A 35-year-old Japanese male presented to the Emergency Department of Okinawa Chubu Hospital with right hemiparesis. He had awakened from sleep with severe, sharp chest pain that was not accompanied by dyspnea. The chest pain subsided within 1 min without treatment, but medical evaluation was sought due to obvious dysarthria and weakness of the right upper and lower limbs. The patient was previously healthy, with no prior hospital admissions, surgeries, medications, or allergies, but bilateral pedal edema had developed 3 months prior to presentation. He had no dyspnea or ambulatory dysfunction and did not seek medical intervention. He worked as a house painter and lived with his wife and children. He had 15 pack-years of exposure to tobacco, and consumed 400 ml of Okinawan spirits nightly. There was no family history of cardiovascular disease, thromboembolism, or chronic kidney disease.
Physical examination revealed that the patient was alert with no distress. He was not obese (BMI 21.4 on admission, when he was edematous), and he was afebrile with a blood pressure of 140/90 mm Hg, a regular pulse of 85 beats/min, and a respiration rate of 25 breaths/min. Oxygen saturation in the room air was 100%. An examination of the head revealed a marked, right-sided facial droop, but was otherwise normal. Carotid upstrokes were symmetric without bruits. The heartbeat was regular without gallops or murmurs, and the lungs were clear; the abdominal examination was also normal. Bilateral pitting edema was present to the knees. There were no rashes or petechiae. Neurological examination revealed intense dysarthria, which made it difficult for him to communicate with others, and right-sided central facial nerve palsy. Both the right arm and leg were at Brunnstrom stage 1, with complete flaccidity and no voluntary movement. Pain and light touch sensation were absent on the right side of his body.
Table 1 contains initial laboratory data. Blood counts revealed leukocytosis and hemoconcentration. Serum albumin was markedly low at 1.8 g/dl. Serum cholesterol, triglyceride, and low-density lipoprotein cholesterol were elevated. The urine protein to creatinine ratio was 7.5 g/g Cr, indicative of high-grade proteinuria. The examination of the urine sediment revealed oval fat bodies, and testing for anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, and anti-phospholipid antibodies were all negative. Hepatitis B and C serologies were negative.
Diffusion-weighted magnetic resonance imaging showed high-intensity areas consistent with acute infarction in the left basal ganglia, left corona radiata, and left cerebral cortex (fig. 1). Contrast-enhanced computed tomography of the neck revealed collateral blood flow around a large embolus in the left carotid artery (fig. 2). Ultrasound of the left carotid revealed the embolus without any plaques or ulcers at the vessel wall (fig. 3). There were no aortic dissections, pulmonary emboli, renal vein thromboses, or deep vein thromboses on the computed tomography. A transthoracic echocardiogram showed normal contractility without dilated chambers, valvular disease, vegetations, intraluminal thrombi, or any findings suggesting pulmonary embolism, such as pulmonary hypertension or right ventricular stress.
A presumptive diagnosis of ischemic cerebrovascular accident caused by a left carotid thromboembolism was attributed to a hypercoagulable state due to NS. Because of the lack of any findings of atherosclerosis or plaques at the left carotid, we believed that embolism was more likely than thrombosis. The origin of the embolus was not detected despite a thorough cardiovascular evaluation. Immediate anticoagulation with unfractionated heparin was employed, and the renal biopsy was deferred. Intravenous methylprednisolone was administered empirically at 1,000 mg/day for 3 days, followed by oral prednisone at 60 mg/day. Cyclosporine was added 30 days later in response to persistent nephrotic-range proteinuria (5.5 g/day on the 28th day). The patient was transferred to a rehabilitation hospital 47 days after first admission.
However, the blood examination performed after transfer revealed abnormal liver function on the 74th day from the first admission, the results of which are detailed in table 1. Serological studies and abdominal ultrasound excluded viral hepatitis or biliary obstruction. He was immediately readmitted under suspicion of drug-induced hepatotoxicity. Medications on admission included prednisolone (50 mg/day), warfarin (2.75 mg/day), cyclosporine (70 mg b.i.d.), sulfamethoxazole/trimethoprim (400/80 mg daily), eicosapentaenoic acid (900 mg b.i.d.), atorvastatin (10 mg/day), lansoprazole (30 mg/day), alfacalcidol (0.25 mug/day), andronate (35 mg/week), and calcium lactate (1 g b.i.d.). All medications except for prednisone were subsequently withheld, and warfarin was replaced by intravenous heparin. The liver test results normalized, but they deteriorated upon rechallenge with warfarin.
At this time, heparin therapy was briefly interrupted to permit a renal biopsy to evaluate refractory NS, with hypoalbuminemia (2.1 g/dl) and proteinuria (5.7 g/day). The biopsy showed MN at stage III of the Ehrenreich and Churg classification. Continued anticoagulation was deemed necessary due to severe persistent hypoalbuminemia and the severe cerebrovascular accident. Warfarin appeared to be clinically intolerable due to idiopathic hepatotoxicity despite a negative lymphocyte stimulation test. Intravenous heparin therapy was incompatible with outpatient rehabilitation.
We discussed the indication of dabigatran, the only available novel oral anticoagulant in Japan at that time, with the patient and also with cardiologists, a neurologist, and the vice-principal of our hospital, all of whom were responsible for the prescription of dabigatran, and we decided to initiate treatment. We also explained and discussed the risks and benefits of dabigatran with the patient and obtained his written and informed consent in advance. Oral dabigatran was administered at a dose of 110 mg b.i.d., and MN was treated with oral prednisone and cyclophosphamide according to Jindal's regimen. Proteinuria decreased from a ratio of 5.1 to 1.6 g/g Cr, and serum albumin rose from 2.3 to 3.7 g/dl over 7 months. He was transferred to the rehabilitation hospital 137 days after stroke onset. At the outpatient clinic, his renal function remained stable, and he did not experience any episodes of edema, bleeding, or thromboembolism. We monitored the activated partial thromboplastin time (aPTT) to predict the risk of bleeding due to excessive anticoagulation. The aPTT values taken 4 h following administration of dabigatran in the morning were stable at around 40 s (standard aPTT was 30 s). A carotid echogram performed 2 years after the initiation of dabigatran revealed a reduced embolus, although it did still occlude the internal carotid.