Prior direct oral anticoagulant dosage and outcomes in patients with acute ischemic stroke and non-valvular atrial fibrillation: A sub-analysis of PASTA registry study.

BACKGROUND AND PURPOSE: Prescribing under-dose direct oral anticoagulants (DOACs) for non-valvular atrial fibrillation (NVAF) is alerted to increase cardiovascular events or death. However, the association between dose selection of DOACs and the clinical course remains unclear. This study aimed to propose a novel criterion for selecting the DOAC dose and investigate clinical characteristics of ischemic stroke (IS) under this criterion. METHODS: We assessed the pooled prospective multicenter registry data of stroke patients taking anticoagulant agents, including IS patients with NVAF and prior DOAC usage. The recommended dose according to the reduction criteria of each DOAC and the selected dose were identified for each patient, and patients were categorized into four groups: no alternative low-dose, selecting low-dose appropriately with all DOACs applicable for reduction criteria; selected low-dose, selecting low-dose appropriately or inappropriately despite at least one DOAC inapplicable for reduction criteria; selected standard-dose, appropriate standard-dose use; and absolute over-dose, inappropriate standard-dose regardless of criteria. We investigated the effects of dose selection of DOACs on short-term poor functional outcomes. RESULTS: 322 patients were included in the analysis. The prevalence of no alternative low-dose, selected low-dose, selected standard-dose, and absolute over-dose was 74 (23%), 144 (45%), 89 (27%), and 15 (5%), respectively. Multivariable analysis found that the selected low-dose group showed significantly poorer functional outcomes than the selected standard-dose group only in patients without renal dysfunction (OR, 2.60; 95% CI, 1.17-6.00; P = 0.0186). CONCLUSIONS: Selecting a low dose DOAC might be associated with poor functional outcomes in patients without renal dysfunction.

Characteristics of Ischemic Versus Hemorrhagic Stroke in Patients Receiving Oral Anticoagulants: Results of the PASTA Study.

Objective Limited data exist regarding the comparative detailed clinical characteristics of patients with ischemic stroke (IS)/transient ischemic attack (TIA) and intracerebral hemorrhage (ICH) receiving oral anticoagulants (OACs). Methods The prospective analysis of stroke patients taking oral anticoagulants (PASTA) registry, a multicenter registry of 1,043 stroke patients receiving OACs [vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulant (NOACs)] across 25 medical institutions throughout Japan, was used. Univariate and multivariable analyses were used to analyze differences in clinical characteristics between IS/TIA and ICH patients with atrial fibrillation (AF) who were registered in the PASTA registry. Results There was no significant differences in cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia, smoking, or alcohol consumption (all p>0.05), between IS/TIA and ICH among both NOAC and VKA users. Cerebral microbleeds (CMBs) [odds ratio (OR), 4.77; p<0.0001] were independently associated with ICH, and high brain natriuretic peptide/N-terminal pro B-type natriuretic peptide levels (OR, 1.89; p=0.0390) were independently associated with IS/TIA among NOAC users. A history of ICH (OR, 13.59; p=0.0279) and the high prothrombin time-international normalized ratio (PT-INR) (OR, 1.17; p<0.0001) were independently associated with ICH, and a history of IS/TIA (OR, 3.37; 95% CI, 1.34-8.49; p=0.0101) and high D-dimer levels (OR, 2.47; 95% CI, 1.05-5.82; p=0.0377) were independently associated with IS/TIA among VKA users. Conclusion The presence of CMBs, a history of stroke, natriuretic peptide and D-dimer levels, and PT-INR may be useful for risk stratification of either IS/TIA or ICH development in patients with AF receiving OACs.

Risk factors, etiology, and outcome of ischemic stroke in young adults: A Japanese multicenter prospective study.

PURPOSE: This study aimed to evaluate the risk factors, etiology, and outcomes of ischemic stroke (IS) in Japanese young adults. METHODS: This was a prospective multicenter study. We enrolled patients aged 16 to 55 years with IS within seven days of the onset of symptoms. We assessed the demographic data, risk factors, stroke etiology, and outcome at discharge. The clinical characteristics were compared between sexes and among age groups. RESULTS: We prospectively enrolled 519 patients (median age, 48 years: 139 females). The mean National Institute of Health Stroke Scale score was 3.6 ± 0.2. The most common risk factors were hypertension (HT) (55%), dyslipidemia (DL) (47%), and current smoking (42%). Body mass index, incidence of current smoking, and heavy alcohol consumption were higher in males. The prevalence of current smoking, HT, DL, and diabetes mellitus increased with aging. The most common etiologic subgroup of IS was small vessel disease (145/510, 28%). Intracranial arterial dissection (IAD) was the most common among the other determined causes (56/115, 49%). The outcome at discharge was relatively good (mRS 0-1, 71.7%); however, poor outcome (mRS ≥ 4) was observed at an incidence of 9.5%. CONCLUSIONS: Most young adults with IS had modifiable risk factors, of which prevalence increased with age. This emphasizes lifestyle improvement to prevent IS in the young population. Furthermore, we indicated that the incidence rate of IAD was high among the other determined causes.

Diagnostic utility and characteristics of CT-based attenuation correction in brain perfusion SPECT/CT in predicting the exacerbation of Alzheimer changes from mild cognitive impairment utilizing voxel-based statistical analysis in comparison with Chang's method.

OBJECTIVE: We examined the diagnostic value of brain perfusion single-photon emission computed tomography (SPECT) using voxel-based statistical analysis with CT-based attenuation correction (CT-AC) by comparing it to that with Chang's AC in mild cognitive impairment (MCI) patients and attempted to locate brain areas that are good indicators predicting the progression of MCI. METHODS: Twenty-six individuals matched for age, educational background and initial Mini-Mental State Examination (MMSE) score of more than 24 underwent SPECT with N-isopropyl-4-[123I]iodoamphetamine and were assigned to 2 groups: the stable MCI (S-MCI) group comprising 11 subjects who maintained their MMSE score (mean 27.0) during at least a 1-year follow-up period (mean 37.2 months) and the progressive MCI (P-MCI) group comprising 15 subjects whose MMSE scores decreased by 3 or more points (from 26.4 to 21.4, mean). The diagnostic values of the two AC methods for discriminating P-MCI from S-MCI were compared using voxel-based statistical analysis in the lobe (Level 2) and lobule/gyrus levels (Level 3). RESULTS: Receiver operating characteristic analysis revealed that the area under the curve (AUC) was higher with CT-AC than with Chang's AC in the left temporal and limbic lobes in Level 2. In Level 3, the AUC in the left middle temporal gyrus was higher with CT-AC (0.852) than with Chang's AC (0.827). There were differences between the gyri/lobules that showed higher AUCs with CT-AC and those that showed higher AUCs with Chang's AC. When the gyri with the 4 highest AUCs were combined, AUC (0.897) and accuracy (84.6%) were better with CT-AC than with Chang's AC (0.806 and 80.8%). Surprisingly, the AUCs in the posterior cingulate gyrus and precuneus, excluding the AUC in the right precuneus with Chang's AC (0.715), were no more than 0.70 and less useful. CONCLUSIONS: CT-AC may allow brain perfusion SPECT to reflect more exact neuropathic changes in MCI that would cause progression of early AD. CT-AC in conjunction with voxel-based statistical analysis could possess higher diagnostic accuracy for exacerbation of disease implying early Alzheimer changes in MCI patients, with decreases in cerebral perfusion in the left temporal and limbic lobes representing good indicators.

An Oculopharyngeal Subtype of Guillain-Barré Syndrome Sparing the Trochlear and Abducens Nerves.

Guillain-Barré syndrome (GBS) comprises a group of polyneuropathies characterized by rapid progression of limb paralysis. Various subtypes of GBS have been reported. The oculopharyngeal subtype of GBS is currently understood to be primarily a cranial polyneuropathy without limb weakness or cerebellar ataxia. In our case of 62-year-old man, gastrointestinal infection was followed by paranesthesia of the hands. He had bilateral ptosis, pharyngeal disorder, and tongue and bifacial weakness. We diagnosed oculopharyngeal subtype of GBS. It responded to intravenous immunoglobulin. This case highlights the need for further characterization of unusual GBS subtypes.

[Successful palliative surgical treatment for drug-resistant epilepsy after anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: Two case reports].

Epilepsy surgery for patients with drug-resistant epilepsy after anti-N-methyl-D-aspartate (NMDA) receptor encephalitis has been rarely reported. The present study reports two patients with anti-NMDA receptor encephalitis, who later underwent epilepsy surgery due to drug-resistant epilepsy. The patients had refractory status epilepticus in the acute phase. The cerebrospinal fluid was positive for anti-NMDA receptor antibodies. Systemic corticosteroid therapy and plasma exchange were effective. Seizure control, however, worsened over several months after discharge, and was refractory to antiepileptic drugs. They underwent palliative epilepsy surgery, and their seizure control improved. Epilepsy surgery should be considered in patients with drug-resistant epilepsy after anti-NMDA receptor encephalitis.

Multicenter Prospective Analysis of Stroke Patients Taking Oral Anticoagulants: The PASTA Registry - Study Design and Characteristics.

OBJECTIVES: The management of atrial fibrillation and deep venous thrombosis has evolved with the development of direct oral anticoagulants (DOAC), and oral anticoagulant (OAC) might influence the development or clinical course in both ischemic and hemorrhagic stroke. However, detailed data on the differences between the effects of the prior prescription of warfarin and DOAC on the clinical characteristics, neuroradiologic findings, and outcome of stroke are limited. DESIGN: The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke (ischemic stroke, transient ischemic attack, and intracerebral hemorrhage) patients receiving OAC in Japan. This study is designed to collect data on clinical background characteristics, drug adherence, drug dosage, neurological severity at admission and discharge, infarct or hematoma size, acute therapy including recanalization therapy or reverse drug therapy, and timing of OAC re-initiation. Patient enrollment started in April 2016 and the target patient number is 1000 patients. CONCLUSIONS: The PASTA prospective registry should identify the status of stroke patients taking OAC in the current clinical practice in Japan.

A case of herpes zoster ophthalmicus preceded one week by diplopia and ophthalmalgia.

A 66-year-old man presented with headache and ophthalmalgia. Diplopia developed, and he was hospitalized. The left eye had abducent paralysis and proptosis. We diagnosed him with Tolosa-Hunt syndrome and administered methylprednisolone at 1 g/day for 3 days. However, the patient did not respond to treatment. No abnormality was found on his MRI or cerebrospinal fluid examination. Tests showed his serum immunoglobulin G4 and antineutrophil cytoplasmic antibody titers were within normal limits. He also had untreated diabetes mellitus (HbA1c 9.2). One week after first presenting with symptoms, herpes zoster appeared on the patient's dorsum nasi, followed by keratitis and a corneal ulcer. Herpes zoster ophthalmicus with ophthalmoplegia was diagnosed. We began treatment with acyclovir (15 mg/kg) and prednisolone (1 mg/kg, decreased gradually). Ophthalmalgia and the eruption improved immediately. The eye movement disorder improved gradually over several months. It is rare that diplopia appears prior to cingulate eruption of herpes zoster ophthalmicus. We speculated that onset of the eruption was inhibited by strong steroid therapy and untreated diabetes mellitus.

A case of Cefepime encephalopathy, being difficult to distinguish from non-convulsive status epilepticus during the treatment of bacterial meningitis.

A 64-year-old man with fever, appetite loss, and pain in the back of the neck visited our hospital. We diagnosed him as having bacterial meningitis because of pleocytosis of the cerebrospinal fluid, and started treatment with antibiotics. Multiple cerebral infarcts were found on brain MRI. We suspected that the origin of the bacterial meningitis was infective endocarditis, and administered Cefepime and Gentamicin according to the guidelines for treatment of infective endocarditis. Three days later, he became drowsy and had myoclonus and flapping of the extremities. An electroencephalograph showed generalized periodic discharge and a triphasic wave pattern. We thought that the cause of disturbance in consciousness was Cefepime-induced encephalopathy, and stopped administration of Cefepime. A few days later, he became clear, and the myoclonus and flapping disappeared. It was difficult to distinguish between non-convulsive status epilepticus and Cefepime-induced encephalopathy. However, since stopping Cefepime treatment had made the patient clear, we diagnosed his condition as Cefepime-induced encephalopathy, which often occurs in patients with renal or liver dysfunction, or in brain infarction or meningitis, which results in blood-brain barrier disruption. Thus, care should be taken when administering Cefepime to such patients.

Partial prediction of postpartum Graves' thyrotoxicosis by sensitive bioassay for thyroid-stimulating antibody measured in early pregnancy.

Graves' disease often occurs after delivery. However, it has been difficult to predict who will develop Graves' hyperthyroidism. We attempted to predict postpartum onset of Graves' disease by measuring anti-TSH receptor antibodies (TRAb) and thyroid-stimulating antibodies (TSAb) in early pregnancy. TRAb was measured by a third generation assay and TSAb was measured by a newly developed sensitive bioassay. In 690 early pregnant women, 2 showed borderline TRAb positive reactions. However, none of them developed Graves' disease after delivery. Thirty-eight of 690 pregnant women were positive for anti-thyroid peroxidase antibodies (TPOAb) and 4 were positive for TSAb. Two of these 4 women developed postpartum Graves' hyperthyroidism. These findings indicate that the third generation TRAb assay was not useful, but that the sensitive TSAb bioassay was moderately useful for predicting the postpartum onset of Graves' hyperthyroidism.

Marked preservation of the visual and olfactory pathways in ALS patients in a totally locked-in state.

MATERIALS AND METHODS: The present paper examines the brains and spinal cords in 7 patients with amyotrophic lateral sclerosis (ALS) receiving artificial respirator support in a totally locked-in state (TLS) neuropathologically in order to clarify whether any anatomical structures in the central nervous system are preserved. RESULTS AND CONCLUSION: We found that the visual and olfactory pathways, hypothalamus, nucleus basalis of Meynert, and commissura anterior were remarkably well preserved, whereas the somatosensory, auditory, and gustatory pathways in the brain stem and/or spinal cord showed severe deterioration.

Hippocampal sclerosis in the parkinsonism-dementia complex of Guam: quantitative examination of neurons, neurofibrillary tangles, and TDP-43 immunoreactivity in CA1.

The cornu ammonis 1 (CA1) area in the hippocampus of the parkinsonism-dementia complex (PDC) of Guam was examined quantitatively with special references to the number of neurons, intraneuronal (i) and extracellular (e) neurofibirillary tangles (NFTs), and TDP-43 (43-kDa trans-activation-responsive region DNA-binding protein)-immunopositive structures, in 24 Chamorro patients with PDC of Guam and seven control Chamorro Guamanians (both groups having no ischemic or anoxic complications). The results were that: (i) in the patients with mildly involved PDC, total numbers of neurons, iNFTs and eNFTs were almost the same as those of neurons of controls; (ii) in patients severely involved, total numbers of neurons, iNFTs and eNFTs decreased markedly; (iii) the decrease of the number of pyramidal neurons in CA1 with positive nuclear TDP-43 was intimately correlated with the decrease in total neuron numbers; (iv) whereas the numbers of neurons and TDP-43-immunopositive intracytoplasmic aggregation in the CA1 area were inversely correlated; and (v) depression of nuclear TDP-43 immuonostainability was not affected by the presence or absence of NFTs. In conclusion, hippocampal sclerosis exists in PDC; there is a possibility of elimination of eNFTs which appeared in the CA1 in patients with PDC and loss of the neurons correlates with disappearance of nuclear TDP-43, but not with appearance of intraneurocytoplasmic TDP-43 aggregation or iNFTs.

Early Stage of Progressive Supranuclear Palsy: A Neuropathological Study of 324 Consecutive Autopsy Cases.

Diagnosing clinical progressive supranuclear palsy (PSP) is challenging. We hypothesize that there are more cases of pathological PSP than have been clinically identified, but its diagnosis is challenging because the initial lesions and progression of PSP have not yet been clarified. The purpose of our study was to clarify the incidence of PSP in consecutive autopsy cases and identify pathological characteristics of early PSP. We investigated 324 consecutive autopsy patients from a general geriatric hospital (age, mean±SD=82.5±8.7 years). Paraffin sections of the midbrain were immunostained with anti 4-repeat tau antibodies (RD4). We selected cases showing RD4-positive neurofibrillary tangles and tufted astrocytes in the midbrain sections. Then, we used anti-phosphorylated tau antibody to immunostain sections from the basal ganglia, subthalamic nucleus, midbrain, pons, medulla, and cerebellum. Of the 324 patients, 35 had RD4-positive structures in the midbrain. From these 35 cases, we excluded those for which autopsies confirmed definite PSP (n=5) and cases of corticobasal degeneration (n=1), Alzheimer's disease (n=11), dementia of grain (n=10), and neurofibrillary tangles predominant forms of senile dementia (n=2), leaving 8 cases. We diagnosed these 8 cases as pure PSP-type tauopathy. Pure PSP-type tauopathy was detected in 2.5% of the consecutive autopsy cases, and this incidence was 1.6 times greater than that of neuropathologically definite PSP. This pure PSP-type tauopathy likely indicates preclinical stages of PSP. Furthermore, the novel neuropathological finding, which we term "preclinical PSP," is unique and has not previously been reported. In order to elucidate the causes and pathological mechanisms of PSP, preclinical PSP should be investigated further.

The potentially protective effect of donepezil in Alzheimer's disease.

BACKGROUND/AIMS: Donepezil is an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD). In this study, we used a voxel-based specific regional analysis system for AD (VSRAD) to analyze the hippocampal volume and to assess the pharmacologic effects of donepezil as a disease modifier. METHODS: A total of 185 AD patients underwent MRI, 120 (43 men and 77 women, 77.8 ± 7.1 years) without and 65 (29 men and 36 women, 78.4 ± 6.0 years) with donepezil treatment. VSRAD was compared in both groups and against a database of 80 normal subjects. The Z-score was used to assess the degree of hippocampal atrophy. RESULTS: No significant difference between the groups was found for age, sex, or Z-scores, but a significant difference was found for mean Mini-Mental State Examination (MMSE) scores (p = 0.02, Student's t test). Single regression analysis showed no significant association between Z-scores and MMSE scores in the treated group (p = 0.494), but a significant association in the untreated group (p = 0.001) was observed. This implies that the MMSE score becomes lower when the Z-score is higher in the untreated group, whereas there is no significant trend in the treated group. CONCLUSION: Donepezil affects the relationship between hippocampal volume and cognitive function and may therefore have a pharmacologic effect as a disease modifier.

[Amyotrophic lateral sclerosis in totally locked-in state].

Seven autopsy patients with amyotrophic lateral sclerosis (ALS) in totally locked-in state (TLS) were examined neuropathologically. The patients were composed of 4 males and 3 females, and 3 with familial, 1 sporadic but with mutation in SOD1 gene, and 3 sporadic patients with unremarkable gene mutation. The brains weighed 715, 783, 1,019, 1,050, 1,170, 1,190 or 1,233 g. The tegmentum of the brain stem was markedly degenerated in every patient, and the tracts relating to the somatic sensory and auditory were involved in the lesions.

Posterior reversible encephalopathy syndrome due to hypercalcemia associated with parathyroid hormone-related peptide: a case report and review of the literature.

We herein report the case of a 58-year-old man with advanced esophageal carcinoma who developed posterior reversible encephalopathy syndrome (PRES). He initially presented with a severe consciousness disturbance. A subsequent examination revealed hypercalcemia and an elevated serum parathyroid hormone-related peptide (PTHrP) level. Magnetic resonance imaging performed on admission and 24 days later showed reversible widespread white matter abnormalities, which confirmed a diagnosis of PRES. The patient's clinical and radiological manifestations improved upon normalization of the serum calcium level. To the best of our knowledge, this is the first report describing hypercalcemia-induced PRES occurring in association with elevated PTHrP.