Increased cerebrospinal fluid adenosine 5'-triphosphate in patients with amyotrophic lateral sclerosis.

BACKGROUND: Extracellular adenosine 5'-triphosphate (ATP) has been suggested to cause neuroinflammation and motor neuron degeneration by activating microglia and astrocytes in amyotrophic lateral sclerosis (ALS). Since we have developed a highly sensitive ATP assay system, we examined cerebrospinal fluid (CSF) ATP levels in patients with ALS whether it can be a useful biomarker in ALS. METHODS: Forty-eight CSF samples from 44 patients with ALS were assayed for ATP with a newly established, highly sensitive assay system using luciferase luminous reaction. CSF samples from patients with idiopathic normal pressure hydrocephalus (iNPH) were assayed as a control. Patients were divided into two groups depending on their disease severity, as evaluated using the Medical Research Council (MRC) sum score. Correlations between the CSF ATP levels and other factors, including clinical data and serum creatinine levels, were evaluated. RESULTS: CSF ATP levels were significantly higher in patients with ALS than in the iNPH (716 ± 411 vs. 3635 ± 5465 pmol/L, p < 0.01). CSF ATP levels were significantly higher in the more severe group than in the iNPH group (6860 ± 8312 vs. 716 ± 411 pmol/L, p < 0.05) and mild group (6860 ± 8312 vs. 2676 ± 3959 pmol/L, p < 0.05) respectively. ALS functional rating scale-revised (ALSFRS-R) (37.9 ± 5.7 vs. 42.4 ± 2.8, p < 0.01) and serum creatinine levels (0.51 ± 0.13 vs. 0.68 ± 0.23 mg/dL, p < 0.05) were significantly lower in the severe group than in the mild group respectively. A negative correlation of CSF ATP levels with MRC sum score was demonstrated in the correlation analysis adjusted for age and sex (r = -0.3, p = 0.08). CONCLUSIONS: Extracellular ATP is particularly increased in the CSF of patients with advanced ALS. CSF ATP levels may be a useful biomarker for evaluating disease severity in patients with ALS.

A Parkinson's disease patient displaying increased neuromelanin-sensitive areas in the substantia nigra after rehabilitation with tDCS: a case report.

Previous studies have reported that transcranial direct current stimulation (tDCS) of the frontal polar area (FPA) ameliorated motor disability in patients with Parkinson's disease (PD). Here we report changes in neuromelanin (NM) imaging of dopaminergic neurons before and after rehabilitation combined with anodal tDCS over the FPA for 2 weeks in a PD patient. After the intervention, the patient showed clinically meaningful improvements while the NM-sensitive area in the SN increased by 18.8%. This case study is the first report of NM imaging of the SN in a PD patient who received tDCS.Abbreviations FPA: front polar area; PD: Parkinson's disease; NM: neuromelanin; DCI: DOPA decarboxylase inhibitor; STEF: simple test for evaluating hand function; TUG: timed up and go test; TMT: trail-making test; SN: substantia nigra; NM-MRI: neuromelanin magnetic resonance imaging; MCID: the minimal clinically important difference; SNpc: substantia nigra pars compacta; VTA: ventral tegmental area; LC: locus coeruleus; PFC: prefrontal cortex; M1: primary motor cortex; MDS: Movement Disorder Society; MIBG: 123I-metaiodobenzylguanidine; SBR: specific binding ratio; SPECT: single-photon emission computed tomography; DAT: dopamine transporter; NIBS: noninvasive brain stimulation; tDCS: transcranial direct current stimulation; MAOB: monoamine oxidase B; DCI: decarboxylase inhibitor; repetitive transcranial magnetic stimulation: rTMS; diffusion tensor imaging: DTI; arterial spin labeling: ASL.

A Case of Liver Cancer with Overlapping Myasthenia Gravis, Myocarditis, Seronegative Autoimmune Autonomic Ganglionopathy, and Myositis Symptoms Induced by Atezolizumab: A Case Report.

An 83-year-old man with hepatocellular carcinoma developed muscle weakness, ptosis, and dyspnea 3 weeks after receiving atezolizumab. Soon after, mechanical ventilation was initiated, which was followed by marked blood pressure spikes. The levels of creatine kinase and troponin-I were significantly elevated, and acetylcholine receptor antibodies were positive. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced myositis, myasthenia gravis (MG), myocarditis, and suspected autoimmune autonomic ganglionopathy (AAG). After immunotherapy, the serum markers and blood pressure normalized, and he was weaned from the ventilator after five months. To our knowledge, this is the first reported case of AAG secondary to ICI-induced myositis, MG, and myocarditis.

Increased Cerebrospinal Fluid Adenosine 5'-Triphosphate Levels in Patients with Guillain-Barré Syndrome and Chronic Inflammatory Demyelinating Polyneuropathy.

Background: Extracellular adenosine 5'-triphosphate (ATP) acts as a signaling molecule in the peripheral nerves, regulating myelination after nerve injury. The present study examined whether the cerebrospinal fluid (CSF) ATP levels in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are related to disease severity. Methods: CSF ATP levels in 13 patients with GBS and 18 patients with CIDP were compared with those in a control group of 16 patients with other neurological diseases (ONDs). In patients with CIDP, CSF ATP levels were compared before and after treatment. The correlations between CSF ATP levels and other factors, including clinical data and CSF protein levels, were also evaluated. Results: Median CSF ATP levels were significantly higher in patients with GBS and CIDP than in those with ONDs. When patients with CIDP were classified into two groups depending on their responsiveness to immunotherapy, median CSF ATP levels were significantly higher in good responders than in ONDs. CSF ATP levels tended to decrease after treatment in patients with CIDP. In patients with CIDP, there is a negative correlation between CSF ATP and CSF protein levels. Conclusions: CSF ATP levels were increased in patients with GBS and CIDP. In particular, CSF ATP levels tended to decrease following treatment in patients with CIDP. CSF ATP levels may be useful biomarkers for the diagnosis or monitoring of therapeutic effects in patients with GBS and CIDP.

Study of hemostatic biomarkers in acute ischemic stroke by clinical subtype.

BACKGROUND: We studied the usefulness of hemostatic biomarkers in assessing the pathology of thrombus formation, subtype diagnosis, prognosis in the acute phase of cerebral infarction, and differences between various hemostatic biomarkers. METHODS: Our study included 69 patients with acute cerebral infarction who had been hospitalized within 2 days of stroke onset. Fibrin monomer complex (FMC), soluble fibrin (SF), D-dimer, thrombin-antithrombin III complex, fibrinogen, antithrombin III, and fibrin/fibrinogen degradation products (FDPs) were assayed as hemostatic biomarkers on days 1, 2, 3, and 7 of hospitalization. RESULTS: In the cardioembolic (CE) stroke group, FMC and SF levels were significantly higher on days 1 and 2 of hospitalization, and D-dimer levels were significantly higher on day 1 of hospitalization, compared to the noncardioembolic (non-CE) stroke group. FDP levels were significantly higher at all times in the CE group compared to the non-CE group. Neither the National Institute of Health Stroke Scale (NIHSS) used during hospitalization nor the modified Rankin Scale (mRS) used at discharge found any significant correlations to hemostatic biomarkers, but the NIHSS score during hospitalization was significantly higher in the CE group than in the non-CE group. CONCLUSIONS: Measurements of hemostatic biomarkers, such as FMC, SF, and D-dimer on the early stage of cerebral infarction are useful for distinguishing between CE and non-CE stroke.

[A case of triple A syndrome with c.463C>T mutation in the AAAS gene].

A 47-year-old woman was admitted to our hospital for scrutiny of limb weakness and orthostatic hypotension that had progressed from childhood. She had been treated for alacrima and esophageal achalasia from childhood. On admission, she had hyperreflexia of upper and lower extremities, distal predominant muscle atrophy in the lower extremities, decreased sensation of the distal extremities, and autonomic neuropathy. Her blood test results ruled out adrenal insufficiency, but Schirmer's test was positive. Given the lacrimation symptoms, esophageal achalasia, and neuropathy, the patient was diagnosed with triple A syndrome in whom a c.463C>T mutation (p.R155C) was found in the AAAS gene by genetic testing. Triple A syndrome is an autosomal recessive inherited disease caused by mutations in the AAAS gene. Genetic testing of the AAAS gene should be considered in patients with one or two of main symptoms of triple A syndrome.

Bilateral subthalamic deep brain stimulation for camptocormia associated with Parkinson's disease.

BACKGROUND: Few multiple case studies of the effects of deep brain stimulation for camptocormia associated with Parkinson's disease have been reported. Although deep brain stimulation was in some cases not effective against camptocormia, it is unclear in which types of patients it was effective in treating camptocormia. OBJECTIVE: We treated 4 Parkinson's disease patients with camptocormia and evaluated their paraspinal muscle status by computed tomography to specify the characteristics of cases of effective treatment. METHODS: The 2 female and 2 male patients in this study were 60-69 years old, with a disease duration from onset to surgery of 7-13 years and a follow-up period of 18-40 months. The electrodes were implanted bilaterally in the subthalamic nuclei. RESULTS: Camptocormia was improved in 3 cases, and was unchanged in the remaining case although other parkinsonian symptoms improved. The computed tomography number of paraspinal muscle in the unimproved patient was much smaller than that in the improved patients. CONCLUSIONS: A relationship may exist between improvement of camptocormia and severity of paraspinal muscle degeneration.

Serum neurofilament light chain in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVES: Neurofilament light chain (NfL) levels have been suggested as reflecting axonal damage in various inflammatory and neurodegenerative disorders, including acquired peripheral neuropathies. We aimed to investigate if serum NfL (sNfL) levels can be a biomarker of disease activity and treatment response in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). MATERIALS AND METHODS: The sNfL levels of eleven newly diagnosed patients with CIDP were retrospectively assayed and compared with seven healthy volunteers. The levels were assayed before and after intravenous immunoglobulin treatment in patients with CIDP and were also assayed in the remission period. RESULTS: Baseline sNfL levels in patients with CIDP before treatment were significantly higher than those in healthy controls. The levels significantly decreased overtime after one month of treatment and in remission period. There were significant negative correlations between the sNfL levels and the disease duration (the interval between the onset of the disease and the time of sampling), and weak correlations between the sNfL levels and overall neuropathy limitations scale. CONCLUSIONS: sNfL may be a potential biomarker reflecting the disease activity in patients with CIDP.

PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan.

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

[Case of branch atheromatous disease presenting capsular warning syndrome].

We report a case of branch atheromatous disease (BAD) presenting capsular warning syndrome, who subsequently showed a complete recovery by the combination therapy as described below. A 54-year-old man with untreated hypertension was admitted to our hospital because of dysarthria and right hemiplegia. The NIHSS on admission was 12 points, but his symptoms soon completely disappeared during examination. After admission administration of aspirin, heparin, atorvastatin and t-PA were started, but stereotyped episodes of dysarthria and the right hemiplegia occurred repeatedly. We added plasma expander, and he thereafter revealed no further ischemic episodes at 22 hours from admission. Over all, he had 15 times of transient ischemic attack with no lasting deficit. The DWI scan obtained 5 hours after the onset demonstrated a high-intensity region in the left putamen to corona radiata. MRA showed no significant abnormalities. He had been diagnosed as having branch atheromatous disease with capsular warning syndrome. The present case suggests that combination therapy including t-PA and plasma expander may be effective to BAD presenting capsular warning syndrome.

Two cases of NMOSD with MRI findings mimicking CADASIL.

PURPOSE: The purpose of this study is to increase awareness of the importance of considering neuromyelitis optica spectrum disorder (NMOSD) as a differential diagnosis for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: We report two NMOSD patients demonstrating magnetic resonance imaging (MRI) abnormalities resembling those of CADASIL. RESULTS: Brain MRIs of both patients showed symmetrical hyperintense signals in the temporal poles and cerebral hemispheres on T2 weighted images. One case also involved the bilateral external capsule. The chief complaint of both patients was loss of visual acuity, and neurologic examination showed no other apparent neurological signs or symptoms. Anti-aquaporin-4 antibodies were detected on serological examination, and NMOSD was subsequently diagnosed. Visual acuity improved following intravenous methylprednisolone therapy. One patient refused further immunological treatment. Although she remained clinically stable, gradual radiographic deterioration was observed. This deterioration then stabilized after the patient commenced oral prednisolone therapy. The other patient was treated with prednisolone and azathioprine. She is clinically stable, but we have observed gradual radiographic deterioration over the past 5 years. CONCLUSION: MRI findings in patients with NMOSD may resemble those of CADASIL, namely symmetrical hyperintensities in the temporal poles, external capsules and cerebral hemispheres. NMOSD is a differential diagnosis for CADASIL, and testing for anti-AQP4 antibodies should be considered.

[A case of clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with infectious endocarditis caused by Staphylococcus aureus].

A 17-year-old woman was admitted to our hospital because of a high fever, consciousness disturbance, and delirious behavior. Methicillin susceptible Staphylococcus aureus (MSSA) infection was confirmed by blood culture. Transthoracic echocardiogram showed no abnormality at first. Diffusion-weighted brain MRI showed a high intensity lesion in the middle portion of the splenium, which was shown as low intensity on apparent diffusion coefficient map. Then, antibiotics therapy was started against suspected bacterial meningitis, while the lumbar puncture was not performed because of the decreased number of platelets. Since the systolic murmur appeared at the apex on day 12, the diagnosis with infectious endocarditis was made by transthoracic echocardiogram. The MRI abnormalities disappeared on day 16 and we diagnosed her with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with infectious endocarditis. This case suggests that MERS can occur associated with infectious endocarditis caused by Staphylococcus aureus.

[Two cases of cardioembolic stroke with stepwise progression].

We reported two patients of cardioembolic stroke with stepwise progression. Magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) showed narrowing of the middle cerebral artery (MCA) in both patients at the acute phase of onset. Case 1 was classified as "undetermined" based on the TOAST classification although his electrocardiogram revealed atrial fibrillation. Case 2 was classified as "large artery atherosclerosis" with no evidence of cardioembolic source at the acute phase of onset. Follow-up MRA was performed at seventeen days after the onset in case 1 and ten days after the onset in case 2 respectively, which showed complete recanalization of the MCA in each case. The presence of cardioembolic source was also detected in both patients at that time, resulting in the final diagnosis of cardioembolic stroke. Cardioembolic stroke may occasionally present in a stepwise manner suggesting a thrombotic process. When MRA shows stenosis or occlusion of the arteries supplying the cortical areas at the acute phase of onset, it is advisable to examine recanalization of these arteries by follow-up MRA with simultaneous efforts to find out the possible embolic source.

[A case of neurolymphomatosis presented as cauda equine syndrome accompanied with M-proteinemia].

A 63-year-old man developed a syndrome of cauda equine, with the numbness which is a left lower extremity from the left buttocks, weakness of left leg, and a dysfunction of bladder and bowel. Enhanced MRI revealed the enhancement of lower cauda equine, and a nerve conduction test revealed decreased F-wave persistency in the tibial nerve and increased F-wave latency in the peroneal nerve on the both sides. M-proteinemia was admitted and myeloma was suspected. By a biopsy of a vertebral arch, we diagnosed with diffuse large B-cell lymphoma. We treated with dexamethasone and R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (prednisolone)), then the symptom was improved. In case of caude equine syndrome with M-proteinemia, a possibility of the malignant lymphoma should also be considered.

Effects of Transcranial Direct Current Stimulation (tDCS) Over the Frontal Polar Area on Motor and Executive Functions in Parkinson's Disease; A Pilot Study.

Parkinson's disease (PD) is a neurodegenerative disorder with motor and non-motor symptoms due to degeneration of dopaminergic neurons. The current pharmacological treatments induce complications associated with long-term use. However, current stimulation techniques for PD treatment, such as deep brain stimulation (DBS), are too invasive. In this context, non-invasive brain stimulation including transcranial direct current stimulation (tDCS) may be a safe and effective alternative treatment for PD. We previously reported that anodal tDCS over the frontal polar area (FPA) improved motor functions in heathy subjects. Therefore, in the present study, effects of tDCS over the FPA on motor and cognitive functions of PD patients were analyzed. Nine PD patients (3 men and 6 women) participated in this cross over study with three tDCS protocols; anodal, cathodal or sham tDCS over the FPA. Each tDCS protocol was applied for 1 week (5 times/week). Before and after each protocol, motor and cognitive functions of the patients were assessed using Unified PD Rating Scale [UPDRS (part III: motor examination)], Fugl Meyer Assessment set (FMA), Simple Test for Evaluating hand Function (STEF) and Trail Making Test A (TMT-A). The results indicated that anodal stimulation significantly decreased scores of motor disability in UPDRS-III compared with sham and cathodal stimulation, and significantly increased scores of motor functions in FMA compared with sham stimulation. Furthermore, anodal stimulation significantly decreased time to complete a motor task requiring high dexterity in STEF compared with those requiring low and medium levels of dexterity. In addition, anodal stimulation significantly decreased time to complete the TMT-A task, which requires executive functions, compared with sham stimulation. To the best of our knowledge, this is the first clinical research reporting that tDCS over the FPA successfully improved the motor and non-motor functions in PD patients. These findings suggest that tDCS over the FPA might be a useful alternative for the treatment of PD patients.

[A case of apical hypertrophic cardiomyopathy complicated by cardiogenic cerebral embolism].

We report a patient with apical hypertrophic cardiomyopahty (AHCM) complicated by a cardiogenic cerebral embolism. A 56-year-old man was admitted to our hospital because of a transient ischemic attack. He had been diagnosed as having AHCM at the age of 39 years. The intravenous administration of heparin was immediately started; however, he developed a weakness in his right fingers on the second day. A brain MRI examination showed multiple small infarctions in the cortex of the left frontal and temporal lobes. Transthoracic echocardiography revealed the hypokinetic movement of the myocardium and a thrombus in the apex. We suspected that the hypertrophic apex had become dilated, causing the formation of the thrombus. He then developed a cardiogenic cerebral embolism. The thrombus in the apex disappeared after the continuous administration of heparin intravenously. Here, we emphasize that patients with AHCM in the dilatation phase must receive warfarin therapy to prevent cardiogenic cerebral embolism.

[Clinical features, neuroimaging and prognosis of adult patients with clinically diagnosed acute-onset encephalitis treated at a teaching neurology center in the Toyama area of Japan].

Although acute viral encephalitis (AVE) and acute disseminated encephalomyelitis (ADEM) are etiologically and pathologically distinct, a differential diagnosis between these two disorders is often difficult, especially if the patient exhibits a disturbance in consciousness. To identify useful clinical differences enabling a differential diagnosis to be made at an early stage, we retrospectively analyzed patients who had been admitted to our hospital within the past seven years because of acute-onset encephalitis with a disturbance in consciousness. Eleven adult patients were classified as having AVE, and 8 adult patients were classified as having ADEM within this period. The clinical characteristics of the two groups were then compared. Patients with AVE exhibited a disturbance in consciousness as their first neurological sign, whereas patients with ADEM initially showed focal signs like spastic paralysis, urinary disturbance and ataxia, which were followed by a disturbance in consciousness. ADEM is usually preceded by infection or vaccination, but obtaining a medical history from patients with disturbed consciousness is often difficult Based on the present analysis, the initial manifestation of focal neurological signs may be very useful for distinguishing ADEM from AVE.

[Two cases of myelitis associated with Sjögren syndrome without xerosis: characteristic MRI findings].

We report two cases of myelitis associated with Sjögren syndrome without xerosis. Case 1: A 30-year old woman developed dysesthesia on both upper extremities and weakness of the right arm. A T2-weighted MRI examination showed a high-intensity signal and a swollen lesion between the first and seventh cervical vertebral levels. She was diagnosed as having primary Sjögren syndrome based on the positive finding of a Saxon test, typical salivary gland scintigraphy findings, and an elevated anti-SS-A antibody titer. We suspected that her myelitis was associated with Sjögren syndrome and treated her using steroid therapy. Although her symptoms were alleviated, her myelitis relapsed at the same location after the cessation of steroid therapy. Case 2: A 31-year-old woman developed dysesthesia on her neck and both upper extremities and exhibited tonic spasm. A T2-weighted MRI examination showed a high-intensity signal and a swollen lesion between the first and sixth cervical vertebral levels. She was diagnosed as having primary Sjögren syndrome based on the positive findings of a Rose Bengal test, a Schirmer's test, and a Saxon test as well as typical salivary gland scintigraphy findings and elevated titers of anti-SS-A and anti-SS-B antibodies. We suspected that her myelitis was associated with Sjögren syndrome and treated her using steroid therapy. Her symptoms improved after steroid therapy. Based on these two cases, we concluded that MRI findings for myelitis associated with Sjögren syndrome are characterized by a swollen lesion of more than three vertebral segments in length, and the relapse tends to occur at the same location.

[Cerebral artery lesion in a patient with infective endocarditis: serial MRI and MRA findings of cerebral artery stenosis].

We reported a case of infective endocarditis (IE) complicated with bacterial meningitis and cerebral artery stenosis. A 22-year-old man was admitted to our hospital because of IE. Although benzylpenicillin administration was continued, he abruptly developed consciousness disturbance on the seventh day. His cerebrospinal fluid indicated bacterial meningitis. MRI with gadolinium (Gd) enhancement showed septic embolism in the left parietal lobe and bi-linear enhancement on the right middle cerebral artery (MCA). MRA demonstrated narrowing of the MCA at the same site as the bi-linear Gd enhancement. We considered that these findings show narrowing of the MCA was due to cerebral arteritis. Intravenous administration of ampicillin and cefpirome gradually improved both IE and cerebral artery stenosis. We wish to emphasize that combination of MRI with Gd enhancement and MRA may be useful not only for diagnosis of cerebral artery stenosis but also for evaluation of treatment effect.

Impact of persistent smoking on long-term outcomes in patients with nonvalvular atrial fibrillation.

BACKGROUND: Although smoking is a risk factor for cardiovascular diseases, little is known about the impact of smoking on long-term outcomes in patients with atrial fibrillation (AF). METHODS: In 426 consecutive patients with nonvalvular AF (mean age, 66 years; 307 men; mean follow-up, 5.8±3.2 years), clinical variables including smoking status, CHADS2, and CHA2DS2-VASc score, incidences of cardiovascular events (stroke, myocardial infarction, or admission for heart failure), bleeding, and mortality were determined. RESULTS: Incidences of intracranial bleeding (0.7% vs 0.1%/year, p<0.01), all-cause mortality (4.9% vs 2.6%/year, p<0.01), and death from stroke (0.8% vs 0.2%/year, p<0.05) were higher in patients with history of smoking than in those without it. Incidence of intracranial bleeding was significantly higher in persistent smokers than in non-persistent smokers (1.2% vs 0.2%/year, p<0.01). History of smoking predicted all-cause mortality [hazard ratio (HR), 2.7; 95% confidence interval (CI), 1.7-4.5; p<0.01] and death from stroke (HR 4.7; 95% CI 1.0-22.3; p<0.05) independent of age, antithrombotic treatment, CHADS2, and CHA2DS2-VASc score. Persistent smoking predicted intracranial bleeding (HR 4.4; 95% CI 1.1-17.6; p<0.05) independent of age and antithrombotic treatment. CONCLUSIONS: Smoking status, independent of age, antithrombotic treatment, and clinical risk factors, predicted long-term adverse outcomes including bleeding events in patients with nonvalvular AF. There might be an obvious impact of persistent smoking on intracranial bleeding.