Identifying causative medications for agranulocytosis: A case report of an older adult with cerebral infarction.

Key Clinical Message: Most drugs that cause adverse events are difficult to identify in critically ill patients undergoing polypharmacy. We share our experience in identifying the causative drug among four suspect drugs administered during emergency treatment. Abstract: We present the case of a 93-year-old man who was admitted for the treatment of cerebrovascular events. The patient was initially prescribed dual antiplatelet therapy with aspirin and clopidogrel along with lansoprazole, Hange-koboku-toh, and elobixibat. On day 36 after admission, the patient was found to have developed agranulocytosis. To improve his cerebrovascular prognosis, we first discontinued medications other than the anticoagulant medicines and initiated filgrastim. We discontinued clopidogrel 9 days after the discontinuation of the other medicines considering his low white blood cell count. One day after the discontinuation of clopidogrel, the agranulocytosis was alleviated. Considering the time course, clopidogrel, lansoprazole, Hange-koboku-toh, and elobixibat were suspected as the culprit medicines. This case highlights the considerable challenges encountered in clinical practice when attempting to identify the drugs responsible for agranulocytosis, particularly in patients on intensive medication therapy.

Distinction in Prevalence of Atherosclerotic Embolic Sources in Cryptogenic Stroke With Cancer Status.

Background Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39-5.40) and CRP (C-reactive protein) (OR, 1.10; 95% CI, 1.01-1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01-1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60-10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09-4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11-4.10) were significantly associated with inactive cancer. Conclusions Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000032957.

[Ischemic Stroke].

CASE: A patient with a history of chronic atrial fibrillation was diagnosed with sudden onset of right hemiparalysis in the hospital. The patient had been normal two hours prior and was referred to the cerebral vascular center. Images: Head CT images showed early ischemic changes in the left frontal lobe, insula, and temporal lobe(Alberta Stroke Program Early CT Score[ASPECTS]: 6 points). A hyperdense internal carotid artery(ICA)sign was found at the top of the left internal carotid artery. MRI DWI-ASPECTS was performed at 6 points. The MRA showed loss of the left internal carotid, anterior cerebral, and middle cerebral arteries. T2*WIs showed a susceptibility vessel sign(SVS)at the top of the left ICA and FLAIR vessel hyperintensity(FVH)in the left ICA to the middle cerebral artery. DIAGNOSIS: The patient was diagnosed with acute cerebral embolism with clinical-DWI mismatch and treated with endovascular therapy. COMMENTARY: Early CT signs are important in determining cerebral ischemic lesions, and hyperdense ICA/MCA signs are useful in identifying occluded vessels. Early ischemic changes can be seen more easily on MRI-DWI, and the location of the occluded vessel can be estimated by evaluating MRA, SVS, and FVH together.

Occurrence and clinicotopographical correlates of brainstem infarction in patients with diabetes mellitus.

BACKGROUND: The goal of the study was to clarify the association between diabetes mellitus (DM) and brainstem infarctions (BSIs) and to investigate the clinicotopographic characteristics of BSIs in patients with diabetes. METHODS: Data were retrospectively reviewed for 1026 consecutive patients admitted to our hospital because of acute cerebral infarctions from January 2004 to August 2010. Acute symptomatic BSIs were explored on radiologic images and classified into multiple infarctions with BSIs, multifocal BSIs, and monofocal BSIs. Isolated BSIs were further classified based on the vertical distribution into midbrain, pontine, and medullary infarctions, and on the horizontal distribution into anterior-dominant, posterior-dominant, and anterior/posterior BSIs. Neurologic symptoms of BSIs and clinical background were compared between DM and non-DM patients. RESULTS: The prevalence of BSIs was 2.6-fold higher (P < .0001) in DM patients. Logistic regression analysis including age, sex, smoking, previous stroke, atrial fibrillation, other cardiac diseases, hypertension, hyperlipidemia, and DM showed that DM was independently associated with BSIs (odds ratio [OR] 2.814; 95% confidence interval [CI] 1.936-4.090; P < .0001). Compared with non-DM patients, DM patients showed more frequent monofocal BSIs (P < .0001) and multifocal BSIs (P = .0296). Monofocal BSIs (n = 114) more frequently involved the pons (P < .0001) and medulla (P = .0212). Anterior-dominant BSIs (P < .0001) were more common in DM patients than in non-DM patients. Symptoms of BSIs included more frequent motor paresis (P = .0180) and less frequent diplopia (P = .0298) in DM patients than in non-DM patients. CONCLUSIONS: DM is important in the development of BSIs, and the associated clinical characteristics include more frequent motor paresis and less frequent diplopia.

The brainstem is at high risk for recurrent noncardioembolic cerebral infarction in association with diabetes mellitus: a hospital-based study.

The goals of the study were to investigate the importance of brainstem infarction (BSI) in recurrent noncardioembolic ischemic stroke and to examine the relevant clinical background. Data were retrospectively reviewed for 655 consecutive patients with acute noncardioembolic infarction who were admitted to our hospital from January 2004 to August 2010. The patients were divided into first-stroke (n = 592) and recurrent-stroke (n = 63) groups. Acute infarcted lesions were explored on MRI, and clinical background factors including age, sex, smoking, atrial fibrillation, coronary heart disease, hypertension, hyperlipidemia and diabetes mellitus (DM) were assessed. The frequency of BSI in the recurrent-stroke group was significantly higher than that in first-stroke patients (30.2 vs. 14.9%, p = 0.0033). No other clinical background factors differed between the two groups. Only the frequency of DM differed significantly among four subgroups formed based on stroke recurrence and BSI (p < 0.0001): DM was present in 63.2% of recurrent-stroke patients with BSI, 54.5% of first-stroke patients with BSI, 27.4% of first-stroke patients without BSI, and 20.5% of recurrent-stroke patients without BSI. We conclude that the brainstem is at high risk for recurrent cerebral infarction in patients with DM.

[Syndrome of inappropriate secretion of anti-diuretic hormone associated with limbic encephalitis due to herpes simplex virus infection--a case report].

We report a case of syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) associated with limbic encephalitis. A 79-year-old woman was admitted with a complaint of fever, disturbance of consciousness and generalized seizure. Her conscious level was E1V2M4 by Glasgow coma scale. Physical examination showed generalized seizure, neck stiffness, hyperreflexia and flaccid paralysis in her all extremities, and pathological reflexes. Blood analysis revealed hyponatremia, decrease of plasma osmolarity, spared secretion of urine sodium and increase of ADH, leading to the diagnosis of SIADH. Cerebrosponal fluid examination showed mild pleocytosis, elevated protein, and normal glucose level. Although herpes simplex virus (HSV) DNA was not detected by the polymerase chain reaction method, titers of anti-HSV IgG antibody elevated chronologically. Brain MRI revealed abnormal T2 and FLAIR high intensities in the cingulate gyrus and hippocampus bilaterally. An EEG revealed periodic synchronous discharges predominantly in the frontal areas. Based on the clinical course, laboratory data, MRI and EEG findings, we diagnosed as SIADH associated with acute limbic encephalitis caused by HSV infection. After the fluid restriction and sodium supply, plasma sodium was normalized. Administration of acyclovir and steroid was not so effective, however her condition improved gradually. Several cases of SIADH associated with limbic encephalitis have been reported; however, the pathophysiology is to be clarified. We thought that in the presented case, SIADH was caused by disturbance of the hormonal control at the hypothalamus on the pituitary gland due to the spreading of inflammation from limbic system to these areas.

Simultaneous determination of selegiline and desmethylselegiline in human body fluids by headspace solid-phase microextraction and gas chromatography-mass spectrometry.

A method for the simultaneous determination of selegiline and its metabolite, desmethylselegiline, in human whole blood and urine is presented. The method, which combines a fiber-based headspace solid-phase microextraction (SPME) technique with gas chromatography-mass spectrometry (GC-MS), required optimization of various parameters (e.g., salt additives, extraction temperatures, extraction times and the extraction properties of the SPME fiber coatings). Pargyline was used as the internal standard. Extraction efficiencies for both selegiline and desmethylselegiline were 2.0-3.4% for whole blood, and 8.0-13.2% for urine. The regression equations for selegiline and desmethylselegiline extracted from whole blood were linear (r(2)=0.996 and 0.995) within the concentration ranges 0.1-10 and 0.2-20 ng/ml, respectively. For urine, the regression equations for selegiline and desmethylselegiline were linear (r(2)=0.999 and 0.998) within the concentration ranges 0.05-5.0 and 0.1-10 ng/ml, respectively. The limit of detection for selegiline and desmethylselegiline was 0.01-0.05 ng/ml for both samples. The lower and upper limits of quantification for each compound were 0.05-0.2 and 5-20 ng/ml, respectively. Intra- and inter-day coefficients of variation for selegiline and desmethylselegiline in both samples were not greater than 8.7 and 11.7%, respectively. The determination of selegiline and desmethylselegiline concentrations in Parkinson's disease patients undergoing continuous selegiline treatment is presented and is shown to validate the present methodology.

Simultaneous determination of ten antihistamine drugs in human plasma using pipette tip solid-phase extraction and gas chromatography/mass spectrometry.

Ten antihistamine drugs, diphenhydramine, orphenadrine, chlorpheniramine, diphenylpyraline, triprolidine, promethazine, homochlorcyclizine, cyproheptadine, cloperastine and clemastine, have been found to be extractable from human plasma samples using MonoTip C18 tips, inside which C18- bonded monolithic silica gel was fixed. Human plasma (0.1 mL) containing the ten antihistamines was mixed with 0.4 mL of distilled water and 25 microL of a 1 M potassium phosphate buffer (pH 8.0). After centrifugation of the mixture, the supernatant fraction was extracted to the C18 phase of the tip by 25 repeated aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C18 phase were then eluted with methanol by five repeated aspirating/dispensing cycles. The eluate was injected into a gas chromatography (GC) injector without evaporation and reconstitution steps, and was detected by a mass spectrometer with selected ion monitoring in the positive-ion electron impact mode. The separation of the ten drugs from each other and from impurities was generally satisfactory using a DB-1MS column (30 m x 0.32 mm i.d., film thickness 0.25 microm). The recoveries of the ten antihistamines spiked into plasma were 73.8-105%. The regression equations for the ten antihistamines showed excellent linearity with detection limits of 0.02-5.0 ng/0.1 mL. The within-day and day-to-day coefficients of variation for plasma were not greater than 9.9%. The data obtained from determination of diphenhydramine and chlorpheniramine in human plasma after oral administration of the drugs are also presented.