore whether serum electrolytes and urine pH levels of children with IESS before ACTH treatment influence the efficacy of ACTH by retrospectively analyzing the data of children with IESS who underwent ACTH treatment for the first time in our hospital. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-439/rc).

Methods

Study cohort

Patients with IESS who received ACTH treatment for the first time in the Pediatric Department of The First Medical Center of the Chinese PLA General Hospital from January 2018 to June 2023 were included in this study.

Inclusion criteria

(I) Patients meeting the diagnostic criteria of IESS (the seizures manifest as flexor, extensor, or mixed epileptic spasms which often occur in clusters; onset of epileptic spasms between 1 and 24 months of age; and an interictal EEG showing hypsarrhythmia, multifocal or focal epileptiform discharges) (1); (II) patients who received first-line ACTH treatment for the first time at our hospital and completed treatment according to the protocol; (III) patients who completed all the necessary investigations to clarify the etiology.

Exclusion criteria

(I) Patients who used other first-line therapies concurrently during ACTH treatment; (II) patients who failed to provide blood or urine samples before treatment; (III) omissions and errors in the recording of medical record information.

Data collection

Clinical data comprised the patient’s sex, age of epilepsy onset, age of epileptic spasms onset, a first seizure type, combination with other seizure types, developmental delay, age at treatment, etiological factors, response to ACTH treatment, serum electrolytes, urine pH, urine specific gravity, and EEG results.

All patients were recorded their time of the first epilepsy occurrence and first epileptic spasm appearance by caregivers, and were divided into two groups according to the first seizure type. While the onset of spasms is between 1–24 months, if it occurs before 3 months of age, other developmental epileptic encephalopathies (DEEs) should be considered (1). Regarding the age of epilepsy onset, the age of ≤3 months was defined as the early infantile epilepsy group, and patients with epileptic spasms onset at the age of >12 or ≤24 months were determined to be late-onset IESS cases (21). The two groups were further divided according to the presence or absence of other seizure types. The general development of IESS patients before the onset of epilepsy was effectively assessed before the consultation, considering any form of developmental lag in mental or motor functioning as abnormal (21).

All patients were treated with slow intravenous ACTH infusion once daily for 2 weeks at ≥2.5 U/kg/day during hospitalization. At present, there are significant differences in the clinical application of ACTH in the treatment of IESS. There is no unified standard for its dosage and type, and there is a lack of corresponding authoritative guidelines. Previous studies have shown that there is no significant difference in treatment effects between high-dose and low-dose ACTH, and low-dose ACTH has more advantages in terms of safety with fewer side effects. Based on these research results, currently, many countries, including the United States and Japan, have gradually started to use low-dose ACTH for treatment. In our institution, we have long been using an ACTH dosage of 2.5 U/kg, and the ACTH we use is extracted from natural sources (22-26). The ACTH used in this study is a naturally extracted preparation, sourced from the pituitary glands of animals such as pigs, cattle, and sheep. Its specification is 25 units per vial, with water for injection as the excipient. It contains no gelatin or other carrier components. This preparation is manufactured by Shanghai No. 1 Biochemical Pharmaceutical Co., Ltd., and its National Drug Approval Number is H31022101. Ancillary tests were performed before treatment, including fasting blood (which typically involve drawing blood after the patient has fasted for a specified period, usually 8–12 hours, to obtain accurate measurements of various blood components such as glucose, lipids, and certain enzymes), serum biochemical, and urine routine examinations (urine pH was measured by colorimetry in 0.5-pH unit increments after obtaining samples at room temperature). All patients underwent a 2–3-hour video EEG during wakefulness and sleep before starting ACTH treatment and were divided into two groups based on the presence or absence of hypsarrhythmia. Based on the patient’s clinical assessment and the etiological classification of previous studies (3,27), we classified all patients into five categories: acquired structural abnormalities, congenital structural abnormalities with genetic/metabolic abnormalities, congenital structural abnormalities without genetic or metabolic abnormalities, congenital genetic/metabolic abnormalities without structural abnormalities, and unknown etiology (21).

Determination of short-term efficacy

Regarding the short-term efficacy of ACTH for IESS treatment, the initial response was defined as the remission of epileptic spasms after using any standardized therapies and lasting for at least 4 weeks. Otherwise, it was considered as no initial response to the medication (27). Throughout the ACTH course, the presence or absence of clinical seizures was documented daily for every patient. And all patients underwent a 2–3-hour video EEG during wakefulness and sleep at the end of the first and second weeks of ACTH treatment. Electroclinical resolution was taken as the positive outcome. Hence, we divided the children into two groups according to treatment efficacy: responsive (no epileptic spasms or other forms of seizures, lasting ≥4 weeks) and non-responsive groups (still having seizures or remission lasting <4 weeks).

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Medical Center of the Chinese PLA General Hospital (No. S2020-337-01) and informed consent was taken from all the patients’ parents or legal guardians.

Statistical analysis

All statistical analyses were performed using the R (version 4.2.2 and MSTATA software. A P value <0.05 indicated statistical significance. Mean ± standard deviation (SD) was used to describe continuous normally distributed variables, while median and interquartile range were used for continuous not normally distributed variables. Frequency (percentage) was used to represent categorical variables. Group comparisons for continuous variables with normal distribution were performed using Welch’s t-test or analysis of variance (ANOVA), whereas non-normally distributed variables were compared using the Wilcoxon rank-sum test or the Kruskal-Wallis test. The Fisher exact test or Chi-squared test was used to compare groups of categorical data. The association between each individual factor and the outcome variable was assessed using univariable logistic regression analysis to study the influencing factors. Based on the results of the univariable analysis, variables with a P value of <0.1 were selected for inclusion in the multivariable analysis model.

Results

From January 2018 to June 2023, 273 patients with IESS received first-line treatment in our hospital for the first time. Among them, 10 children were treated with VGB as first-line therapy, while the remaining 263 children were treated with ACTH according to the standard protocol. Seventy-seven children did not successfully provide urine or venous blood samples before ACTH treatment. Thus, 186 were finally included in the study (Figure 1).

Figure 1 Enrolment flowchart for the study cohort. ACTH, adrenocorticotropic hormone; IESS, infantile epileptic spasm syndrome.

Out of 186 patients, 73 (39.2%) were female, and 113 (60.8%) were male. The age of the seizure onset was 5.5 (4.0, 8.0) months, and the age of the epileptic spasms onset was 6.0 (4.0, 8.0) months. In 36 (19.4%) children, other seizure types were present before epileptic spasms. Twenty-six children (14.0%) had epilepsy onset within 3 months of age, 25 children (13.4%) had epileptic spasms onset after 1 year of age, and 26 children (14.0%) presented with other seizure types concurrently. We classified them according to clinical data (IESS classification): (I) acquired structural abnormalities (n=47, 25.3%); (II) congenital structural abnormalities with genetic abnormalities, congenital (n=19, 10.2%); (III) congenital structural anomalies without genetic abnormalities (n=56, 30.1%); (IV) congenital genetic abnormalities without structural abnormalities (n=20, 10.8%); (V) unknown etiology (n=44, 23.7%) (Table 1).

Patients were divided into two groups based on the effectiveness of ACTH treatment, with 82 patients in the responsive group and 104 in the non-responsive group. The median age at first ACTH treatment was slightly lower in the responsive group than in the non-responsive group (8.0 and 9.5 months, respectively), although this difference was not statistically significant (P=0.22). The median lead time between the first epileptic spasm onset and the start of ACTH treatment was 1.5 months (range, 1–3 months) in the responsive group, significantly shorter than that in the non-responsive group (median 2.25 months, range, 1–5.25 months). This difference was statistically significant (P=0.01) (Table 1).

The analysis of serum electrolyte levels in the children before ACTH treatment showed that the median value of serum inorganic phosphates was 1.86 (1.75, 1.96) mmol/L in the responsive group and 1.93 (1.79, 2.01) mmol/L in the non-responsive group. There was no statistically significant difference between the two groups (P=0.07). The analysis found no significant difference in serum sodium, potassium, calcium, and chloride levels between the two groups. The median urinary pH was 7.0 in the responsive group and 6.5 in the non-responsive group. Urinary pH was significantly higher in the responsive group (P=0.01), although there was no significant difference in urine-specific gravity between the two groups (Table 1).

Significant differences were observed in the age of seizure onset, with a higher proportion of patients in the responsive group experiencing epileptic spasms onset after 3 months of age (92.7% in the responsive group and 80.8% in the non-responsive group, P=0.02). In contrast, there were no significant differences in sex, first seizure type, combination with other seizure forms, late- or early-onset epileptic spasms, hypsarrhythmia presence, the presence of developmental delay before the epileptic spasms onset, and the etiology-based IESS classification (Table 1).

The outcome of ACTH treatment was assessed by one-way logistic regression analyses, showing significant associations for several independent factors. A shorter lead time from first epileptic spasm onset to the start of ACTH treatment was associated with a better outcome (P=0.008). Higher pre-treatment urinary pH was linked to greater efficacy of ACTH therapy (P=0.03). Children with early-onset epilepsy (seizure onset at ≤3 months) respond poorly to ACTH therapy (P=0.03). And the IESS classification (congenital genetic abnormalities without structural abnormalities) was also associated with a worse response to ACTH therapy (P=0.03). Pre-treatment inorganic phosphate levels with P values <0.1 were likewise included in the final multifactorial model (Table 2).

In the multifactorial analysis assessing the outcome of ACTH treatment, a shorter lead time from epileptic spasm onset to treatment initiation was more likely to result in a positive response to ACTH treatment [odds ratio (OR) =0.86; 95% confidence interval (CI): 0.77–0.95; P=0.005]. Similarly, elevated serum inorganic phosphate levels were associated with an increased risk of no response to ACTH treatment (OR =0.13; 95% CI: 0.02–0.94; P=0.043). Conversely, pre-treatment higher urine pH was more likely to result in a positive response to ACTH treatment (OR =1.80; 95% CI: 1.10–2.96; P=0.02). Children with early-onset epilepsy (seizure onset at ≤3 months) were more unlikely to have a short-term response to ACTH (OR =0.30; 95% CI: 0.11–0.84; P=0.02). Compared to children with IESS of unknown etiology, patients with congenital genetic abnormalities without structural abnormalities were less likely to have a short-term response to ACTH treatment (OR =0.26; 95% CI: 0.07–0.89; P=0.03). In contrast, acquired structural abnormalities, congenital structural abnormalities with genetic abnormalities, and congenital structural anomalies without genetic abnormalities had no statistically significant impact on the treatment outcome (Table 3).

Discussion

IESS is a severe infantile developmental and epileptic encephalopathy. Many infants have poor developmental outcomes regardless of the outcome of epileptic seizures, with the severity of developmental delay being related to the etiology and timeliness of treatment (23). ACTH is one of the preferred first-line treatments for IESS, with the time of treatment initiation possibly being significantly associated with prognosis. Consistent with our findings, established studies showed that shorter lead time is associated with better treatment response and subsequently improved developmental outcomes (28,29). Knupp et al. also demonstrated that children who received the first treatment within 4 weeks of onset had a higher response rate than those who received their first treatment later (30). As the duration of epileptic spasms and the time from the treatment initiation to epileptic spasms remission increase, the risk of intellectual disability significantly increases, suggesting that prompt treatment is essential to avoid or minimize the negative impact of epileptic spasms on psychomotor developmental outcomes (31). Therefore, early definitive diagnosis and initiation of first-line treatment may positively impact disease control and long-term prognosis. Considering that treatment outcome is also related to the age of seizure onset, we found that children with seizures in early infancy (<3 months) were less likely to respond to ACTH treatment. Other early-onset DEE should be considered if the age of onset is <3 months (1). Previous studies indicated that children with Ohtahara syndrome, a group of children who present with seizures early in life (<3 months of age), are at risk of transitioning to IESS, with seizures in this group being usually drug-resistant (1), which may explain the phenomenon found in our study. The diagnostic criteria for IESS lack precision and strict exclusion rules. The core diagnostic element is the occurrence of epileptic spasm attacks within the age range of 1 to 24 months. All the children included in this study not only meet the above necessary diagnostic criteria but also exhibit clear developmental delay after the onset of the disease. EEG shows hypsarrhythmia, which is highly consistent with the diagnostic criteria of IESS. It is particularly noted that for the group of children with an onset age of less than 3 months, there should be vigilance for early-onset epileptic encephalopathy, such as Ohtahara syndrome, early myoclonic encephalopathy, etc. During the dynamic development of the disease, these children are highly likely to progress to other types of epilepsy syndromes. However, based on a comprehensive analysis of the onset age, seizure pattern, and EEG characteristics of the children at the time of the onset of the disease, the diagnosis of IESS made by us is fully reasonable and reliable.

While categorizing the etiology, our study found that compared with unknown etiology, children with IESS with congenital genetic abnormalities without structural abnormalities were less likely to have a short-term response to ACTH therapy. Thus, genetic factors play an important role in IESS treatment. A cohort study published in 2022 also suggested that patients with a genetic etiology were more likely to have unfavorable treatment outcomes compared to those with an unknown etiology (27). Surana et al. showed that the prevalence of drug-resistant epileptic spasms could reach 55% in patients with congenital genetic abnormalities (excluding patients with congenital structural abnormalities with genetic abnormalities) (29). Among the 186 children with IESS, our study cohort had 20 children with congenital genetic abnormalities without structural abnormalities, and 15 of them did not respond to the first ACTH treatment, accounting for 75% (Table 1), which is similar to the previous conclusions. Therefore, the standard treatment of IESS should consider the efficacy according to the etiology, and active genetic testing is more conducive to predicting the efficacy and prognosis of the disease while clarifying the etiology.

Ca²⁺ can influence the ACTH release, while ACTH induces a transient increase in intracellular Ca²⁺ (32). A retrospective study of 129 patients by Meng et al. found that the serum Ca²⁺ level was significantly associated with a good response to the combined treatment including ACTH and antiseizure medications (ASMs), with a good response to the first treatment showing a significant predictive value for the long-term prognosis of epilepsy (9). However, our findings did not suggest a significant difference in serum Ca²⁺ levels between responsive and non-responsive groups, which may require multicentric research with a larger sample size for further validation. It is also necessary to assess the correlation of pre- and post-treatment serum Ca²⁺ levels with treatment outcome and long-term prognosis.

Regarding the relationship between phosphate and epilepsy, some studies suggested that hypophosphatemia is associated with tonic-clonic seizures, with one-third of patients showing an early rise and fall in phosphate levels within 2 hours of the end of such seizure (19,33). Coutinho et al. supported the idea that hypophosphatemia can be used as a biomarker for seizures (34). Previous studies have shown that increased expression and activity of corticotropin-releasing hormone (CRH) can trigger IESS (2). ACTH can treat IESS by downregulating the expression of CRH (35,36). CRH, via excessive glucocorticoids, disrupts phosphorus metabolism and ultimately leads to hypophosphatemia (37,38). Our study found lower pre-treatment serum inorganic phosphate levels were associated with better short-term response to ACTH therapy. Hence, serum inorganic phosphate may also play an important role in ACTH treatment for IESS.

The systemic acid-base imbalance influences the central nervous system. The excitability of neuronal circuits is remarkably modulated by changes in pH, with elevated pH increasing excitability and acidosis having the opposite effect (14,15). Some studies showed that lowering brain acidity can eliminate chronic seizures; thus, normalizing brain acidity may be an effective treatment for intractable epilepsy (39-41). For example, a ketogenic diet can cause respiratory changes, subsequently creating an acidotic environment within the brain. This diet-induced brain acidification achieved remarkable success in reducing the number of epileptic spasm attacks and improving abnormal EEG manifestations, opening up a novel avenue for the clinical treatment of IESS (42). Urine pH collection is more acceptable as a non-invasive method for infants and toddlers. Studies on ASMs found that drugs such as sodium valproate and topiramate control seizures by lowering brain pH and increasing urine pH (43-46). The relationship between IESS and urine pH remains unclear at present. A study of West syndrome patients found that urinary pH gradually increased after ACTH therapy and stayed elevated (47). Our study revealed a significant correlation: the higher the pre-treatment urine pH, the greater the likelihood of a positive response to ACTH treatment. This finding offers a new perspective and a potential evaluation index for predicting the efficacy of ACTH in IESS treatment.

Nevertheless, there are several limitations in this study. First, this was a single-center retrospective study with a single source of samples, restricting the universality and extrapolation of the research results to some extent. Simultaneously, since research subjects were mostly infants and toddlers at a relatively young age, this particular age group poses a tremendous challenge to sample collection. Some children failed to successfully provide blood or urine samples before treatment, resulting in the loss data for this part and necessitating their exclusion from the final analysis. Such selective sample loss is highly likely to introduce bias at the data level, deviating the research results from the real situation. Therefore, great caution must be exercised when interpreting and applying our results. Second, considering the special daily routine and nursing difficulties of infants and toddlers, uniformly setting an exact sample collection time point, such as early morning, is almost impossible for all research subjects. Although the human body regulates the acid-base balance, which can buffer the impact of time factors on acid-base indicators to a certain extent, it cannot completely rule out the potential interference with the research results. However, this influence is relatively minor compared to other factors. Third, this study had certain limitations in the choice of the urine pH testing technique. Despite simple operation and low cost, the colorimetric method adopted has significant deficiencies in testing precision; thus, accurate urine pH values are difficult to obtain. Since this study was based on a retrospective analysis of previous data, there were numerous practical difficulties in re-acquiring data and updating the testing method. Therefore, this technical defect was difficult to be effectively remedied within the current research framework. In the future, actively exploring and introducing more advanced and precise urine pH testing techniques, such as the ion-selective electrode method, is recommended to enhance the quality and reliability of research data and provide a more solid technical foundation for the in-depth exploration of the pathophysiological mechanisms of epilepsy and optimization of treatment strategies. Fourth, due to various reasons, patients were unable to undergo video EEG follow-up after one month. Besides, the efficacy of ACTH in the treatment of IESS is highly susceptible to the combined influence of multiple factors, such as the age of onset, the timing of treatment intervention, and potential etiologies. It is worth noting that the complexity of the related causative genes far exceeds the current level of understanding, and they may independently trigger dynamic changes in the urinary pH value during the disease progression. Given the interaction of the above factors and the uncertainty of their influencing mechanisms, when evaluating the results of this study, a scientific and rigorous attitude should be maintained, the data should be interpreted cautiously, and potential confounding factors should be fully considered.

Conclusions

Our study demonstrated a negative association between the lead time of treatment and the first-line response to ACTH. Therefore, the earlier the ACTH treatment is initiated, the greater the likelihood of achieving a short-term response. However, obtaining a short-term response is often more difficult for children experiencing epileptic seizures in the early stage of life and those with a genetic etiology. Notably, in contrast to previous studies, our study also suggested that an increase in urine pH and a decrease in inorganic phosphate levels may be associated with the ACTH response. The underlying reason might be related to the homeostatic mechanism regulating the acid-base balance. This may have indicative significance for precision treatment. At the same time, it is also necessary to incorporate the patient’s information to provide accurate suggestions for personalized treatment. Accordingly, conducting rigorous verification and analysis through a multicenter and larger cohort study in the future is needed to explore this phenomenon.

Acknowledgments

We acknowledged all the medical staffs who were involved in our study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-439/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-439/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-439/prf

Funding: This research was funded by the general project of National Key Research and Development Program of China (Nos. 2023YFC2706405 and 2022YFC2705300), Capital’s Funds for Health Improvement and Research (No. 2024-2-5082), the Key Project of Innovation Cultivation Fund of the Seventh Medical Center of Chinese PLA General Hospital (No. QZX-2023-1), CAAE Epilepsy Research Fund - UCB Fund (Applied Research) (Grant No. CU-2023-057), and Innovation Talent Fund of Senior Department of Pediatrics, The Seventh Medical Center of PLA General Hospital (No. QZX-04-EKLHJH-3).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-439/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the First Medical Center of the Chinese PLA General Hospital (No. S2020-337-01) and informed consent was taken from all the patients’ parents or legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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