Periodontal Treatment and Ischemic Stroke

A bulk of observational evidence suggests an association between periodontitis and recurrent vascular events in ischemic stroke survivors. One plausible biological mechanism relies on the systemic inflammatory response posed by periodontitis together with changes in the normal function of the vascular endothelium which might lead to recurrence in these population. A non-pharmacological anti-inflammatory treatment (non-surgical periodontal therapy) has shown to reduce systemic inflammatory markers and improve endothelial function. Therefore, we propose to carry out a 1-year follow-up pilot randomized controlled clinical trial to investigate whether control of local and systemic inflammation as well as improve function of the vascular endothelium can lead to reduce the risk of recurrence in patients diagnosed from ischemic stroke.

Every year 71,780 Spaniards develop an stroke and of these 13% do not survive, which makes this disease the second most common cause of death in Spain. Within stroke survivors, it is estimated that 30% are left with some type of disability. The most common type of stroke is ischemic (corresponding to 80% of total stroke cases) which is caused by obstruction of cerebral arteries or by a clot that forms within the brain's own blood vessel or by a clot that is produced elsewhere in the circulatory system and travels to the brain. One of the main factors that contribute to increased morbidity and mortality and hospitalization in stroke patients are recurrent vascular events (RVE) (ie acute myocardial infarction, new stroke / transient ischemic attack or death due to vascular causes). Depending on the stroke subtype, study population and study follow-up, RVEs occur between 1% and 25%. Therefore, the prevention and/or reduction of the number of RVE after stroke would significantly reduce the large accumulated public health burden associated with this type of neurological disease.

The systemic inflammatory response plays a key role in focal cerebral ischemia and in the mechanisms of progression of cerebral infarction, as it is associated with an increased risk of stroke and RVE after a first ischemic stroke. In fact, markers of systemic inflammation such as interleukin 6 (IL-6), C-reactive protein (CRP) or tumor necrosis factor alpha (TNF-α) have been shown to be stroke predictors capable of modifying stroke risk by themselves as well as the risk of suffering a stroke regardless of conventional vascular risk factors. On the other hand, atherosclerosis is considered today as an inflammatory disease and contributes to a large proportion of strokes, both directly due to large vessel atherosclerosis and indirectly due to cardioembolism as a result of cardiac arrhythmias caused by coronary artery disease or emboli after myocardial infarction. A prospective cohort study demonstrated that elevated levels of IL-6 in peripheral blood is a good predictor of future RVE in stroke patients. In addition, one of the links between potential vascular risk factors, systemic inflammation, platelet activation, atherosclerosis and subsequently the appearance of cerebral infarcts is endothelial dysfunction characterized by a reduction in the biological capacity of the endothelium. In this sense, endothelial dysfunction measured by flow-mediated vasodilation (FMD) in the brachial artery is considered a predictor of future vascular complications.

Periodontitis is an immuno-inflammatory disease caused by oral bacteria that is characterized by the destruction of the supporting tissues of the tooth (gum and bone) that, if left untreated, can lead to tooth loss. In Spain, it is estimated that only 5% of the adult population has healthy gums, more than half suffer from gingivitis (reversible inflammation of the gingiva) and an average 38% have periodontitis, increasing this figure to 65% in the elderly 55 years. Worldwide, the most advanced forms of the disease are considered the sixth most prevalent disease in humans, affecting approximately 11% of the adult population worldwide. The main problem with periodontitis is that the harmful effects that produces are not only confined to the oral cavity but also have systemic effects. A meta-analysis of epidemiological studies has found that patients with advanced periodontitis have almost 3-fold increased risk of having large vessel ischemic stroke compared to those without periodontitis. Similar data have been obtained for cerebral small vessel disease (ie, lacunar infarction). Furthermore, in patients who have already had an ischemic stroke, the risk of suffering a second vascular event after two years of follow-up is 2 times higher in those with advanced periodontitis compared to subjects with healthy gums.

Non-surgical periodontal treatment has proven to be a safe and effective non-pharmacological treatment model for not only controlling periodontal infection and inflammation, but is also capable of reducing inflammation at the systemic level (peripheral levels of IL-6 and CRP) as well as improving endothelial function (measured by FMD).

Due to the fact that there is a solid epidemiological relationship between both pathologies and that an increase in the systemic inflammatory response and endothelial dysfunction may be possible mechanisms involved in this association, as well as in the increased risk of RVE development in this population, we propose to carry out a pilot randomized controlled clinical trial to evaluate the effect of non-surgical periodontal treatment on markers of systemic inflammation, endothelial function as well as stroke recurrence in patients with ischemic stroke.

Eligibility Criteria:
Inclusion Criteria:

* Aged \>18 years old.
* Non-severely disabling initial ischemic stroke (mRS≤3) in the last 90 days.
* With diagnosis of severe periodontitis (generalized stage III-IV).
* Presence of at least 10 teeth in the mouth.

Exclusion Criteria:

* Patients receiving periodontal treatment in the last 12 months.
* Stroke due to intracranial hemorrhage, dissection, veno-occlusive disease, drugs, trauma or vasculitis.
* Previous neurological impairment that would make detection of a subsequent event difficult.
* Comorbidities that may limit survival \<12 months.
* Brain CT/MRI that shows a lesion other than stroke as a cause of syndrome.
* History of medical conditions requiring antibiotic prophylaxis prior to dental exam.
* Pregnants or breastfeeding.
* Known allergy or hypersensitivity to local anesthesia thst cannot be medically managed.
* Patients with bleeding disorders or