Relationship between Helicobacter pylori infection and white matter lesions in patients with migraine

Migraine is a multifactorial and neurovascular condition characterized by recurrent headache episodes accompanied by autonomic nervous system disorder [1, 2]. One-third of migraine patients have an aura. Migraine affects over 17% of women and 5–8% of men [2]. Although the exact pathophysiology of migraine has not been elucidated as yet, in patients with a genetic predisposition, exogenous and endogenous stimuli may trigger pain attacks [3]. Various mechanisms, including pain mediators such as calcitonin gene-related peptides, and neurotransmitters such as serotonin, are currently discussed in the physiopathology of migraine [4].

Helicobacter pylori (H. pylori) is a gram-negative, microaerophilic, spiral-shaped and flagellated bacterium [5]. H.pylori is responsible for infection, chronic active gastroenteritis, duodenal and gastric ulcer and even stomach cancer [6]. Relationship between H.pylori infection and heart diseases such as coronary heart disease, vascular diseases such as primary Raynaud’s phenomenon, neurological diseases such as migraine, Alzheimer’s disease, and mild cognitive impairment, and numerous extraintestinal conditions such as iron deficiency anemia have been recently studied and discussed [7‐9]. However, no consensus has been reached, and the results remain controversial.

Recently, many studies investigating the effect of H. pylori infection on migraine physiopathology have been published [6, 10]. The role of H. pylori in the pathogenesis of migraine has been suggested based on the relationship between the host immune response to bacteria and the extended-release of vasoactive substances [11‐14]. The inflammatory response to H. pylori infection in humans comprises infiltration of lymphocytes, neutrophils, and monocytes, into the gastric mucosa and submucosa [15, 16]. The activation and aggregation of immune cells in the gastric mucosa and submucosa includes epithelial-derived chemotactic peptides (chemokines), such as interleukin IL-8 and growth-regulated oncogene (GRO) -α, bacterial chemotaxis, and proinflammatory cytokines released by mononuclear phagocytes, such as tumor necrosis factor-alpha (TNF-α), IL-1, and IL-8 [16, 17]. Vasoactive substances and psychological or physical stress that can determine the clinical signs and symptoms of the disease, special foods, and sex hormones are among the well-known trigger factors that may induce cerebral vascular hyper-reactivity [14, 18].

Migraine has been identified as an independent risk factor for hyperintense lesions seen in the white matter in cerebral magnetic resonance imaging (MRI) [19]. Nonspecific white matter lesions (WML) appear as hyperintense lesions in T2-weighted (T2W) or fluid-attenuated inversion recovery (FLAIR) sequences. The main pathological features of WML are demyelination, pale myelin, vacuolization, and oligodendrocyte apoptosis [20]. There are many studies focusing on the anatomy, cerebral blood flow autoregulation, blood-brain barrier disruption, venous collagenosis and genetic factors of WML to understand its pathogenesis [20, 21]. In this study, we investigated H. pylori infection as a risk factor for WML in patients with migraine and evaluated their relationship.

The evaluation was made of a total of 526 migraine patients who met the inclusion criteria, comprising 397 (75.5%) females and 129 (24.5%) males with a mean age of 45.57 ± 13.46 years (range, 18–69 years). The mean age was 45.17 ± 13.288 years for females and 46.80 ± 13.955 years for males (Table 1).

The WML rates on brain MRI of patients with migraine are shown in Table 1. The age of the 277 (52.7%) WML negative migraine patients was 40.30 ± 12.56 years, and of the 249 (47.3%) WML positive patients was 51.43 ± 11.92 years (p <  0.05). As the patient’s age increased, the incidence of WML also increased (Fig. 3).

A total of 315 (59.8%) subjects with positive H. pylori were detected. Among those patients 178 (33.8%) of them were WML positive (p <  0.05) (Table 1). WML was 2.5-fold higher on brain MRI in patients with H. pylori-positive migraine (odds ratio: 2.562, 95% CI 1.784–3.680) (Table 2). WML was negative in 137 (26.0%) patients who were H. pylori-positive. WML was positive in 71 (13.5%) on brain MRI in patients who were negative for H. pylori.

In migraine patients with hypertension, WML was negative in 60 (11.4%) patients, and positive in 112 (21.3%) patients (p < 0.001). In migraine patients with diabetes mellitus, WML was not detected in 31 (5.9%) patients, and WML findings were found in 41 (7.8%) patients (p > 0.079).

There was no significant difference between DM and migraine patients with WML.

The univariate and multivariate logistic regression analyses were performed to evaluate the association between gender, H. pylori, hypertension, DM, and hypertension + DM in predicting WML development in migraine patients. The univariate analysis revealed that age, H. pylori, and hypertension were significantly associated with WML in this patient group (p < 0.05). The age (OR = 1.07, 95% CI: 0.01–0.04, p < 0.001), H. pylori (OR = 2.48, 95% CI: 1.65–3.72, p < 0.001), hypertension (OR = 4.52, 95% CI: 2.82–7.231, p < 0.001), and hypertension + DM (OR = 0.12, 95% CI: 0.03–0.54, p = 0.002), had significant associations in predicting WML according to the multivariate logistic regression analysis (Table 2). The presence of hypertension had a higher odds ratio value than the other variables.

Many risk factors have been defined for developing of WML in literature. In our study, we primarily aimed to determine the role of H. pylori status, in patients diagnosed with episodic migraine. Additionally, we also evaluated the patients’ demographic characteristics and if they were diagnosed with hypertension and/or DM. We detected that age, H. pylori and hypertension was significantly associated with WML in patients involved (p < 0.05). However, there were no significant relationship was present between gender, DM and WML.

Colonization of H. pylori in the stomach leads to humoral and cellular immune reactions that generally do not result in bacterial clearance [16]. The role of inflammation caused by H. pylori infection is still under debate in neurological conditions such as migraine, Guillain-Barré syndrome, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and other inflammatory conditions such as ischemic stroke [23]. H. pylori infection results in a chronic inflammatory response with the local and systemic secretion of multiple inflammatory mediators. This response includes the chemokines, TNF-α, IL-8, macrophage chemotactic protein-1, and GRO [23, 24]. Studies investigating the relationship between H. pylori and migraine are ongoing [10, 13, 25].

WMH refers to lesions seen on MRI with ischemic features, which cause clinical signs or other stroke-related symptoms [26]. These lesions show an extensive dispersion in subcortical and deep white matter [27]. Incidentally, WMH on MRI increase in the population as they age and occur in up to 80% of individuals in the eighth decade, compared to about 10% of middle-aged individuals [28]. One study revealed that the prevalence of the WMH lesion in 65 migraine patients was 43.1% at varying degrees of hyperintensity [23]. In another study, a wide range of WMH frequency (4–71%) was reported for migraine patients [29]. The current study determined WML in 249 (47.3%) of 526 migraine patients, consistent with the literature.

Increasing age has been defined as a significant risk factor for WML [30, 31].

WMH are commonly seen as multiple, small, dotted lesions in deep or periventricular white matter and are primarily observed in T2-weighted or FLAIR sequences [32]. Different hypotheses have been proposed regarding the mechanisms underlying WML in migraine patients. These are vascular risk factors (atherosclerosis, migraine, vasculitis, amyloid angiopathy) and non-vascular risk factors, such as cardiac abnormalities including inflammatory, metabolic, genetic, and neoplastic risk factors, infections, endothelial dysfunction, drugs, and the patent foramen ovale. Etiologically, infectious agents of WML include Herpes simplex virus, and Cytomegalovirus, encephalitis, neurosyphilis, central nervous system cryptococcal infection, progressive multifocal leukoencephalopathy, neuroborreliosis, human immunodeficiency virus encephalopathy, Whipple’s disease, Lyme encephalopathy, and subacute sclerosing panencephalitis [33‐35]. In the present study, the effect of H. pylori infection, one of the risk factors for WML, was investigated in subjects with migraine. WML was detected on brain MRI at a rate 2.5-fold higher in H pylori-positive migraine patients (odds ratio: 2.562, 95% CI 1.784–3.680) (Table 1). This result was statistically significant. When previous studies on this subject were searched, no literature on the association between H. pylori and WML was found. In this respect, the current study can be considered as the first study on this subject.

Previous studies thought that these lesions are related to vascular risk factors and small vessel disease. This finding may be regarded as evidence for the ischemic origin. However, recent pathology studies have suggested a more complex pathophysiology [36]. In the multiple model regression analysis performed in the current study, in which risk factors related to the development of WML in migraine patients were evaluated collectively, H. pylori, age, hypertension and hypertension along with DM were seen to statistically significantly increase the occurrence of WML (p < 0.05).

The relationship between migraine and hypertension has been discussed for many years, and no definite conclusion has yet been reached as to whether there is a relationship. Hypertension and migraine are prevalent diseases in the general population, and their association suggests coincidental [37, 38]. Migraine can occur at a younger age and pose a risk for hypertension. In a prospective cohort study conducted in Finland, a self-reported physician diagnosis of migraine at baseline was related with an approximately 1.4-fold increased risk of diagnosing with hypertension after adjustments for age, gender, living alone, physical activity, body mass index, occupational training, and alcohol consumption [39]. In other studies, it has been suggested that increased systolic blood pressure predisposes migraine patients to the formation of white matter hyperintensities [29, 40]. In the current study, WML was more common in patients with coexisting migraine and hypertension than those without (p < 0.05). Therefore, a diagnosis of hypertension with the increasing age of the patient can be said to be a risk factor for the development of WML.

WML has been considered to indicate injury of small vessels in the periventricular and subcortical areas, and autopsy series have indicated that the pathogenesis of WML consists of myelin pallor, tissue myelin rarefaction, and enlargement of perivascular spaces [41]. However, evidence that DM and WML may be related is inconsistent [42, 43]. The co-existence of atrophy with greater WML volume suggests that type 2 DM may be related to mixed pathology in the brain [44]. In our study, no significant difference was determined regarding the WML detection rate in patients with DM and migraine (p > 0.05). Factors that advance the formation of WML in older subjects with diabetes have not been fully defined. As the consequences of DM, hypertension, dyslipidemia or other possible vascular risk factors have not been fully defined. There is a need for further studies.

In conclusion, in most neurological diseases, WML occurs due to the combination of multiple factors. The results of this study indicated that one of these factors could be H. pylori, as the presence of H. pylori was seen to increase the development of WML in subjects with migraine. The increase in comorbid conditions and age with H. pylori further increased the incidence of WML. Therefore, it was concluded that H. pylori infection, as a chronic infection, can be counted among the risk factors for the development of WML in migraine patients. Thus, it can be considered that H. pylori eradication will be essential to reduce the development of WML in subjects with migraine and consequently reduce the risk of morbid conditions such as stroke due to WML. Nevertheless, further prospective studies are needed for a better understanding of this issue.