A Case of Endovascular Treatment for In-Hospital Stroke with COVID-19 under Protected Code Stroke.

Objective: Coronavirus disease 2019 (COVID-19) is characterized by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and presents with respiratory symptoms. Overall, 5.7% of COVID-19 patients with severe respiratory status have been reported to develop acute cerebrovascular diseases (CVDs), and 41.3% of COVID-19 cases were considered nosocomial infections. Therefore, Protected Code Stroke, which is a guideline for acute stroke management that takes into account the safety of healthcare workers, has been developed. We created an operational manual for COVID-19 in the endovascular treatment center of our hospital and report our experience treating acute stroke in a COVID-19 patient. Case Presentation: A 67-year-old man presented with a 5-day history of fever. Chest CT showed ground glass opacity (GGO) on admission, and the polymerase chain reaction (PCR) test for COVID-19 was positive. Dysarthria, right-sided hemiparesis, and aphasia were discovered on the morning of the third day after hospitalization. MRI showed an acute ischemic stroke at the left corona radiata and occlusion of the left middle cerebral artery (MCA). Progression of right-sided hemiparesis and exacerbation of respiratory status developed after the MRI. Tracheal intubation was performed, and the patient was treated with intravenous alteplase and mechanical thrombectomy (MT). Recanalization of blood flow was not obtained, and the neurological deficits remained. Conclusion: MT was performed for large-vessel occlusion (LVO) in a COVID-19 patient during the COVID-19 pandemic. Safety for healthcare workers and appropriate rapid treatment for acute stroke patients are both vital in the current environment.

Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm.

OBJECTIVE: We examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH. METHODS: Fifty-one HFS patients receiving BoNT/A therapy were recruited. Patients' characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined. We diagnosed headache types according to The International Classification of Headache Disorders, 3rd edition, beta. Numerical Rating Scale (NRS) and Headache Impact Test-6 (HIT-6) scores for headache severity were compared between the 6-week baseline before BoNT/A therapy and 6-week follow-up after BoNT/A therapy. RESULTS: Of 51 patients with HFS, 17 (33.3%) reported worsening or new onset of headache (especially TTH) associated with HFS (Group-S), and 34 were not aware of headache (Group-N). Twelve patients (70.6%) in group-S reported improvement of headache after BoNT/A therapy. NRS (from 7 [5-9] to 0 [0-5], p<0.01) and HIT-6 (from 55 [54-64] to 44 [36-52], p<0.001) scores were significantly improved after BoNT/A therapy. Logistic regression analysis revealed significant interaction between TTH associated with HFS and the presence of stress factors (odds ratio 43.11: 2.95-629.39, p<0.001) and history of chronic headache (odds ratio 28.53: 2.96-275.10, p<0.001). CONCLUSIONS: Primary headache, especially TTH, is associated with HFS. BoNT/A therapy for HFS may also be indirectly effective for treatment of TTH.

Characteristics of Cerebral White Matter Lesions on MRI in Juvenile Patients with Migraine.

OBJECTIVE: Cerebral white matter lesions (WMLs) have been frequently observed on MRI in patients with migraine. We investigated characteristics of WMLs in migraine and tried to determine the relationship between its causal mechanism and arteriosclerosis. METHODS: A head MRI was performed in juvenile migraine patients. The distributions of deep and periventricular WMLs were separately studied in the anterior and posterior circulation. Grading was conducted according to the Fazekas classification. Arteriosclerotic risk factors were identified, and their effects on WMLs were investigated. RESULTS: WMLs were observed in 85 (40.5%) of 210 patients in our hospital. This is significantly higher than the 10 (19.2%) of 63 patients in the control group (p < 0.01). WMLs were significantly observed on the anterior territory of the deep white matter (p < 0.01) and the posterior territory of the periventricular white matter (p < 0.05). Multivariable analysis revealed that the occurrence of WMLs was not related to arteriosclerotic risk factors, while migraine (p < 0.01) and aging (p < 0.05) were significant risk factors. CONCLUSION: While migraine was a risk factor of WMLs, its relationship with arteriosclerotic factors was weak. Accordingly, a mechanism other than arteriosclerosis may be involved.

Theoretical analysis of headache recurrence in patients administered triptans for migraine based on receptor occupancy.

BACKGROUND: In this study, we retrospectively analyzed the relationship between headache recurrence and serotonin 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Triptans marketed in Japan (sumatriptan, zolmitriptan, eletriptan, rizatriptan, naratriptan) were investigated. METHODS: Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. We examined the relationships between recurrence rate and elimination half-lives, and Ф1B and Ф1D, as calculated from the time-course of plasma drug concentration obtained from other studies. The time until Ф1B and Ф1D became 50% or less, 40% or less, and 30% or less was calculated as duration time to examine the relationship with recurrence rate. RESULTS: For Ф1B, eletriptan remained at a low level. For Ф1D, it was indicated that all triptans obtained an occupancy of 80% or higher at maximum. For all items, though recurrence tended to be lower along with longer half-life, no significant statistical correlation was found. For both Ф1B and Ф1D, the recurrence rate tended to be lower as the duration became longer. In addition, a significant correlation was observed for Ф1D (p < 0.05). For clarifying the Ф value and time period most closely correlated with recurrence rate, recurrence and Ф1B and Ф1D at 6, 12, and 18 h after administration were calculated. The most significant correlation was observed between recurrence rate and Ф1D at 12 h after administration (p < 0.01). CONCLUSIONS: As an index for evaluating headache recurrence following triptan administration, recurrence rate and Ф1D value at 12 h after administration were found to be most closely correlated and useful for analysis. Our results indicate that headache recurrence inhibition can be evaluated using these values.

Theory-based analysis of clinical efficacy of triptans using receptor occupancy.

BACKGROUND: Triptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. METHODS: To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (Acp, AФ1B, AФ1D) were calculated. RESULTS: Our calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and Acp · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and AΦ1B · AUCΦ1B or AΦ1D · AUCΦ1D that was not affected by the drug and the form of administration. CONCLUSIONS: These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.

Relationship between atherosclerotic risk factors and aortic plaques in patients with first-ever ischaemic stroke.

OBJECTIVE: Aortic plaque is considered a risk factor of ischaemic stroke, and both ulceration and plaque thickness are considered important. However, the relative importance of aortic plaque and carotid plaque remains unclear. The purpose of this study is to clarify the relation between aortic and carotid plaque lesions and atherosclerotic risk factors in patients with acute ischaemic stroke. METHODS: We enrolled 76 patients with first-ever ischaemic stroke, undergoing transoesophageal echocardiography, whose aetiology of ischaemic stroke was unknown. We divided the patients into two groups according to aortic plaque thickness, based on previous reports, i.e., a high-risk group (over 4mm) and a low-risk group (less than 4mm). We also examined several atherosclerotic risk factors. RESULTS: Mean age, gender and hypertension was not significantly different between the low-risk and high-risk group. HDL-cholesterol (P<0.01), LDL/HDL ratio (P<0.05), non-HDL-cholesterol (P<0.05), HbA1c (P<0.05) and eGFR (P<0.01) were significantly different between the two groups. Max plaque thickness in the carotid artery was correlated with aortic plaque lesions. CONCLUSION: Multiple atherosclerotic risk factors are associated with greater aortic plaque lesions. Aortic plaque is important not only as an embolic source, but also as one of the atherosclerotic markers.

[Evaluation of drug information service available for physicians regarding low-dose aspirin-induced gastrointestinal lesions].

Low-dose aspirin-induced gastrointestinal lesions are becoming an important problem in clinical practice. In our investigation of such adverse effects, we obtained 4 important findings considered useful for physicians, as follows; 1) even when aspirin was given at a dose, the incidence rate of gastrointestinal lesions was higher than with other non-steroidal anti-inflammatory drugs (NSAIDs), 2) the odds ratios for gastrointestinal lesions induced by aspirin with a histamine H2 receptor antagonist and proton pump inhibitor were 0.6 and 0.4, respectively, as compared with aspirin alone, 3) it is difficult to administer aspirin, which exerts an antiplatelet effect, without inducing gastrointestinal lesions, and 4) these gastrointestinal lesions appears early, especially within 2 years after administration. We distributed a questionnaire to 41 physicians to confirm our findings, and compared high (n=20) and low (n=21) frequency aspirin prescription groups. The recognition rate of points 1 and 3 noted above in the high group was significantly elevated as compared to the low group, whereas there no significant difference in regard to the information in point 4 between the groups and the rate of recognition was low. Moreover, only 27% of the surveyed physicians were familiar with all 4 points. Prior to receiving this information, 17% of the physicians gave no related instructions their patients, which was reduced to 0% after receiving this information. Furthermore, 98% of those surveyed found the information to be useful. Our results suggest that these 4 points of information regarding potential adverse gastrointestinal effects of low-dose aspirin are useful for physicians.

The evaluation method for antiplatelet effect of acetylsalicylic acid.

Reduced platelet aggregation by acetylsalicylic acid administration has been associated with adverse outcomes in patients with thrombotic diseases, thus it is important to determine aspirin resistance in those cases. The antiplatelet effect of acetylsalicylic acid is rarely measured, but it has many problems. The aim of this study was to find the evaluation method for antiplatelet effect after administration of acetylsalicylic acid. We developed a particle counting method based upon laser light scattering, and utilized the platelet aggregation agonists, collagen, at 0.25, 0.5 and 1.0 µg/mL, and adenosine diphosphate (ADP), at 0.5, 1.0 and 2.0 µM, to determine their effective concentrations. Seventeen healthy volunteers were administered acetylsalicylic acid at 162 mg/day, with platelet aggregation determined before and 20 min after administration. In all subjects, the rate of platelet aggregation induced by 1.0 µg/mL of collagen before taking acetylsalicylic acid was the highest value obtained, while 20 min after acetylsalicylic acid administration, aggregation induced by collagen at 1.0 µg/mL was significantly decreased as compared to before administration. As for the other concentrations of collagen and all those of ADP tested, platelet aggregation was either not significantly induced before taking acetylsalicylic acid or the rate of aggregation was not significantly decreased after taking acetylsalicylic acid. Our results indicate that collagen at 1.0 µg/mL is appropriate as a platelet aggregation agonist for evaluating the antiplatelet effect of acetylsalicylic acid. Thus, it is useful that the measurement is performed only once.

Preventive effect of cyproheptadine hydrochloride in refractory patients with frequent migraine.

Cyproheptadine hydrochloride (CH) is rarely used to treat adult patients with migraine in Japan because it causes sleepiness. In this study, we investigated the preventive effect of CH in 12 patients who had failed to respond to conventional preventive treatments among 103 migraine patients treated at our hospital. These 12 subjects had all received unsuccessful migraine prophylaxis with lomerizine, valproic acid and topiramate, or had discontinued these treatments due to adverse reactions. Initially, the subjects were given 4 mg CH before sleeping. In those who experienced no clinically significant sleepiness following the treatment, the drug was orally administered at 4 mg after breakfast as well (8 mg per day in total). Drug efficacy was evaluated by examining the frequency of migraine at one month and three months after the start of treatment. The frequency of migraine was dramatically reduced in all patients within 7 to 10 days after starting treatment. The average frequency of migraine during the three-month period was 2.6 episodes per month, representing a significant (p < 0.01) reduction from the pretreatment frequency of over 10 per month. Our results indicate that CH may be effective as a migraine-preventive treatment for patients in whom conventional drugs have been ineffective or have caused side effects. But this study is not a double blind randomized trial, and an open study with no control group.

Prediction of antiplatelet effects of aspirin in vivo based on in vitro results.

The aim of this study was to establish a method to predict the antiplatelet effects of aspirin in vivo based on in vitro results. Aspirin in 5 different concentrations was added to the platelet-rich plasma samples, and the rates of platelet aggregation induced by collagen were determined in vitro. In addition, platelet aggregation and plasma drug concentration values were determined in vivo before and after the administration of aspirin (162 mg). The 50% effective concentration (EC50) values obtained from the in vivo and in vitro experiments were shown to have relevance, because the EC50 ratio for each subject was the same (0.23 ± 0.03). The actual and predicted values for the rate of inhibition of platelet aggregation were well correlated (P < .0001, r = .95) when the predicted rate was determined using the present method. Our results suggest that the antiplatelet effects of aspirin can be predicted using blood samples obtained before its administration.

Theoretical investigation of aspirin dosage regimen to exhibit optimal antiplatelet effects and decrease risk of upper gastrointestinal lesions.

We investigated dosage regimens for aspirin therapy in regard to antiplatelet effects in patients without gastrointestinal lesions. Findings for inhibition of biosynthesis of thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2)) were simulated based on pharmacokinetic and pharmacodynamic models using an irreversible process of inhibition of cyclooxygenase-1 (COX-1) by aspirin. We found that the inhibition of biosynthesis of TXB(2) at a steady state was greater than 90% when the dose of aspirin administered exceeded 81 mg, which was considered to exhibit a sufficient antiplatelet effect. Furthermore, it was confirmed that a dose of 162 mg or more is needed to exert an immediate antiplatelet effect on the initial day of administration. On the other hand, the inhibition of biosynthesis of PGE(2) ranged from 40-90% when aspirin was administered at a dose of 10.125-324 mg. Thus, the risk of gastrointestinal lesions differed in a dosage-dependent manner. The biosynthesis inhibition of PGE(2) was calculated to be 37.9%, with that value set as the target level for prevention of gastrointestinal disorders. We also noted a difference between platelets and gastric mucosa cells in regard to the turnover rate of COX-1, and attempted to simulate the inhibition of biosynthesis of TXB(2) and PGE(2) following administration of aspirin. However, it was not possible, as the inhibition of biosynthesis of TXB(2) was greater than 90% and that of PGE(2) was less than 37.9%, even with various dosage regimens. Our findings suggest that it is difficult to determine a rational dosage regimen of aspirin to exert an antiplatelet effect without inducing gastrointestinal lesions.

[Investigation of the combination of aspirin with non-steroidal anti-inflammatory drugs].

It has been reported that non-steroidal anti-inflammatory drugs (NSAIDs) interact with aspirin to influence its antiplatelet effect. For example, there have been reported that the rate of platelet aggregation inhibition associated with aspirin was significantly decreased when ibuprofen was taken before administration of aspirin, as compared with aspirin alone. In this study, we investigated the prescriptions on combination of aspirin with NSAIDs. The subjects were consisted of 1212 patients who were prescribed aspirin in March, 2008 in Tokai University Hachioji Hospital. The patients prescribed combination of aspirin with NSAIDs were 8.1% and 18.6% of those were prescribed in the order of adminstration to induce drug interaction. The pharmacists should provide information about drug interactions of aspirin with NSAIDs to the doctors and patients, and it is necessary to pay attention of these interactions.

[Evaluation of the development of gastroduodenal lesions in patients treated with low-dose aspirin or non-steroidal anti-inflammatory drugs].

Aspirin irreversibly inhibits the enzyme cyclooxygenase-1 and depresses the production of thromboxane A(2), and also exerts antiplatelet effects. On the other hand, it also depresses the production of prostaglandin E(2) (PGE(2)) and induces gastroduodenal lesions, which are often seen in patients taking aspirin. The aim of this study was to clarify the degree of gastroduodenal lesions induced by low-dose aspirin. We investigated the incidence rate of such lesions induced by aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), and performed theoretical evaluations in a retrospective study. The incidence rates of gastroduodenal lesions in the low-dose aspirin (n=1103) and NSAIDs (n=1856) groups were 2.54% and 0.27%, respectively, which was significantly greater in the aspirin group. Furthermore, the calculated value of inhibition rate of gastric PGE(2) was significantly correlated with the actual value after administration of aspirin or NSAIDs (r=0.902, p<0.05), which suggested that the calculated value reflected the actual value. The calculated value of aspirin (98.9%) was higher than that of NSAIDs (3.67-70.8%) after administration of the drugs with the standard doses. Our findings indicate that the incidence rate of gastroduodenal lesions induced by low-dose aspirin was higher than that of those induced by NSAIDs. Therefore, we were able to perform a theoretical evaluation of the occurrence of gastroduodenal lesions.

[Investigation into the effect of gastric secretion inhibitor for the prevention of upper gastrointestinal lesions associated with low-dose aspirin].

In this study, we investigated the effect of histamin H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) for the prevention of upper gastrointestinal lesions associated with low-dose aspirin. We carried out a retrospective study of 2811 patients who had been prescribed low-dose aspirin (Bayaspirin® 100 mg) for more than 30 days at Tokai University Hachioji Hospital from 2006 to 2008. We classified them into three groups: aspirin alone group (n=1103), aspirin with H2RA group (n=844) and aspirin with PPI group (n=864). Patients who developed upper gastrointestinal lesions were diagnosed with gastric ulcer, duodenal ulcer, gastritis or duodenitis by gastroscopy. We then compared the incidence of upper gastrointestinal lesions among the groups. The incidence in aspirin alone group, aspirin with H2RA group and aspirin with PPI group was 2.54%, 1.54% and 1.04%, respectively; that of aspirin with PPI group being significantly lower (p<0.05). Additively, the odds ratio (OR) of aspirin with H2RA group and aspirin with PPI group was 0.60 (95% confidence interval [95%CI]: 0.31-1.17) and 0.40 (95% CI: 0.19-0.86) as compared with aspirin alone group, respectively. The upper gastrointestinal lesions were developed within two years in all groups. Our results suggest that the combined administration of low-dose aspirin and PPI is effective for the prevention of upper gastrointestinal lesions associated with low-dose aspirin. Also, the pharmacists should be especially careful for upper gastrointestinal lesions development within two years after administration of low-dose aspirin, regardless of combined whether H2RA or PPI.

Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome.

Satisfactory results have not yet been obtained in therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome (APS). We therefore compared single antiplatelet therapy and a combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with APS.The subjects were 20 ischemic stroke patients with antiphospholipid antibody, 13 with primary antiphospholipid syndrome and 7 with SLE-related antiphospholipid syndrome. Diagnosis of APS was based on the 2006 Sydney criteria. Eligible patients were randomly assigned to either single antiplatelet therapy (aspirin 100 mg) or a combination of antiplatelet and anticoagulation therapy (target INR: 2.0-3.0; mean 2.4+/-0.3) for the secondary prevention of stroke according to a double-blind protocol. There was no significant difference between the two groups in age, gender, NIH Stroke Scale on admission, mRS at discharge, or rate of hypertension, diabetes mellitus, hyperlipidemia, or cardiac disease. We obtained Kaplan-Meier survival curves for each treatment. The primary outcome was the occurrence of stroke. The mean follow-up time was 3.9+/-2.0 years. The cumulative incidence of stroke in patients with single antiplatelet treatment was statistically significantly higher than that in patients receiving the combination of antiplatelet and anticoagulation therapy (log-rank test, p-value=0.026). The incidence of hemorrhagic complications was similar in the two groups. The recent APASS study did not show any difference in effectiveness for secondary prevention between single antiplatelet (aspirin) and single anticoagulant (warfarin) therapy. Our results indicate that combination therapy may be more effective in APS-related ischemic stroke.

[Ischemic stroke with antiphospholipid antibody].

Antiphospholipid syndrome is considered to be associated with a hypercoagulable state that leads to stroke and other ischemic events, and is currently diagnosed based on the modified Sapporo criteria that was proposed in 2006. Antiphospholipid antibodies (aPL) comprise a heterogeneous group of autoantibodies. Among them, the level of beta2-glycoprotein I-dependent anticardiolipin antibody, lupus anticoagulant (LA), and IgG anticardiolipin antibody are commonly measured. Recently, phosphatidylserine dependent anti-prothrombin antibody has been suggested to be closely related to LA. aPL is an independent risk factor for a first-ever ischemic stroke, especially in young female patients. It is still debatable whether aPL is a marker for recurrent stroke risk. The precipitating factors for the occurrence of stroke are beta2-GPI-dependent aCL, aGPL, and aCL levels of greater than 40, and the simultaneous presence of LA. Several mechanisms are considered to be involved in the thrombotic process in patients with antiphospholipid antibodies. Activation of protein C is impaired in patients with aPL. Beta2-GPI has simultaneous procoagulant and anticoagulant effects. Cardiac valvular involvement, which could be the cause of cardiogenic embolism, is prevalent in patients with aCL. In addition, the presence of aPL is associated with the development of atherosclerosis. Recently, it has been proposed that endothelial cells, monocytes, and platelets were reported to be activated by beta2-GPI: further, p38 mitogen-activated protein kinase has been reported to be phosphorylated. Several therapeutic options are available for the prevention of ischemic stroke in patients with aPL. For cases of cryptogenic ischemic stroke and positive aPL antibodies, antiplatelet therapy is reasonable. Oral anticoagulation with a target international normalized ratio (INR) of 2 to 3 is reasonable for patients with ischemic stroke who meet the criteria for antiphospholipid syndrome with venous and arterial occlusive disease in multiple organs.

[Case of juvenile stroke caused by methylenetetrahydrofolate reductase deficiency].

The patient had suffered from left hemiparesis at the age of thirteen months, and acute ischemic stroke of unknown etiology had been diagnosed at that time. His hemiparesis gradually disappeared and he was discharged two weeks after the onset without disability. At the age of 17 years, MRI following minor head trauma revealed cerebral infarctions located at the right corona radiata and basal ganglia. Laboratory findings showed hyperhomocysteinemia. Genetic study disclosed methylenetetrahydrofolate reductase deficiency (MTHFRD) (valine/valine type). MTHFRD is not detected by the routine infantile mass screening test for congenital amino acid metabolic disease, and should be considered in any patient with ischemic stroke at under two years of age.

A case of bilateral medial medullary infarction presenting with "heart appearance" sign.

Bilateral medial medullary infarction (bilateral MMI) is an extremely rare cerebrovascular accident presenting with quadriplegia as the initial symptom and resulting in poor functional prognosis. Diagnosis of bilateral MMI has become possible based on brain MRI findings in recent years, but is still very difficult to diagnose. In the present case, brain MRI was performed 9 hours after the onset, and the infarcted area was detected only by diffusion-weighted MRI. However, changes over time were clearly detected by FLAIR-MRI on days 3, 5 and 7, but it is essential to confirm the disease by DW-MRI in the early stage.The infarct observed on horizontal MRI sections showed the characteristic "heart appearance" sign. For an early diagnosis of bilateral MMI, it is essential to bear in mind that characteristic findings may be obtained by diffusion-weighted MRI.