Meta-analysis of Association between Helicobacter pylori Infection and Epilepsy
Gang Yao1, Ping Wang2, Xiang-Dan Luo3 and Ting-Min Yu1*
1Department of Neurology, The Second Hospital of Jilin University, China
2Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, China
3Department of Nutrition, The Second Hospital of Jilin University, China
*Corresponding author: Tingmin Yu, MD, PhD, Department of Neurology, The Second Hospital of Jilin University, Changchun, China, Tel: +86-0431-88796298, E-mail: email@example.com
Int J Brain Disord Treat, IJBDT-2-016, (Volume 2, Issue 2), Original Article; ISSN: 2469-5866
Received: September 08, 2016 | Accepted: December 02, 2016 | Published: December 06, 2016
Citation: Yao G, Wang P, Xiang-Dan L, Ting-Min Y (2016) Meta-analysis of Association between Helicobacter pylori Infection and Epilepsy. Int J Brain Disord Treat 2:016. 10.23937/2469-5866/1510016
Copyright: © 2016 Yao G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Despite recent research focus on the association between Helicobacter pylori (H. pylori) infection and epilepsy there is no consensus about the findings. To obtain a more comprehensive estimate of the association we conducted a meta-analysis to determine the prevalence of H. pylori infection in epilepsy patients and healthy controls. PubMed, EMBASE, Cochrane Library, Web of Science, Google Scholar and CINAHL were searched to identify eligible studies. Four studies were selected for inclusion, involving 418 cases (232 patients with epilepsy and 186 controls). Overall, the prevalence of H. pylori infection in patients with epilepsy was higher than that in control groups. (46.98% vs. 26.34%, OR = 2.58, 95% CI: 1.15-5.82, P = 0.02). Subgroup analysis revealed that the levels of H. pylori infection in epilepsy patients was greater than that in control group by using ELISA (OR = 5.36, 95% CI: 2.62-10.95, P < 0.00001), but it was not statistically significant difference when using 13C urea breath test (OR = 1.36, 95% CI: 0.75-2.46, P = 0.32). Our analysis demonstrated that the association between H. pylori infection and epilepsy is a significant positive correlation. Whether H. pylori infection is a risk factor for epilepsy should thus be addressed in large-scale and prospective studies.
Epilepsy, Helicobacter pylori, Prevalence, Meta-analysis
Helicobacter pylori (H. pylori) is a gram-negative bacterium and mainly associated with chronic gastritis, peptic ulcer disease, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma [1,2]. Furthermore, some reports have discerned a relationship between H. pylori infection and extra-gastrointestinal diseases such as cirrhosis, pancreatic cancer, coronary heart disease, stroke, migraine, Alzheimer's disease and Multiple sclerosis [3-8]. As these results remain controversial, the interactions between H. pylori and humans are suggested to be extremely sophisticated .
Recently, there has been some research interest in the association between H. pylori infection and epilepsy. Several studies evaluating the possible association between H. pylori infection and epilepsy have been published [10-15]. Some studies have reported a significant positive correlation between H. pylori infection and epilepsy [11,12]. However, others have failed to determine any association between H. pylori infection and epilepsy [10,13]. In 2011, Asadi-Pooya et al  reported that treating H. pylori infection in patients with refractory epilepsy did not significantly change the seizure frequency. To obtain a more comprehensive estimate of the association we conducted a meta-analysis to determine the prevalence of H. pylori infection in patients with epilepsy and controls.
A systematic search of PubMed, EMBASE, Cochrane Library, Web of Science, Google Scholar and CINAHL was performed to identify potentially relevant publications from the date of database origination through August 2016. They were searched for abstracts using the terms ("Helicobacter pylori" [Mesh] OR "Campylobacter pylori" [Title/Abstract] OR "Campylobacter pyloridis" [Title/Abstract] OR "Campylobacter pyloris" [Title/Abstract] OR "Helicobacter nemestrinae" [Title/Abstract]) AND ("Epilepsy" [Mesh] OR "Epilepsies" [Title/Abstract] OR "Seizure Disorder" [Title/Abstract] OR "Seizure Disorders" [Title/Abstract] OR "Seizures, Epileptic" [Title/Abstract] OR "Epileptic Seizures" [Title/Abstract] OR "Epileptic Seizure" [Title/Abstract] OR "Seizure, Epileptic" [Title/Abstract] OR "Single Seizure" [Title/Abstract] OR "Seizure, Single" [Title/Abstract] OR "Seizures, Single" [Title/Abstract] OR "Single Seizures" [Title/Abstract] OR "Epilepsy, Cryptogenic" [Title/Abstract] OR "Cryptogenic Epilepsies" [Title/Abstract] OR "Cryptogenic Epilepsy" [Title/Abstract] OR "Epilepsies, Cryptogenic" [Title/Abstract] OR "Status epilepticus" [Title/Abstract] OR "Aura" [Title/Abstract] OR "Auras" [Title/Abstract] OR "Awakening Epilepsy" [Title/Abstract] OR "Epilepsy, Awakening" [Title/Abstract]). There was no language restriction. Two investigators independently selected all titles and abstracts identified by the initial search.
The inclusion criteria were as follows: (1) The studies had to be case-control, cross-sectional or case-cohort in design; (2) studies that provided the raw data on H. pylori infection in both the epilepsy group and the control group. Studies were excluded if: (1) The studies had no control groups; (2) The articles were review articles, laboratory studies, or studies of animals. To ensure homogeneity in data the two investigators performed the data extraction independently.
Calculation of dichotomous variables was conducted using the odds ratio (OR) with the 95% confidence interval (CI) as the summary estimates to measure the strength of the association of H. pylori infection and Epilepsy. Heterogeneity was tested using the I2 statistic test, which is a quantitative measure of inconsistency across studies. I2 values of above 25%, 50% and 75% being considered to indicate low, medium, and high heterogeneity, respectively. Heterogeneity was also determined by Q-test, and it was considered indicative of significant heterogeneity when P values were less than 0.1. When the effects were assumed to be homogeneous (I2 < 50%) a fixed-effects model was used; otherwise, the random-effects model was more appropriate . Statistical significance was set at P values of less than 0.05. The meta-analysis was performed using Review Manager 5.3 software.
Identification of eligible studies
We identified 54 articles from PubMed, EMBASE, Cochrane Library, Web of Science, Google Scholar and CINAHL. Of these articles most were excluded after reading the titles and abstracts, mainly because they were reviews or were not relevant to the meta-analysis, leaving 11 that appeared to fulfill the inclusion criteria. Following more thorough scrutiny, an additional 7 articles were excluded. Finally, a total of 4 prospective articles including 232 cases of Epilepsy and 186 participants were included in the meta-analysis [10-13]. A detailed flowchart of the selection process is presented in figure 1.
Figure 1: Flow diagram of the study selection process. View Figure 1
The main characteristics of the 4 included studies are presented in table 1. Four studies involved 232 patients with epilepsy, with a total H. pylori infection rate of 46.98% (109/232). The sample size of the control groups was 186, of which 49 were H. pylori-positive (26.34%). Concerning the H. pylori measure methods, two studies used ELISA, and two studies used the 13C urea breath test (13C-UBT). Okuda, et al.  divided the epilepsy subjects into two subgroups: idiopathic generalized epilepsy (IGE) and idiopathic localization-related epilepsy (ILE). Ozturk, et al.  separated the Epilepsy patients into poor prognosis and good prognosis groups. Asadi-Pooya, et al.  determined the frequency of infection with H. pylori among two groups of patients with epilepsy: patients with idiopathic generalized epilepsy (IGE) and patients with temporal lobe epilepsy (TLE) due to mesial temporal sclerosis. Razak, et al.  investigated the association of H. pylori infection with generalised epilepsy and partial epilepsy.
Table 1: Characteristics of the 4 included studies. View Table 1
Results of meta-analyses
Overall, the prevalence of H. pylori infection in patients with epilepsy was higher than that in control groups. (46.98% vs. 26.34%, OR = 2.58, 95% CI: 1.15-5.82, P = 0.02) (Figure 2). The heterogeneity was high (P = 0.03, I2 = 68%). We performed a subgroup analysis to further investigate the factors impacting the overall results.
Figure 2: Overall meta-analysis of the prevalence of H. pylori infection in the epilepsy group compared with the control group. View Figure 2
Using stratified analysis based on different methods, the data revealed that the prevalence of H. pylori infection in epilepsy patients was greater than that in control group by using ELISA in two studies (OR = 5.36, 95% CI: 2.62-10.95, P < 0.00001), but it was not statistically significant difference when using 13C urea breath test in other two studies (OR = 1.36, 95% CI: 0.75-2.46, P = 0.32) (Figure 3).
Figure 3: Subgroup analysis according to different detection methods for the association of H.pylori infection with Epilepsy. View Figure 3
The association between epilepsy and H. pylori infection is controversial [10-15]. In this meta-analysis we provide an overview of the relationship between H. pylori positiveity and epilepsy with a total of 418 subjects from four eligible studies. Overall the prevalence of H. pylori infection in epilepsy patients (46.98%, 109/232) was higher than in control individuals (26.34%, 49/186) (P = 0.02), indicating that H. pylori infection may be a risk factor for epilepsy.
Epilepsy may be triggered by immunological mechanisms as a result of H. pylori infections. Autoimmunity was recently suggested to be involved in the pathology of epilepsies . Bartolomei, et al.  found that detection of anti-GM1 antibodies could allow identification of patients with partial epilepsy associated with an autoimmune response. H. pylori could indirectly influence the brain function due to the release of multiple cytokines such as IL-1,IL-6,TNF-α,which involved in the blood–brain barrier (BBB) disruption and pathogenesis of neuronal inflammatory damage in epilepsy [19,20]. Kountouras, et al.  have hypothesized that H. pylori might be a potential therapeutic target in epilepsy.
We conducted a further analysis based on different detection methods, the results showed that the prevalence of H. pylori infection in epilepsy patients was higher than that in control groups by using ELISA [11,12], but it was not statistically significant difference using 13C-UBT [10,13]. The anti-H. pylori IgG-ELISA is a common method for detecting H. pylori seropositivity in clinics. It is well suitable for large-scale population surveys . 13C-UBT is a detection method based on the carbon dioxide and ammonia produced by H. pylori converting urea and has high specificity and sensitivity . 13C-UBT reveals the active (present) infection, whereas the serology can reveal the past infection. However, it may be impossible to directly compare the 13C-UBT results due to the difference in UBT protocols across different clinical centers generated differences in breath sample collection times and intervals, as well as influences on delaying gastric emptying [21,22].
There are some limitations in our study. First, the analysis was conducted on a small number of case-control studies, and the cases included in these studies are also limited and lack of high-quality data. Second, the lack of individual data has limited further subgroup analyses of gender and epilepsy sub-type. Finally, some articles published in non-English languages might be missed.
In summary, the present study showed that the association between epilepsy and H. pylori infection is a significant positive correlation. Whether H. pylori infection is a risk factor for epilepsy should thus be addressed in large-scale and prospective studies.
This study was supported by National Natural Science Foundation of China (Grant No. 81500953), The Program of Jilin Provincial Science & Technology Department (Grant No. 20150520143JH), Jilin Provincial Development and Reform Commission Project (2014N151), and Norman Bethune Program of Jilin University (Grant No. 2015215).
Kusters JG, van Vliet AH, Kuipers EJ (2006) Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 19: 449-490.
Banatvala N, Mayo K, Megraud F, Jennings R, Deeks JJ, et al. (1993) The cohort effect and Helicobacter pylori. J Infect Dis 168: 219-221.
Kountouras J, Zavos C, Polyzos SA, Katsinelos P, Deretzi G (2015) Association between cirrhosis and Helicobacter pylori-related brain pathologies. Eur J Gastroenterol Hepatol 27: 183.
Bulajic M, Panic N, Lohr JM (2014) Helicobacter pylori and pancreatic diseases. World J Gastrointest Pathophysiol 5: 380-383.
Huang WS, Tseng CH, Lin CL, Tsai CH, Kao CH (2014) Helicobacter pylori infection increases subsequent ischemic stroke risk: a nationwide population-based retrospective cohort study. QJM 107: 969-975.
Faraji F, Zarinfar N, Zanjani AT, Morteza A (2012) The effect of Helicobacter pylori eradication on migraine: a randomized, double blind, controlled trial. Pain Physician 15: 495-498.
Kountouras J, Boziki M, Zavos C, Gavalas E, Giartza-Taxidou E, et al. (2012) A potential impact of chronic Helicobacter pylori infection on Alzheimer's disease pathobiology and course. Neurobiol Aging 33: e3-4.
Smyk DS, Koutsoumpas AL, Mytilinaiou MG, Rigopoulou EI, Sakkas LI, et al. (2014) Helicobacter pylori and autoimmune disease: cause or bystander. World J Gastroenterol 20: 613-629.
Xiao M, Wang Y, Gao Y (2013) Association between Helicobacter pylori infection and pancreatic cancer development: a meta-analysis. PLoS One 8: e75559.
Asadi-Pooya AA, Dehghani SM, Petramfar P, Emami M, Mahmoodi M (2012) Helicobacter pylori infection in patients with epilepsy. Seizure 21: 21-23.
Okuda M, Miyashiro E, Nakazawa T, Minami K, Koike M (2004) Helicobacter pylori infection and idiopathic epilepsy. American Journal of Medicine 116: 209-210.
Ozturk A, Ozturk CE, Ozdemirli B, Yucel M, Bahcebasi T (2007) Helicobacter pylori infection in epileptic patients. Seizure 16: 147-152.
Razak MRA, Tan HJ, Razlan H, Ibrahim NM, Sutan R (2012) Prevalence of helicobacter pylori infection in epilepsy patients in a teaching hospital in Malaysia. Neurology Asia 17: 293-296.
Asadi-Pooya AA, Dehghani SM, Emami M (2011) Effect of treating helicobacter pylori infection on seizure frequency in patients with refractory epilepsy. Iran J Neurol 10: 51-53.
Sabetay S, Kaplan L, Weller B (2012) Epileptic patients have an increased risk of carbamazepine toxicity during triple therapy for Helicobacter pylori infection: A case presentation and review of the literature. European Journal of Neurology 19: 248.
Su J, Zhou XY, Zhang GX (2014) Association between Helicobacter pylori infection and migraine: A meta-analysis. World J Gastroenterol 20: 14965-14972.
Cojocaru IM, Cojocaru M (2010) Reactions of the immune system in epilepsy. Maedica (Buchar) 5: 201-206.
Bartolomei F, Boucraut J, Barrie M, Kok J, Dravet C, et al. (1996) Cryptogenic partial epilepsies with anti-GM1 antibodies: a new form of immune-mediated epilepsy? Epilepsia 37: 922-926.
Friedman A, Kaufer D, Heinemann U (2009) Blood-brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy. Epilepsy Res 85: 142-149.
Kountouras J, Zavos C, Deretzi G, Polyzos SA, Katsinelos P, et al. (2011) Helicobacter pylori might be a potential therapeutic target in epilepsy. Medical Hypotheses 76: 763.
Feng H, Zhou X, Zhang G (2014) Association between cirrhosis and Helicobacter pylori infection: a meta-analysis. Eur J Gastroenterol Hepatol 26: 1309-1319.
Schmilovitz-Weiss H, Sehayek-Shabat V, Eliakim R, Skapa E, Avni Y, et al. (2012) Applicability of a short/rapid 13C-urea breath test for Helicobacter pylori: retrospective multicenter chart review study. BMC Gastroenterol 12: 8.