This is the first randomized-controlled study to investigate the efficacy of treating H. pylori infection on seizure frequency in children with drug-resistant IGE. We found that H. pylori eradication therapy leads to significant improvement in seizures (≥ 50% SFR); on average, five patients would have to receive H. pylori eradication therapy for one additional patient to have improved seizure control. Moreover, eradicating H. pylori infection resulted in a lower occurrence of status epilepticus and lower need for escalation of ASMs with no significant adverse effects. This indicates that eradicating H. pylori infection could be a promising therapeutic option to control seizures in children with drug-resistant IGE, but further confirmatory studies are warranted.

Our study findings are in disagreement with Asadi-Pooya et al. [14] who reported that treating H. pylori infection is not significantly associated with change of seizure frequency in patients with refractory epilepsy. However, Asadi-Pooya et al. [14] study is markedly underpowered with too small sample size of only nine patients, and it lacks a control group, which raises concerns about possible selection bias and confounding. Furthermore, our study included only patients with IGE, while Asadi-Pooya et al. [14] mostly included patients with temporal lobe epilepsy; it is possible that H. pylori eradication therapy is more effective in patients with IGE than other epilepsy types, but this postulation remains to be confirmed by future studies.

Observational studies on the association between H. pylori infection and epilepsy have shown inconsistent results. Okuda et al. [10] and Ozturk et al. [11] reported a significantly higher prevalence of H. pylori infection among patients with epilepsy, and that H. pylori infection is associated with worse prognosis. In contrast, Asadi-Pooya et al. [12] showed no significant difference in prevalence of H. pylori infection between adult epileptic patients and healthy controls. However, the healthy control group was older than both epileptic groups, which could confound the results since H. pylori prevalence is higher among older individuals [18]. Moreover, given the reported high prevalence of H. pylori infection, a higher number of participants would be required for an adequately powered study. In another study, adult epileptic patients had more prevalent H. pylori infection than healthy controls (64.3% vs. 35.7%), but the difference did not reach statistical significance likely due to the small sample size [13]. A meta-analysis of these four observational studies concluded that the prevalence of H. pylori infection is significantly higher among epileptic patients than healthy population (46.98% vs. 26.34%, OR 2.58) [3].

The association between H. pylori infection and epilepsy may be attributed to several biological mechanisms. First, a cross-mimicry between H. pylori and human cellular phospholipids may result in H. pylori-induced autoimmune reaction with production of anticardiolipin antibodies [10]. Studies have shown that patients with epilepsy, particularly idiopathic epilepsy, have an increased prevalence of autoantibodies, including anticardiolipin antibodies [19,20,21]. Importantly, one study reported that H. pylori eradication therapy is associated with gradual resolution of neurological symptoms in a patient with antiphospholipid antibody syndrome [22]. Another possible mechanism is H. pylori infection-induced low-grade systemic inflammation with local secretion of proinflammatory mediators (e.g., interleukin-8,-6, -1beta, -10-12, tumor necrosis factor, interferon gamma) [2, 23]. Persistent release of proinflammatory mediators into the systemic circulation may induce disruption of blood-brain barrier, neuroinflammation, and neurotoxicity, all of which contribute to the pathogenesis of epilepsy and lowering of seizure threshold [3, 18, 23]. Additionally, H. pylori infection may induce the release of multiple neurotransmitters, such as serotonin, dopamine, acetylcholine, adrenaline, and noradrenaline [24]. Furthermore, H. pylori infection may lead to neuronal/axonal damage, formation of free radicals, and changes in the expression of neuropeptides, such as vasoactive intestinal peptide and c-fos [24]. Last, H. pylori infection may induce alterations in the composition of gut microbiome, which may be associated with poor response of epileptic patients to ASMs [25,26,27,28].

Of note, it is possible that H. pylori eradication therapy might help control seizures in children with drug-resistant IGA by mechanisms other than eradication of H. pylori infection. For instance, clarithromycin has the potential to inhibit the metabolism and increase serum levels of carbamazepine [29]. Additionally, proton pump inhibitors exert antioxidant, anti-inflammatory, and anti-apoptotic effects, which may play a protective role in the pathogenesis of epilepsy and neurodegenerative diseases [30]. Of note, pantoprazole has been shown to significantly improve seizures in pentylenetetrazole‑induced epileptic seizures in rats [31].

Our findings go in line with studies showing that treating H. pylori infection improves clinical outcomes of patients with certain neurological disorders, such as Parkinson disease and Alzheimer’s disease, which emphasizes the microbial-neurological connection and the gut-brain interface [23, 32, 33]. Given that H. pylori infects more than half of population worldwide, further studies are required to investigate its role in the pathogenesis of neurological and seizure disorders and the potential value of H. pylori eradication therapy [23, 29].

The key strengths of the current study include its randomized controlled study design, conducting both intention-to-treat and per-protocol analyses, and the focus on meaningful clinical outcomes. However, we acknowledge some study limitations. First, the relatively small sample size might preclude study power to detect some statistically significant associations. Moreover, while the outcome assessors were blinded to study group allocation, the lack of blinding for participants and treating physicians leaves the room for potential bias. In addition, H. pylori infection was not confirmed by endoscopic biopsy and histopathological examination. The diagnosis of H. pylori infection was based on HpSA testing, which is a widely available and cost-effective technique for primary diagnosis and eradication monitoring with sensitivity and specificity of 95% and 97.6%, respectively [1, 2]. While we can not absolutely exclude the possibility that some participants might have false positive HpSA testing, this is unlikely to affect study findings since such possible participants with false positive results would be randomly distributed between the study and comparison group, and such non-differential misclassification might result in biasing the risk ratio towards rather than away from the null. However, more specific diagnostic tests for H. pylori infection are certainly recommended in future studies. Another limitation is related to the lack of extensive laboratory or neurophysiological studies to unravel the exact pathophysiological mechanisms for seizure improvement following H. pylori eradication therapy. Future studies should delve deeper into these mechanisms (e.g., assessing inflammatory markers, gut microbiome analysis, neuroimaging studies) to explain how H. pylori interacts with neurological health and predisposes to epilepsy. Furthermore, the short follow-up period (2.5 months) is not enough to determine whether the observed benefits of H. pylori eradication are sustainable over the long-term, which is particularly important when considering epilepsy as a chronic condition that demands consistent management. Finally, this study included children with drug-resistant IGE from a single center in Egypt. Accordingly, the findings may not be generalizable to populations from different regions or with varied dietary and microbiome profiles, which could be addressed by a broader and multi-center approach in future studies.