Assessment of Serum IgG Titers to Various Periodontal Pathogens Associated with Atrial Fibrillation in Acute Stroke Patients.

OBJECTIVES: There is accumulating evidence that periodontal disease is associated with atrial fibrillation (AF) or stroke, but it is unclear which causative species of periodontal disease are present in stroke patients with AF. We aimed to investigate the associations between AF and specific periodontal pathogens using serum titers of IgG antibodies of bacteria in acute stroke patients. MATERIALS AND METHODS: Acute stroke patients were registered at two hospitals. Serum samples were evaluated for titers of antibodies against 9 periodontal pathogens (16 genotypes) using ELISAs. We identified AF in patients according to the following criteria: (1) a history of sustained or paroxysmal AF or (2) AF detection upon arrival or during admission. We carried out propensity score matching to categorize the patients as those with AF and those without. RESULTS: Of the 664 acute stroke patients, 123 (18.5%) had AF. After propensity score matching, 234 patients were selected. Patients with AF had a higher prevalence of positive serum titers of antibodies against Porphyromonas gingivalis (FimA type III) and Porphyromonas gingivalis (FimA type V) than those without AF (59.0% vs. 39.3%, p=0.004 and 58.2% vs. 40.2%, p=0.009, respectively). CONCLUSIONS: Porphyromonas gingivalis, especially FimA type III and type V, might be associated with AF in stroke patients.

cnm-Positive Streptococcus mutans and diffusion-weighted imaging hyperintensities in acute intracerebral hemorrhage.

BACKGROUND: Strains of Streptococcus mutans expressing the cell surface collagen-binding protein, Cnm, encoded by cnm (cnm-positive S. mutans), are associated with hypertensive intracerebral hemorrhage (ICH) and the occurrence of cerebral microbleeds (CMBs). Small diffusion-weighted imaging (DWI) hyperintensities in patients with acute ICH are also associated with CMBs. However, the association between cnm-positive S. mutans and DWI hyperintensities is unclear. Hence, this study aimed to investigate the association between cnm-positive S. mutans and DWI hyperintensities in patients with acute ICH. METHODS: Patients with acute ICH were prospectively registered at three hospitals. Dental plaque specimens were collected within 4 days after admission, and cnm-positive S. mutans was detected using the polymerase chain reaction. Magnetic resonance imaging at 14 ± 5 days after admission was used to evaluate DWI hyperintensities and CMBs. RESULTS: A total of 197 patients were enrolled in this study. cnm-positive S. mutans was detected in 30 patients (15.2%), and DWI hyperintensities were observed in 56 patients (28.4%). Patients with cnm-positive S. mutans had a higher frequency of DWI hyperintensities (50.0% vs 24.6%; p = 0.008) and a higher number of CMBs (5.5 vs 1.5; p < 0.001) than those without cnm-positive S. mutans. Multivariable logistic analysis revealed that the presence of cnm-positive S. mutans was independently associated with DWI hyperintensities (OR 2.38; 95% CI 1.01-5.61; p = 0.047) after adjusting for several confounding factors. CONCLUSION: This study found an association between the presence of cnm-positive S. mutans and DWI hyperintensities in patients with acute ICH.

Prospective Observational Study for the Comparison of Screening Methods Including Tongue Pressure and Repetitive Saliva Swallowing With Detailed Videofluoroscopic Swallowing Study Findings in Patients With Acute Stroke.

BACKGROUND: Simple, noninvasive, and repeatable screening methods are essential for assessing swallowing disorders. We focused on patients with acute stroke and aimed to assess the characteristics of swallowing screening tests, including the modified Mann Assessment of Swallowing Ability score, tongue pressure, and repetitive saliva swallowing test (RSST), compared with detailed videofluoroscopic swallowing study (VFSS) findings to contribute as a helpful resource for their comprehensive and complementary use. METHODS AND RESULTS: We enrolled first-ever patients with acute stroke conducting simultaneous assessments, including VFSS, modified Mann Assessment of Swallowing Ability score, tongue pressure measurement, and RSST. VFSS assessed aspiration, laryngeal penetration, oral cavity residue, vallecular residue, pharyngeal residue, and swallowing reflex delay. Screening tests were compared with VFSS findings, and multiple logistic analysis determined variable importance. Cutoff values for each abnormal VFSS finding were assessed using receiver operating characteristic analyses. We evaluated 346 patients (70.5±12.6 years of age, 143 women). The modified Mann Assessment of Swallowing Ability score was significantly associated with all findings except aspiration. Tongue pressure was significantly associated with oral cavity and pharyngeal residue. The RSST was significantly associated with all findings except oral cavity residue. Receiver operating characteristic analyses revealed that the minimum cutoff value for all VFSS abnormal findings was RSST ≤2. CONCLUSIONS: The modified Mann Assessment of Swallowing Ability is useful for broadly detecting swallowing disorders but may miss mild issues and aspiration. The RSST, with a score of ≤2, is valuable for indicating abnormal VFSS findings. Tongue pressure, especially in oral and pharyngeal residues, is useful. Combining these tests might enhance accuracy of the swallowing evaluation.

Association of serum anti-periodontal pathogen antibody with ischemic stroke.

BACKGROUND: Periodontitis increases the risk of atherosclerotic cardiovascular disease and ischemic stroke. In this study, we evaluated whether serum antibody levels against individual periodontal pathogens are significantly associated with ischemic stroke subtypes and their risk factors. METHODS: Patients with acute ischemic stroke (n = 132; 74 male and 58 female, 71.3 ± 10.7 years) and patients with no previous stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. Stroke subtype was evaluated based on the Trial of Org 10172 in Acute Stroke Treatment classification. Serum was obtained from each patient after obtaining their consent to participate in the study. The levels of serum antibodies against Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg) and Prevotella intermedia (Pi) were evaluated by ELISA. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured by nephelometry. RESULTS: Serum hs-CRP levels were significantly associated with acute ischemic stroke even after controlling for acute ischemic stroke, hypertension, diabetes mellitus and bulb/ internal carotid artery (ICA) atherosclerosis which were statistically selected (coefficient 0.245, 95% CI 0.142-0.347, p < 0.0001). The serum-antibody level of Pi was significantly higher in atherothrombotic-stroke patients than in patients with no previous stroke (p = 0.0035). Detectable serum anti-Pg antibody was significantly associated with atrial fibrillation (overall χ(2) = 35.5, R(2) = 0.18, n = 209, p < 0.0001; anti-Pg antibody: OR 4.36, 95% CI 1.71-12.10, p = 0.0017), and detectable serum anti-Pi antibody was significantly associated with bulb/ICA atherosclerosis after controlling for the statistically selected associated factors (overall χ(2) = 46.1, R(2) = 0.18, n = 209, p < 0.0001; anti-Pg antibody: OR 16.58, 95% CI 3.96-78.93, p < 0.0001). The levels of serum anti-Pi antibody were significantly associated with atherothrombotic stroke with the statistically selected associated factors excluding bulb/ICA atherosclerosis (overall χ(2) = 77.0, R(2) = 0.44, n = 129, p < 0.0001; anti-Pi antibody: OR 23.6, 95% CI 2.65-298.2, p = 0.008). However, when we included bulb/ICA atherosclerosis in this model, the levels of serum anti-Pi antibody were no longer significantly associated with atherothrombotic stroke (overall χ(2) = 98.0, R(2) = 0.56, n = 129, p < 0.0001; anti-Pi antibody: p = 0.107). CONCLUSIONS: Our results suggest that anti-Pg antibody is associated with atrial fibrillation and that anti-Pi antibody is associated with carotid artery atherosclerosis. In addition, anti-Pi antibody may be associated with atherothrombotic stroke through its association with carotid artery atherosclerosis. Thus, periodontitis may lead to serious systemic diseases.

Risk Assessment of Cnm-Positive Streptococcus mutans in Stroke Survivors (RAMESSES): Protocol for a Multicenter Prospective Cohort Study.

Introduction: The role of commensal microbiota in systemic diseases, including brain diseases, has attracted increasing attention. Oral infectious diseases, such as dental caries and periodontitis, are also involved in cerebrovascular diseases and cognitive impairment. Cerebral microbleeds (CMBs) and intracerebral hemorrhage due to small vessel disease (SVD), are presumably associated with a high risk of vascular cognitive impairment and stroke. We previously reported that Streptococcus mutans (S. mutans, the main pathogen of dental caries), harboring the cnm gene that encodes the collagen-binding protein Cnm, is associated with the development of hypertensive intracerebral hemorrhage and aggravation of CMBs. We also proposed a mechanism by which the circulating Cnm-expressing S. mutans causes intracerebral hemorrhage or CMBs; it binds to denuded basement membranes mainly composed of collagen IV through damaged tight junctions or it directly invades endothelial cells, resulting in blood-brain barrier injury. In November 2018, we initiated a multicenter, prospective cohort study (RAMESSES: Risk Assessment of Cnm-positive S. mutans in Stroke Survivors; UMIN Clinical Trials Registry: UMIN000045559) to explore the longitudinal association between Cnm-positive S. mutans and CMBs with comprehensive dental findings, which should determine the effect of Cnm-positive S. mutans in the oral cavity on the risk of CMB development and cognitive decline. Methods: Fifteen domestic institutes will be enlisted to enroll 230 patients who have at least one CMB in the deep brain area and develop a stroke within the past year. The prevalence of Cnm-positive S. mutans based on oral specimens and dental hygiene will be examined. The primary outcome is the number of newly developed deep CMBs. The secondary outcomes include the new development of lobar, subtentorial, or any type of CMBs; symptomatic intracerebral hemorrhage or ischemic stroke; changes in cognitive function or frailty; major bleeding; all-cause mortality; and antibody titers against periodontal pathogens. The observation period will be 2 years. Discussion: The 2-year longitudinal prospective cohort study is expected to establish the role of Cnm-positive S. mutans in SVD including CMBs and intracerebral hemorrhage from the perspective of the "brain-oral axis" and provide guidance for novel prophylactic strategies against Cnm-positive S. mutans-induced SVD.

Effect of tooth loss and nutritional status on outcomes after ischemic stroke.

OBJECTIVES: Tooth loss, closely associated with malnutrition, increases the risk for cardiovascular disease. The aim of this study was to examine the link between tooth loss, nutritional status, and stroke outcomes. METHODS: We retrospectively analyzed 195 consecutive patients with acute ischemic stroke who were evaluated for tooth loss. Tooth loss was classified as mild or severe. Nutritional status was evaluated using the Controlling Nutritional Status (CONUT) score. A poor neurologic outcome was defined as a score of 3 to 6 on the modified Rankin Scale at 3 mo post-stroke onset; a score of 0 to 2 was defined as a good outcome. RESULTS: A significant correlation was observed between tooth loss and the CONUT score at admission (ρ = 0.156; P = 0.034). Patients with poor outcomes had higher CONUT scores (P < 0.001) and a greater frequency of severe tooth loss (P = 0.025). On multivariate analysis, severe tooth loss (odds ratio [OR], 3.93; 95% confidence interval [CI], 1.31-11.8) and the CONUT score (OR, 1.33; 95% CI, 1.02-1.74) were independently associated with poor stroke outcomes. CONCLUSIONS: Nutritional status was associated with tooth loss among patients with acute ischemic stroke. Severe tooth loss and a higher CONUT score were independently associated with poor stroke outcomes.

Serum IgG titers to periodontal pathogens predict 3-month outcome in ischemic stroke patients.

Several cohort studies have shown that periodontal disease is associated with an increased risk for stroke. However, it remains unclear whether serum antibody titers for a specific periodontal pathogen are associated with outcome after ischemic stroke, and which kinds of pathogens are associated with ischemic stroke. We examined the relationship between serum IgG titers to periodontal pathogens and outcome in ischemic stroke patients. A total of 445 patients with acute ischemic stroke (194 female [44.0%], mean age 71.9±12.3 years) were registered in this study. Serum IgG titers to 9 periodontal pathogens (Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Prevotella nigrescens, Fusobacterium nucleatum, Treponema denticola, Tannerella forsythensis, Campylobacter rectus, Eikenella corrodens) were evaluated using the enzyme-linked immunosorbent assay (ELISA) method. An unfavorable outcome was defined as a 3 or higher on the modified Rankin Scale. The proportion of patients with unfavorable outcome was 25.4% (113 patients). Based on multivariate logistic regression analysis, numbers of IgG antibodies positive for periodontal pathogens (odds ratio 1.20, 95% CI 1.02-1.41, p = 0.03) were independent predictors of unfavorable outcome in ischemic stroke patients.

Association between periodontal disease due to Campylobacter rectus and cerebral microbleeds in acute stroke patients.

Oral health conditions and cerebral small vessel disease, such as white matter lesions or cerebral microbleeds (CMBs), are associated with the incidence of stroke. The purpose of this study was to examine the associations between oral health conditions (serum IgG titers of periodontal pathogens) with the presence or severity of CMBs in acute stroke patients. From January 2013 to April 2016, acute stroke patients were registered in two hospitals. Serum samples were evaluated for antibody titers against 9 periodontal pathogens using the ELISA method. The cut-off points for reactivity (the positive decision point) to each antigen were defined as more than a mean ELISA unit + 1 standard deviation (after logarithmic transformation) in all subjects. CMBs were evaluated on T2*-weighted MRI. In all, 639 patients were evaluated (ischemic, n = 533 and hemorrhagic, n = 106; 73.1 ± 12.9 years old). Among these patients, 627 were available for CMB evaluation. Among the 9 evaluated periodontal pathogens, only Campylobacter rectus (C. rectus) was associated with the presence of CMBs. the prevalence of positive serum antibody titers against C. rectus was higher among patients with CMBs than among those without CMBs (14.6% vs. 8.7%, P = 0.025). In addition, positive serum antibody titers against C. rectus remained one of the factors associated with the presence of CMBs in multivariate logistic analysis (odds ratio 2.03, 95% confidence interval 1.19-3.47, P = 0.010). A positive serum antibody titer against C. rectus was associated with the presence of CMBs in acute stroke patients.

Serum IgG titers against periodontal pathogens are associated with cerebral hemorrhage growth and 3-month outcome.

To assess the influence of periodontal disease on cerebral hemorrhage and its clinical course, we examined the association of the serum IgG titer of periodontal pathogens with hemorrhage growth and 3-month outcome. We consecutively enrolled 115 patients with acute cerebral hemorrhage (44 females, aged 71.3 ± 13.1 years) and used ELISA to evaluate the serum IgG titers of 9 periodontal pathogens: Porphyromonas gingivalis, Aggregatibacter (A.) actinomycetemcomitans, Prevotella intermedia, Prevotella nigrescens, Fusobacterium (F.) nucleatum, Treponema denticola, Tannerella forsythensis, Campylobacter rectus, and Eikenella corrodens. Significant hematoma growth was defined as an increase in the volume of >33% or an absolute increase in the volume of >12.5 mL. A poor outcome was defined as a 3 or higher on the modified Rankin Scale. We observed hemorrhage growth in 13 patients (11.3%). Multivariate analysis revealed that increased IgG titers of A. actinomycetemcomitans independently predicted the elevated hemorrhage growth (odds ratio 5.26, 95% confidence interval 1.52-18.25, p = 0.01). Notably, augmented IgG titers of F. nucleatum but not A. actinomycetemcomitans led to a poorer 3-month outcome (odds ratio 7.86, 95% confidence interval 1.08-57.08, p = 0.04). Thus, we demonstrate that elevated serum IgG titers of A. actinomycetemcomitans are an independent factor for predicting cerebral hemorrhage growth and that high serum IgG titers of F. nucleatum may predict a poor outcome in patients with this disease. Together, these novel data reveal how systemic periodontal pathogens may affect stroke patients, and, should, therefore, be taken into consideration in the management and treatment of these individuals.

[Ultrasonographic diagnosis of inflammatory neuropathies].

Ultrasonographic nerve enlargement has primarily been reported in patients with inflammatory neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy, Guillain-Barre syndrome, vasculitic neuropathy and leprosy. Nerve ultrasonography is a promising diagnostic supportive tool for inflammatory neuropathies. The ultrasonographic findings that are currently useful are 1) nerve enlargement primarily suggests the existence of inflammatory or demyelinating neuropathies and 2) for patients with CIDP or demyelinating Charcot-Marie-Tooth disease, the pattern of nerve enlargement is noted, and this pattern is useful for discriminating between these diseases. More precise evidence of ultrasonographic findings for inflammatory neuropathies should be established in the future.

Ultrasonographic nerve enlargement of the median and ulnar nerves and the cervical nerve roots in patients with demyelinating Charcot-Marie-Tooth disease: distinction from patients with chronic inflammatory demyelinating polyneuropathy.

Demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyneuropathy (CIDP) are both demyelinating polyneuropathies. The differences in nerve enlargement degree and pattern at multiple evaluation sites/levels are not well known. We investigated the differences in nerve enlargement degree and the distribution pattern of nerve enlargement in patients with demyelinating CMT and CIDP, and verified the appropriate combination of sites/levels to differentiate between these diseases. Ten patients (aged 23-84 years, three females) with demyelinating CMT and 16 patients (aged 30-85 years, five females) with CIDP were evaluated in this study. The nerve sizes were measured at 24 predetermined sites/levels from the median and ulnar nerves and the cervical nerve roots (CNR) using ultrasonography. The evaluation sites/levels were classified into three regions: distal, intermediate and cervical. The number of sites/levels that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined from the 24 sites/levels and from the selected eight screening sites/levels, respectively. The cross-sectional areas of the peripheral nerves were markedly larger at all evaluation sites in patients with demyelinating CMT than in patients with CIDP (p < 0.01). However, the nerve sizes of CNR were not significantly different between patients with either disease. When we evaluated ESN of four selected sites for screening from the intermediate region, the sensitivity and specificity to distinguish between demyelinating CMT and CIDP were 0.90 and 0.94, respectively, with the cut-off value set at four. Nerve ultrasonography is useful to detect nerve enlargement and can clarify morphological differences in nerves between patients with demyelinating CMT and CIDP.