A decision tree model for predicting high mono-N-desethylamiodarone concentrations and reducing tissue toxicity in patients with low-dose amiodarone therapy: A multicentral retrospective cohort study.

OBJECTIVE: High plasma levels of mono-N-desethylamiodarone (MDEA), an active amiodarone metabolite, may be associated with tissue toxicity in heart failure (patients with heart rhythm disturbances); therefore, a tool that can identify patients for whom therapeutic drug monitoring (TDM) of MDEA is required. This multicenter study aimed to develop a decision tree (DT) model that can identify patients with heart rhythm disturbances at high MDEA concentrations. MATERIALS AND METHODS: A multicenter retrospective cohort study was conducted, including 157 adult patients with heart failure who received oral amiodarone treatment. A χ2 automatic interaction-detection algorithm was used to construct a DT model. In the DT analysis, the dependent variable was set as an MDEA trough plasma concentration of ≥ 0.6 µg/mL during the steady-state period. Explanatory variables were selected as factors with p < 0.05 in multivariate logistic regression analysis. RESULTS: The adjusted odds ratios for the daily dose of amiodarone and body mass index were 1.01 (95% coefficient interval: 1.008 - 1.021, p < 0.001) and 0.91 (95% confidence interval: 0.834 - 0.988, p = 0.025), respectively. For DT analysis, the risk of reaching plasma MDEA concentrations ≥ 0.6 µg/mL was relatively high, combined with a daily dose of amiodarone > 100 mg and body mass index ≤ 22.3 kg/m2 at 69.0% (20/29), and its trend was also detected in the sensitivity analysis. CONCLUSION: Patients taking a daily amiodarone dose > 100 mg and with a body mass index ≤ 22.3 kg/m2 warrant TDM implementation for MDEA to minimize the risk of MDEA-induced tissue toxicity.

Machine Learning-Based Prediction of Digoxin Toxicity in Heart Failure: A Multicenter Retrospective Study.

Digoxin toxicity (plasma digoxin concentration ≥0.9 ng/mL) is associated with worsening heart failure (HF). Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of adverse drug reactions. The present study aimed to construct a flowchart using DT analysis that can be used by medical staff to predict digoxin toxicity. We conducted a multicenter retrospective study involving 333 adult patients with HF who received oral digoxin treatment. In this study, we employed a chi-squared automatic interaction detection algorithm to construct DT models. The dependent variable was set as the plasma digoxin concentration (≥ 0.9 ng/mL) in the trough during the steady state, and factors with p < 0.2 in the univariate analysis were set as the explanatory variables. Multivariate logistic regression analysis was conducted to validate the DT model. The accuracy and misclassification rates of the model were evaluated. In the DT analysis, patients with creatinine clearance <32 mL/min, daily digoxin dose ≥1.6 µg/kg, and left ventricular ejection fraction ≥50% showed a high incidence of digoxin toxicity (91.8%; 45/49). Multivariate logistic regression analysis revealed that creatinine clearance <32 mL/min and daily digoxin dose ≥1.6 µg/kg were independent risk factors. The accuracy and misclassification rates of the DT model were 88.2 and 46.2 ± 2.7%, respectively. Although the flowchart created in this study needs further validation, it is straightforward and potentially useful for medical staff in determining the initial dose of digoxin in patients with HF.

Hyperthyroidism-induced Cerebral Venous Thrombosis Presenting as Chronic Isolated Intracranial Hypertension.

A 38-year-old woman with untreated Graves' disease was admitted to our hospital because of headache and diplopia for 3 months. A neuro-ophthalmic examination showed bilateral papilledema and abducens nerve paralysis. The cerebrospinal fluid pressure was extremely high. Brain magnetic resonance imaging showed cerebral venous thrombosis in the superior sagittal and right transverse and sigmoid sinuses. Laboratory investigations revealed elevated factor VIII and von Willebrand factor levels. The patient recovered after propylthiouracil and anticoagulation therapy. We herein report a rare case of cerebral venous thrombosis with hyperthyroidism presenting as chronic isolated intracranial hypertension. Hyperthyroidism can induce a hypercoagulable state and lead to venous thromboembolism.

Granulomatosis with Polyangiitis Presenting with Thrombovasculitic and Necrotizing Pachy- and Leptomeningitis Accompanied by a Brain Tumor-like Lesion.

We report a case of granulomatosis with polyangiitis (GPA) presenting with hypertrophic pachymeningitis with a huge brain tumor-like lesion. A 57-year-old man acutely developed consciousness disturbance. Magnetic resonance imaging revealed a right frontal lobe mass with thickened, contrast-enhanced dura. Computed tomography revealed sinusitis and multiple lung nodules. The presence of proteinase 3-anti-neutrophil cytoplasmic antibody indicated GPA. Histopathology of the excised brain tissues revealed thrombovasculitis with heavy neutrophilic infiltration in the pachy- and leptomeninges covering an ischemic cerebral cortex. The patient improved with corticosteroids and rituximab. Our case warrants considering GPA as a cause of hypertrophic pachymeningitis with brain-tumor like lesions.

Multiple brain infarctions and endomyocarditis in ANCA-negative eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a small vessel necrotizing vasculitis characterized by asthma and eosinophilia. Ischemic stroke is a rare complication of the disease. We herein report a case involving a 77-year-old woman with sinusitis who developed embolic stroke and splenic infarctions. Laboratory tests revealed hypereosinophilia and elevated troponin-T and N-terminal pro-brain natriuretic peptide. Antineutrophil cytoplasmic antibodies (ANCA) studies were negative. Skin biopsy showed infiltration of eosinophils into the arterial walls. These clinicopathological findings led to the diagnosis of EGPA. We also found the evidence of endomyocarditis as revealed by multimodality cardiac imaging. The patient underwent continuous immunosuppressive and anticoagulation therapy, and the infarctions did not recur. This report highlights the importance of histologically proven vasculitis with eosinophil infiltration and careful examination for cardiac involvement, especially in ANCA-negative patients.

[Ischemic optic neuropathy despite pulse methylprednisolone therapy in a giant cell arteritis patient with perineural optic nerve enhancement].

A 76-year-old woman with a 1-month history of headache, jaw claudication, scalp tenderness, and blurred vision was admitted to our hospital. Erythrocyte sedimentation rate was highly elevated. Brain MRI showed marked perineural optic nerve enhancement and superficial temporal artery enhancement bilaterally. Neuro-ophthalmic examination detected left dominant decline in critical fusion frequency whereas visual acuity, visual fields, and ophthalmoscopy were normal. Intravenous pulse methylprednisolone was administered for 3 days to treat suspected giant cell arteritis (GCA); however, visual acuity in the left eye declined and horizontal hemianopia developed. Ophthalmoscopy revealed pallid optic disc edema on the left. Histopathologic examination of a right temporal artery biopsy specimen showed intimal thickening, mild mural inflammation consisting predominantly of lymphocytes with occasional giant cells, and focal disruption of the internal elastic lamina, consistent with GCA. Perineural optic nerve enhancement on contrast-enhanced MRI may be a valuable clue for diagnosing ischemic optic neuropathy and may indicate the need for urgent treatment.

[A case of spontaneous middle cranial fossa cerebrospinal fluid leak presenting as recurrent bacterial meningitis].

A 19-year-old man with a history of Chiari type I malformation was admitted to our hospital two times within a 2-month period because of bacterial meningitis. Cerebrospinal fluid (CSF) analysis showed neutrophilic pleocytosis and hypoglycorrhachia. During the second admission, we became aware of hearing loss on the right since age 15 years. High-resolution temporal bone CT showed soft tissue opacification of the right epitympanum and external auditory canal. Tissue biopsy resulted in CSF otorrhea and pneumocephalus. CT cisternography revealed a temporal bone CSF leak. Brain MRI showed a dural defect localized to the anterior petrous apex. Using a combined middle cranial fossa-transmastoid approach, the dural defect and associated arachnoid granulations were located along the superior side of the greater petrosal nerve and repaired. A CSF leak without underlying pathology, such as trauma, surgery, or congenital abnormality, is defined as spontaneous. Spontaneous CSF leak should be considered as a cause of recurrent bacterial meningitis even when CSF otorrhea and fluid behind the tympanic membrane are clinically absent.

Therapeutic Experience of Progressive Multifocal Leukoencephalopathy Development during Ofatumumab Therapy for Chronic Lymphocytic Leukemia.

A 79-year-old man experienced cognitive impairment and visual field defects during ofatumumab therapy for chronic lymphocytic leukemia refractory to combination chemotherapy. Magnetic resonance imaging revealed T1-weighted low-intensity and T2-weighted high-intensity lesions with patchy gadolinium enhancement in the subcortical white matter. A diagnosis of progressive multifocal leukoencephalopathy was made after the detection of John Cunningham virus (JCV) DNA in his cerebrospinal fluid (CSF). Following plasma exchange and the administration of mirtazapine and mefloquine, the JCV DNA levels in the CSF decreased. However, the patient died 55 days after treatment was initiated. Ofatumumab treatment appears to be associated with the development of progressive multifocal leukoencephalopathy.

Licochalcones extracted from Glycyrrhiza inflata inhibit platelet aggregation accompanied by inhibition of COX-1 activity.

Licochalcones extracted from Glycyrrhiza inflata are known to have a variety of biological properties such as anti-inflammatory, anti-bacterial, and anti-tumor activities, but their action on platelet aggregation has not yet been reported. Therefore, in this study we investigated the effects of licochalcones on platelet aggregation. Collagen and U46619, a thromboxane A2 receptor agonist, caused rabbit platelet aggregation, which was reversed by pretreatment with licochalcones A, C and D in concentration-dependent manners. Among these compounds, licochalcone A caused the most potent inhibitory effect on collagen-induced platelet aggregation. However, the licochalcones showed marginal inhibitory effects on thrombin or ADP-induced platelet aggregation. In addition to rabbit platelets, licochalcone A attenuated collagen-induced aggregation in human platelets. Because licochalcone A also inhibited arachidonic acid-induced platelet aggregation and production of thromboxane A2 induced by collagen in intact platelets, we further examined the direct interaction of licochalcone A with cyclooxygenase (COX)-1. As expected, licochalcone A caused an inhibitory effect on both COX-1 and COX-2 in vitro. Regarding the effect of licochalcone A on COX-1 enzyme reaction kinetics, although licochalcone A showed a stronger inhibition of prostaglandin E2 synthesis induced by lower concentrations of arachidonic acid, Vmax values in the presence or absence of licochalcone A were comparable, suggesting that it competes with arachidonic acid at the same binding site on COX-1. These results suggest that licochalcones inhibit collagen-induced platelet aggregation accompanied by inhibition of COX-1 activity.