Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan.

AIMS: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. METHODS: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. RESULTS: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. CONCLUSION: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

The Influence of Aneurysm Size on the Outcomes of Endovascular Management for Aneurysmal Subarachnoid Hemorrhages: A Comparison of the Treatment Results of Patients with Large and Small Aneurysms.

The influence of aneurysm size on the outcomes of endovascular management (EM) for aneurysmal subarachnoid hemorrhages (aSAH) is poorly understood. To evaluate the outcomes of EM for ruptured large cerebral aneurysms, we retrospectively analyzed the medical records of patients with aSAH that were treated with coiling between 2013 and 2020 and compared the differences in outcomes depending on aneurysm size. A total of 469 patients with aSAH were included; 73 patients had aneurysms measuring ≥10 mm in diameter (group L), and 396 had aneurysms measuring <10 mm in diameter (group S). The median age; the percentage of patients that were classified as World Federation of Neurological Surgeons grade 1, 2, or 3; and the frequency of intracerebral hemorrhages differed significantly between group L and group S (p = 0.0105, p = 0.0075, and p = 0.0458, respectively). There were no significant differences in the frequencies of periprocedural hemorrhagic or ischemic events. Conversely, rebleeding after the initial treatment was significantly more common in group L than in group S (6.8% vs. 2.0%; p = 0.0372). The frequency of a modified Rankin Scale score of 0-2 at discharge was significantly lower (p = 0.0012) and the mortality rate was significantly higher (p = 0.0023) in group L than in group S. After propensity-score matching, there were no significant differences in complications and outcomes between the two groups. Rebleeding was more common in large aneurysm cases. However, propensity-score matching indicated that the outcomes of EM for aSAH may not be affected markedly by aneurysm size.

Epidemiology of post-suboccipital craniotomy headache: A multicentre retrospective study.

The detailed epidemiology and mechanism of post-craniotomy headaches are not well understood. This study aimed to establish the actual clinical incidence and causes of post-craniotomy headaches. Suboccipital craniotomy surgeries performed in six institutions within the five-year study period were included. This study included 311 patients (138 males, 173 female; mean age, 59.3 years old). A total of 145 patients (49%) experienced post-craniotomy headaches. Microvascular decompression surgery, craniectomy and facial spasms were significant risk factors for post-craniotomy headaches. In most cases, the post-craniotomy headaches disappeared within one month; however, some patients suffered from long-term headaches. The craniotomy site and the methods of dura and skull closures should be individually determined for each patient. However, to prevent post-craniotomy headaches, craniotomy, instead of craniectomy, may be considered.

Difficulty of diagnosing a mucor-induced aneurysm arising in segment P4 of the posterior cerebral artery - A case report.

Background: Identification of causative pathogen for fungal aneurysm is frequently difficult. We reported the case of a fungal aneurysm caused by Mucor arising in segment P4 of the posterior cerebral artery (PCA) detected only by histopathological examination. Case Description: A 50-year-old female complained of nausea and vomiting. Computed tomography showed an intracranial hemorrhage in the left occipital lobe and acute hydrocephalus due to intraventricular hemorrhaging. Digital subtraction angiography performed after external drainage showed a cerebral aneurysm in segment P4 of the left PCA. Surgical excision of the aneurysm and end-to-end anastomosis of the PCA were performed. A histopathological examination revealed that the aneurysm had been caused by a Mucor infection. Conclusion: In fungal aneurysm cases, especially those involving Mucor infections, it is difficult to identify the causative fungal infection based on cultures, imaging, and serological tests. Therefore, surgical excision and histopathological diagnosis are important for diagnosing such cases if possible.

The effects of antithrombotic therapy on head trauma and its management.

The number of patients with traumatic intracranial hemorrhage (tICH) that are taking antithrombotics (ATs), antiplatelets (APs) and/or anticoagulants (ACs), has increased, but the influence of it for outcome remains unclear. This study aimed to evaluate an influence of AT for tICH. We retrospectively reviewed all patients with tICH treated between 2012 and 2019, and analyzed demographics, neurological status, clinical course, radiological findings, and outcome data. A total of 393 patients with tICH were included; 117 were on AT therapy (group A) and 276 were not (group B). Fifty-one (43.6%) and 159 (57.6%) patients in groups A and B, respectively, exhibited mRS of 0-2 at discharge (p = 0.0113). Mortality at 30 days was significantly higher in group A than in group B (25.6% vs 16.3%, p = 0.0356). Multivariate analysis revealed that higher age (OR 32.7, p < 0.0001), female gender (OR 0.56, p = 0.0285), pre-injury vitamin K antagonist (VKA; OR 0.42, p = 0.0297), and hematoma enlargement (OR 0.27, p < 0.0001) were associated with unfavorable outcome. AP and direct oral anticoagulant were not. Hematoma enlargement was significantly higher in AC-users than in non-users. Pre-injury VKA was at high risk of poor prognosis for patients with tICH. To improve outcomes, the management of VKA seems to be important.

Response to pembrolizumab in a patient with primary lung adenocarcinoma originated from indium lung.

BACKGROUND: Indium is a metal used as a compound called indium-tin oxide for liquid crystal display. Its inhalation causes lung toxicity, resulting in a new occupational lung disease called indium lung. Although the carcinogenicity of indium has been reported in an animal model, its carcinogenicity in humans is unknown. CASE PRESENTATION: This is the first reported case of a primary lung cancer originating from indium lung. In this report, we describe a 46-year-old man with interstitial pneumonia-type indium lung diagnosed 16 years ago. The initial symptom was left chest pain, and computed tomography showed a mass adjacent to the aorta with left pleural effusion. Specimens collected using video-assisted thoracoscopy revealed an adenocarcinoma with a high expression of programmed cell death-ligand 1 (cT4N0M1a stage IVA). Although the lesions showed a remarkable aggressive nature, the patient benefited from pembrolizumab, a monoclonal antibody against programmed cell death 1, which was used as second-line therapy for 2 years. CONCLUSIONS: It is important for clinicians to be aware of lung cancer development in indium-exposed workers or in patients with indium lung, as this could have an aggressive behavior. Treatment with immune checkpoint inhibitors is an option even in patients with interstitial pneumonia-type indium lung.

Prediction of the Cerebral Hyperperfusion Phenomenon after Carotid Endarterectomy Using a Transit Time Flowmeter.

The purpose of this study was to investigate the relationship between the cerebral hyperperfusion phenomenon (CHP) and carotid artery flow volume as measured by a transit time flowmeter during carotid endarterectomy (CEA). We retrospectively investigated 74 patients who underwent both transit time flowmetry and single photon emission computed tomography (SPECT). The flow volumes of the internal carotid artery (ICA) before and after the endarterectomy were recorded during surgery as the pre- and the post-ICA (mL/min), respectively. We defined the difference between the pre- and the post-ICA as the ΔIC (mL/min). Two independent board-certified neurosurgeons analyzed the asymmetry index (affected side/contralateral side) of regional qualitative cerebral blood flow before and after the CEA respectively. We defined the CHP as an excessive increase in this asymmetry index between preoperative and postoperative SPECT. The CHP was observed in five of the 74 patients (6.8%). The pre-ICA of the CHP cases was significantly lower than that of the non-CHP cases (in mL/min, median 29 vs. 97; P = 0.01). The ΔIC of the CHP cases was significantly higher than that of the non-CHP cases (in mL/min, median 154 vs. 50; P = 0.002). The cut-off value of the ΔIC was 81 mL/min (sensitivity 100%, specificity 78.3%, area under the curve 0.912). The findings of this study suggest that the ΔIC is associated with the CHP. The transit time flowmeter is useful to predict the CHP during surgery.

Early retreatment after surgical clipping of ruptured intracranial aneurysms.

BACKGROUND: Although a rerupture after surgical clipping of ruptured intracranial aneurysms is rare, it is associated with high morbidity and mortality. The causes for retreatment and rupture after surgical clipping are not clearly defined. METHODS: From a prospectively maintained database of 244 patients who had undergone surgical clipping of ruptured intracranial aneurysms, we selected patients who experienced retreatment or rerupture within 30 days after surgical clipping. Aneurysm occlusions were examined by microvascular Doppler ultrasonography and indocyanine green video-angiography. Indications for retreatment included rerupture and partial occlusion. We analyzed the characteristics and causes of early retreatment. RESULTS: Six patients (2.5%, 95% CI 0.9 to 5.3%) were retreated within 30 days after surgical clipping, including two patients (0.8%, 95% CI 0.1 to 2.9%) who experienced a rerupture. The retreated aneurysms were found in the anterior communicating artery (AcomA) (n = 5) and basilar artery (n = 1). Retreatment of the AcomA (7.5%) was performed significantly more frequently than that of other arteries (0.56%) (p < 0.01). A laterally projected AcomA aneurysm (17.4%) was more frequently retreated than were other aneurysm types (2.3%). Cases of laterally projecting AcomA aneurysms tended to result from an incomplete clip placed using a pterional approach from the opposite side of the aneurysm projection. CONCLUSIONS: Despite developments, the rates of retreatment and rerupture after surgical clipping remain similar to those reported previously. Retreatment of the AcomA was significantly more frequent than was retreatment of other arteries. Patients underwent retreatment more frequently when they were originally treated for lateral type aneurysms using a pterional approach from the opposite side of the aneurysm projection. The treatment method and evaluation modalities should be considered carefully for AcomA aneurysms in particular.

Clinical outcomes of intracerebral hemorrhage in hemodialysis patients.

BACKGROUND: Chronic renal failure (CRF) is associated with a high incidence of stroke. In particular, the mortality rate for intracerebral hemorrhage (ICH) patients with hemodialysis (HD) due to advanced stage CRF is high, and the annual number of such cases is increasing. Therefore, we retrospectively investigated 5 years of clinical data from patients with ICH in our institution to reveal differences in the clinical courses of HD and non-HD patients and to identify risk factors for poor outcomes in ICH patients with HD. METHODS: Three hundred sixty-six consecutive patients with nontraumatic spontaneous ICH, 91% of whom did not receive HD (non-HD group) and 9% of whom received HD for the treatment of CRF (HD group), were enrolled. Clinical data, including the presence of intraventricular hemorrhage (IVH), microbleeds, modified Rankin scale scores, previous medical disease history, the presence of HD, and the days on which ICH occurred, were evaluated. RESULTS: In a comparison of HD patients and non-HD patients, the HD patients had higher rates of hematomas in the basal ganglia, IVH, use of antihypertensive drugs, antidiabetic drugs, and antiplatelet/anticoagulants. The mortality rate was higher in the HD group (44%) than in the non-HD group (21%). In the HD group, the risk factors associated with mortality were hematoma volume, the presence of IVH, and lack of antihypertensive drug use. Eighty-five percent of the ICH occurred on intermittent HD days or before the HD procedure on an HD day. CONCLUSIONS: Mortality in ICH patients with HD was associated with lack of antihypertensive drug use. Therefore, strict control of blood pressure is needed in HD patients to prevent ICH, especially on intermittent HD days or before the HD procedure.

Pilot study of the safety of starting administration of low-dose aspirin and cilostazol in acute ischemic stroke.

Progressive stroke is a serious problem due to the associated morbidity and mortality. Aspirin is recommended for acute ischemic stroke, but does not reduce the frequency of stroke progression. No standard treatment has been approved for the prevention of stroke progression. Cilostazol, which reduces platelet aggregation about 3 hours after single administration, does not increase the frequency of bleeding events when compared with aspirin or a placebo. Moreover, the combination of 100 mg aspirin and 200 mg cilostazol does not increase the frequency of bleeding events compared with only 100 mg aspirin, and thus is expected to prevent stroke progression with a high degree of safety. The present study investigated the safety of this combination of two drugs administered at the above concentrations in 54 patients with acute ischemic stroke within 48 hours of stroke onset. Modified National Institutes of Health Stroke Scale (NIHSS) measurements were performed at baseline and again on day 4 to 7. Progressive stroke was defined as an increase greater than or equal to 1 point on NIHSS. Patient scores on the modified Rankin Scale (mRS) were evaluated at baseline and 3 months after enrollment. Stroke progression occurred in 11.1% of the patients. The percentages of patients with mRS score from 0 to 2 were 42.6% and 75% at baseline and 3 months, respectively. No symptomatic intracranial hemorrhage or major extracranial hemorrhage occurred. These results suggest that administration of aspirin and cilostazol is safe for acute ischemic stroke.

Mild encephalitis/encephalopathy with a reversible splenial lesion: evaluation by diffusion tensor imaging. Two case reports.

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinico-radiological syndrome with a very particular clinical course. Three patients with MERS were evaluated by various sequences of magnetic resonance imaging with diffusion tensor imaging. Initial diffusion-weighted imaging showed reduction in the apparent diffusion coefficient values in the lesions, which completely resolved with the elimination of symptoms. However, diffusion anisotropy of the lesions showed no remarkable abnormalities in the early or delayed phases. These results may indicate that white matter architecture is preserved in both early and delayed phases in MERS.

Evaluation of ventriculomegaly using diffusion tensor imaging: correlations with chronic hydrocephalus and atrophy.

OBJECT: Ventriculomegaly is a common imaging finding in many types of conditions. It is difficult to determine whether it is related to true hydrocephalus or to an atrophic process by using only imaging procedures such as MR imaging after traumatic injury, stroke, or infectious disease. Diffusion tensor (DT) imaging can distinguish the compression characteristics of white matter, indicating that increased diffusion anisotropy may be related to white matter compression. In this preliminary study, the authors compared the DT imaging findings of ventriculomegaly with those of chronic hydrocephalus or atrophy to clarify the potential of diffusion anisotropy in the identification of hydrocephalus. METHODS: Ten patients with chronic hydrocephalus, 8 patients with atrophy (defined by conventional devices and surgical outcome), and 14 healthy volunteers underwent DT imaging. Images were acquired before and after shunting or once in cases without shunting. The fractional anisotropy (FA) values at many points around the lateral ventricle were evaluated. RESULTS: The FA patterns around the lateral ventricle in the chronic hydrocephalus and atrophy groups were different. Especially in the caudate nucleus, FA was increased in the chronic hydrocephalus group compared with the atrophy group. Furthermore, the FA values returned to normal levels after shunt placement. CONCLUSIONS: Assessment of the FA value of the caudate nucleus may be an important, less invasive method for distinguishing true hydrocephalus from ventriculomegaly. Further research in a large number of patients is needed to verify the diagnostic ability of this method.

Neurocysticercosis as solitary parenchymal lesion confirmed by mitochondrial deoxyribonucleic acid sequence analysis.

A 38-year-old Japanese woman presented with neurocysticercosis manifesting as mild hemiparesis. Magnetic resonance (MR) imaging with gadolinium showed a solitary parenchymal lesion. MR spectroscopy of the mass showed a relatively low N-acetylaspartate peak. Enzyme-linked immunosorbent assay of the patient's cerebrospinal fluid using antibodies against several parasite antigens was negative. Surgical resection of the lesion was performed. The histological findings showed the possibility of parasitic infection such as neurocysticercosis, although the definitive type of parasite was not confirmed. Sequencing of cytochrome c oxidase subunit 1 gene of mitochondrial deoxyribonucleic acid indicated the Asian genotype of Taenia solium. We propose that these new diagnostic techniques should be used more widely, especially for solitary lesions of neurocysticercosis.

Levodopa treatment for patients in persistent vegetative or minimally conscious states.

The persistent vegetative state (PVS) and the minimally conscious state (MCS) are conditions of altered consciousness after severe brain damage due to a variety of pathologies. However, the specific pathophysiological mechanisms and a therapeutic strategy for intervention have not as yet been established. We review previous reports of levodopa treatment for patients in PVS, MCS, or other mental disorders, and have focused on five representative cases: four of PVS and one of MCS after severe brain injury. In summary, our review suggests the effectiveness of levodopa treatment is probably dependent upon the following criteria: (1) Diagnosis of PVS or MCS as distinct from other related conditions, (2) Concomitant symptoms of parkinsonism, and (3) Concomitant neuroradiological findings of high intensity lesions in the dopaminergic pathway on T2 weighted MRI. The apparent success of levodopa in the five cases described may reflect a specific subgroup of PVS and MCS patients, where the administration of levodopa is effective. However, we should not regard PVS or MCS as a single entity, since levodopa is unlikely to be effective in all cases. Therapeutic strategies should aim to identify the key pathophysiological mechanism for each patient and target interventions accordingly.