Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

First evidence of tick-borne encephalitis (TBE) outside of Hokkaido Island in Japan.

Tick-borne encephalitis (TBE) is an infection of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is endemic in parts of Europe and Asia. TBEV is transmitted to humans primarily by Ixodes ticks. There have been 5 TBE cases identified in Japan, all on the northern island of Hokkaido. Rodents with TBEV antibodies and Ixodes ticks have been identified throughout Japan, indicating that TBEV infection might be undiagnosed in Japan. Residual serum and cerebrospinal fluid (CSF) collected in 2010-2021 from 520 patients ≥1 year-of-age previously hospitalized with encephalitis or meningitis of unknown etiology at 15 hospitals (including 13 hospitals outside of Hokkaido) were screened by ELISA for TBEV IgG and IgM antibodies; TBEV infection was confirmed by the gold standard neutralization test. Residual serum was available from 331 (63.6%) patients and CSF from 430 (82.6%) patients; both serum and CSF were available from 189 (36.3%). Two patients were TBE cases: a female aged 61 years hospitalized for 104 days in Oita (2000 km south of Hokkaido) and a male aged 24 years hospitalized for 11 days in Tokyo (1200 km south of Hokkaido). Retrospective testing also identified a previous TBEV infection in a female aged 45 years hospitalized for 12 days in Okayama (1700 km south of Hokkaido). TBEV infection should be considered as a potential cause of encephalitis or meningitis in Japan. TBE cases are likely undiagnosed in Japan, including outside of Hokkaido, due to limited clinical awareness and lack of availability of TBE diagnostic tests.

White Embolus-induced Basilar Artery Occlusion Due to Pulmonary Vein Invasion of a Metastasis of a Malignant Melanoma.

An 80-year-old woman presented with impaired consciousness after malignant melanoma resection. Magnetic resonance angiography showed basilar artery occlusion, which was subjected to mechanical thrombectomy for recanalization. A pathological analysis of the retrieved embolus revealed that it was derived from a metastasis of malignant melanoma. Contrast-enhanced chest computed tomography showed multiple pulmonary metastases, one of which was in the right upper lobe and invaded the pulmonary vein. To our knowledge, this is the first case of white embolus-induced cerebral embolism due to pulmonary vein invasion of a metastasis of a pathologically diagnosed malignant melanoma.

Japanese spotted fever with post-infectious encephalitis.

Japanese spotted fever (JSF) is a rickettsial disease caused by Rickettsia japonica. To the best of our knowledge, there have only been five reported cases of JSF involving the central nervous system. A 74-year-old man was admitted after 1 week of fever and maculopapular rash. JSF was definitively diagnosed by PCR; however, the patient showed mental disturbance and abnormal behavior. After intravenous immunoglobulin, his mental state and behavior improved. The findings of cerebrospinal fluid analysis, electroencephalography, and 99 mTcHM-PAO single photon computed emission tomography suggested post-infectious encephalitis. JSF causes post-infectious encephalitis and early treatment is recommended.

Short-term aneurysm formation and rupture due to septic embolism diagnosed with a thrombus retrieved from another occluded artery.

Background: In rare cases, septic embolism is diagnosed on the basis of pathological findings of retrieved thrombi. Infected aneurysms can rapidly form and rupture after septic embolism, leading to a poor prognosis. We report a case of subcortical hemorrhage due to an infected aneurysm forming shortly after septic embolism in the left anterior cerebral artery. Case Description: In this case, the diagnosis of septic embolism was made on the basis of pathological findings of a thrombus retrieved from the simultaneously occluded left middle cerebral artery, and endovascular embolization of the infected aneurysm was performed. Conclusion: The pathological findings of a retrieved thrombus were useful for making a diagnosis of septic embolism. The possibility of short-term formation and rupture of an infected aneurysm after septic embolism should be noted. Endovascular embolization of occluded vessels due to septic embolism may prevent aneurysm formation and subsequent bleeding.

Serial assessment of multimodality imaging in anti-leucine-rich glioma-inactivated 1 antibody encephalitis: A case report.

In autoimmune encephalitis, abnormalities of diffusion-weighted imaging (DWI), fluid-attenuated inversion recovery (FLAIR), arterial spin labeling (ASL) in magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) have been reported. However, there are few studies of long-term follow-up of imaging. We report a case of anti-leucine-rich glioma-inactivated 1 antibody encephalitis whose MRI (DWI, FLAIR and ASL), 99mTcHM-PAO SPECT (PAO-SPECT) and 18F-FDG-PET were evaluated through the clinical course. ASL, PAO-SPECT and 18F-FDG-PET consistently showed abnormalities in almost the same area. Serial assessment of these imaging modalities is useful in evaluating disease activity and efficacy of treatment.

[Myelomatous meningitis: a case report].

We present the case of a 67-year-old woman with meningeal carcinomatosis who was treated with chemotherapy for refractory multiple myeloma, and was in remission. She was admitted to our hospital because of tonic seizures and disturbance of consciousness. Monoclonal CD 138-positive plasma cells were detected in her cerebrospinal fluid. Cranial MRI showed gadolinium enhancement of diffuse meninges and cranial nerves. We diagnosed the patient with systemic epilepsy due to meningeal carcinomatosis and administered antiepileptic drugs and intrathecal chemotherapy; however, she showed little improvement, and she passed away on hospital day 74 because of disease progression. Multiple myeloma is known to be associated with neurological symptoms such as peripheral neuropathy, myelopathy, and radiculopathy; however, central nervous system involvement in multiple myeloma is uncommon. We should consider central nervous system involvement in multiple myeloma, such as meningeal carcinomatosis, given the importance of early detection and therapeutic intervention.

[Tetanus: the clinical features of 11 cases].

Tetanus is an infectious disease induced by wound invasion of Clostridium tetani, which is ubiquitous among soil. Many more cases are reported in Japan than in other developed countries. In this study, we report 11 cases of tetanus experienced at our hospital and discuss the preceding trauma and treatment course. The mean age at onset was 68 years old (35-86 years) and 7 cases required intensive care. Some preceded injuries were clearly contaminated, and others were small and minor. Even minor injuries developed serious tetanus. Trauma was not identified in 2 cases yet both used their family garden every day and had a high risk of exposure to C tetani, suggesting that micro-wounds may have been a gateway to entry. The average length of stay in the intensive care unit was 28 days (4-73 days) and average total hospitalization was 55 days (13-114 days). Only 4 out of 11 cases were diagnosed correctly by the initial physician and others, especially when the trauma was minor or absent, were misdiagnosed even when presenting with characteristic symptoms like lockjaw and posterior neck stiffness. Tetanus should be diagnosed based on medical history and physical examination due to lack of high specific testing. Therefore, a detailed history taking is required, including hobbies in addition to the appropriate neurological examination, thereby facilitating a quick diagnosis and commencement of treatment as soon as possible.

[Primary angiitis of the central nervous system with cerebral infarction and spinal hemorrhage].

A 61-year-old woman presented with acute intense lower back pain and weakness in her left leg. She also presented with throbbing headache on the same day. On admission, muscle weakness in her left leg, lower left quadrantanopia and left lower extremity deep sensory disturbance were observed. Laboratory data showed no coagulopathy and autoimmune antibody was negative. Cerebrospinal fluid examination showed bloody and inflammatory findings. Brain MRI revealed cerebral infarction with multiple intracranial arterial stenosis and convexal subarachnoid hemorrhage. Spinal MRI revealed spinal hemorrhage in the cervical, thoracic, and part of the lumbar spine. Because these lesions occurred simultaneously, we made a diagnosis of vasculitis. After high dose corticosteroids therapy was undertaken, the multiple arterial stenosis improved. Primary angiitis of the central nervous system is sometimes difficult to distinguish from reversible cerebral vasoconstriction syndrome in its initial stage; although symptoms, examination findings and treatment differ in both.

Questionnaire survey on the process of specialty training in neurology in Japan.

Documentation of the current status of specialty training to become a neurologist in Japan would represent an important basis for constructing better neurology training program in the planned reform of the specialty training system in Japan. The committee for future neurology specialty system of Japanese Society of Neurology (JSN) conducted a questionnaire survey on the process of specialty training of each trainee for neurology in board-certified educational facilities and semi-educational facilities throughout Japan. The response rate was 46.2% in all facilities and 87.5% in medical universities. The training process of 905 trainees over 5 grades was clarified, which was estimated to be about 80% of all the relevant subjects. Specialty training dedicated to neurology was started at the 3rd year of residency in 87.8% of subjects. During the 3 years following junior residency, 51.3% of subjects ran the rotation training between university and city hospital, whereas 36.5% was trained within the same institution throughout the 3 years of training period.

Suvorexant-Induced Dream Enactment Behavior in Parkinson Disease: A Case Report.

ABSTRACT: Suvorexant is a new insomnia drug, and it is generally safe and well tolerated. Here, we report a rare but potentially important adverse effect of suvorexant in a patient with Parkinson disease.

Cerebral Air Embolism with Pneumomediastinum Resulting from Emesis: A Case Report.

Cerebral air embolism (CAE) is a rare cause of stroke. Most cerebral air emboli are caused by iatrogenic factors, such as invasive cardiac and pulmonary procedures. Here, we report an unusual case of CAE not related to any medical intervention. An 87-year-old woman became unresponsive after vomiting. A computed tomography (CT) scan of the head 6 hours after the onset of the vomiting revealed multiple air emboli, mainly in the watershed area between the right anterior and middle cerebral arteries. Magnetic resonance imaging with T2* gradient echo showed the air emboli as granular hypointensities. Diffusion-weighted imaging revealed an area of hyperintensity along the cortical region of the right frontal lobe. Head CT scans showed that the size and number of the air emboli rapidly decreased on day 2 and disappeared on day 9. We also performed a chest CT and found pneumomediastinum, which gradually improved over the clinical course. We also found pulmonary fibrosis and bronchiectasis, suggesting an underlying pulmonary vulnerability. In this case, the emesis may have been a trigger for the CAE, which was followed by pneumomediastinum. This case suggests that CAE can occur in a noniatrogenic situation, especially in a patient with pulmonary vulnerability.

Open-label study to evaluate the pharmacodynamics, clinical efficacy, and safety of meropenem for adult bacterial meningitis in Japan.

The aim of this study was to assess the efficacy, safety, and concentration of meropenem in cerebrospinal fluid when meropenem (2 g every 8 h) was administered to Japanese adult patients with bacterial meningitis. Five Japanese patients (mean age 60.6 years [range 35-71]) were enrolled. Infection with Streptococcus pneumoniae (three patients), Streptococcus salivarius (one patient), and Staphylococcus aureus (one patient) was confirmed by cerebrospinal fluid culture. Meropenem (2 g every 8 h) was administered to all five patients. Treatment duration ranged from 14 to 28 days (mean 22.6 days). All the patients were successfully treated. The concentration of meropenem in cerebrospinal fluid ranged from 0.27 to 6.40 µg/ml up to 8.47 h and was over 1 µg/ml 3 h after starting meropenem infusion. In each patient, the present study confirmed for the first time that the concentration of meropenem in cerebrospinal fluid exceeded the minimal inhibitory concentration for these pathogens. Eleven clinical and laboratory adverse events considered to be related to meropenem were observed in all patients, but no serious adverse event and no discontinuance of treatment due to adverse events occurred. Thus meropenem appeared to be a well-tolerated and effective agent for Japanese adult patients with bacterial meningitis. 2 g every 8 h of meropenem was delivered to CSF and its concentration was exceed in MICs for the detected pathogens.

A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.

OBJECTIVE: To identify other causative genes for Andersen-Tawil syndrome, which is characterized by a triad of periodic paralysis, cardiac arrhythmia, and dysmorphic features. Andersen-Tawil syndrome is caused in a majority of cases by mutations in KCNJ2, which encodes the Kir2.1 subunit of the inwardly rectifying potassium channel. METHODS: The proband exhibited episodic flaccid weakness and a characteristic TU-wave pattern, both suggestive of Andersen-Tawil syndrome, but did not harbor KCNJ2 mutations. We performed exome capture resequencing by restricting the analysis to genes that encode ion channels/associated proteins. The expression of gene products in heart and skeletal muscle tissues was examined by immunoblotting. The functional consequences of the mutation were investigated using a heterologous expression system in Xenopus oocytes, focusing on the interaction with the Kir2.1 subunit. RESULTS: We identified a mutation in the KCNJ5 gene, which encodes the G-protein-activated inwardly rectifying potassium channel 4 (Kir3.4). Immunoblotting demonstrated significant expression of the Kir3.4 protein in human heart and skeletal muscles. The coexpression of Kir2.1 and mutant Kir3.4 in Xenopus oocytes reduced the inwardly rectifying current significantly compared with that observed in the presence of wild-type Kir3.4. CONCLUSIONS: We propose that KCNJ5 is a second gene causing Andersen-Tawil syndrome. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles.