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POEMS Syndrome Associated With Ischemic Stroke
Kyusik Kang, MD;
Kon Chu, MD;
Dong-Eog Kim, MD;
Sang-Wuk Jeong, MD;
Jun-Won Lee, MD;
Jae-Kyu Roh, MD, PhD
Arch Neurol. 2003;60:745-749.
ABSTRACT
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Background A syndrome variously combining peripheral neuropathy, visceromegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS syndrome) is a rare variant of plasma cell dyscrasia with multisystemic manifestations. Acute ischemic strokes in patients with POEMS syndrome have rarely been reported, and the pathophysiologic mechanism of this disease is unknown. Fibrinogen is reported to be an independent risk factor for cerebrovascular disease and is correlated with the interleukin 6 level in the plasma. The serum level of interleukin 6 is high in the active stage of POEMS syndrome.
Objective To describe the neuroimaging findings and fibrinogen levels in patients with POEMS syndrome.
Design Case series.
Setting The neurology department of a tertiary referral center.
Methods Three patients with an acute cerebral infarction associated with POEMS syndrome underwent magnetic resonance imaging, diffusion-weighted imaging, magnetic resonance angiography, transcranial Doppler ultrasonography, and serum fibrinogen level and serum C-reactive protein level analysis. The serum fibrinogen level before the stroke was collected retrospectively from the hospital medical records.
Results There was an elevated fibrinogen level in all of the patients. In 2 patients, unilateral or bilateral end artery border-zone infarcts were observed on the brain magnetic resonance imaging scan. The serum fibrinogen level was high before the stroke in 2 patients.
Conclusions The POEMS syndrome can be associated with stroke, particularly end artery border-zone infarctions. We suggest that an elevated fibrinogen level might play a role in the pathogenesis of stroke.
INTRODUCTION
THE ACRONYM POEMS was first suggested by Bardwick and colleagues1 to describe a syndrome variously combining peripheral neuropathy, visceromegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Ischemic diseases of the coronary and lower limb arteries have often been reported in patients with POEMS syndrome.2-3 However, acute ischemic strokes in patients with POEMS syndrome have rarely been reported, and the pathophysiologic mechanism of this disease is unknown. We report 3 cases of acute cerebral ischemic stroke associated with POEMS syndrome, and suggest a possible pathologic mechanism.
METHODS
From June 1, 2000, to May 31, 2001, 3 consecutive patients with POEMS syndrome who experienced an acute ischemic stroke underwent brain magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) using previously described methods.4 Magnetic resonance angiography of the intracranial and extracranial vessels and/or transcranial Doppler ultrasonography was used to document the presence of large-artery disease. All subjects underwent a structured clinical interview, physical and neurologic examinations, electrocardiography, echocardiography, and laboratory testing, including serum fibrinogen level and C-reactive protein (CRP) level analysis. The serum fibrinogen level from before the onset of the stroke, if available, was collected retrospectively from the hospital medical records. The epidemiologic and clinical characteristics of the patients are summarized in Table 1.
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Summary of Patient Characteristics*
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RESULTS
PATIENT 1
This patient was a 42-year-old man with a history of sensorimotor polyneuropathy, splenomegaly, lymphadenopathy, hypothyroidism, hyperpigmentation, and myocardial infarction. He was admitted to the hospital with weakness of the right arm. A neurologic examination revealed right-sided central type facial palsy, dysarthria, and monoparesis of the right arm. Deep tendon reflexes were diminished in all limbs, and sensation was impaired in both legs. The serum fibrinogen and CRP levels were 0.603 g/dL (17.7 µmol/L) and 1.1 mg/dL, respectively, on day 3. Four months before onset, the serum fibrinogen level had been 0.557 g/dL (16.4 µmol/L). This patient did not have polycythemia. Lupus anticoagulant, anti–phospholipid antibody, and activated protein C resistance were not detected. This patient had mild thrombocythemia. Echocardiography showed akinesia of the anterior, anterolateral, and inferolateral wall. On the MRI and DWI scans, there were left anterior cerebral artery–middle cerebral artery (MCA) border-zone infarctions (BZIs) and MCA–posterior cerebral artery BZIs (Figure 1). Magnetic resonance angiography showed a hypoplastic right precommunicating anterior cerebral artery segment and fetal type circulation in the right posterior cerebral artery. Transcranial Doppler ultrasonography revealed increased mean flow velocities of the left anterior cerebral artery, the left MCA, and the right internal carotid artery siphon.
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Figure 1. Brain magnetic resonance imaging scan of patient 1. Fluid-attenuated inversion recovery images show high signal intensity in the left frontoparietal lobe (A) and the left anterior and posterior border-zone areas (B).
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PATIENT 2
This patient was a 48-year-old woman with a history of polyneuropathy, hepatomegaly, hypothyroidism, M protein, hyperpigmentation, gangrene of the left foot, and human herpesvirus 8–associated Castleman disease. She had a 5 pack-year history of smoking. She was admitted to the hospital because of acute weakness in all limbs. The findings on physical examination included quadriplegia, hypoesthesia involving the distal parts of both legs, and areflexia in all extremities. Her fibrinogen level was 0.594 g/dL (17.5 µmol/L) on day 3. It had been 0.706 g/dL (20.8 µmol/L) 1 month before admission. Her CRP level was 0.9 mg/dL on day 10. Polycythemia, thrombocythemia, lupus anticoagulant, anti–phospholipid antibody, and activated protein C resistance were not observed. Echocardiography showed a mildly decreased systolic function of the left ventricle and a small amount of pericardial effusion. An MRI scan revealed bilateral posterior cerebral artery infarcts and bilateral end artery BZIs (Figure 2). On magnetic resonance angiography, there was stenosis of the left proximal MCA.
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Figure 2. Brain magnetic resonance imaging scan of patient 2. Fluid-attenuated inversion recovery images show high signal intensity in the bilateral end artery border zones (A) and the bilateral occipital lobes (B).
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PATIENT 3
This patient was a 52-year-old woman with a 2-year history of uncontrolled hypertension. Six months before hospital admission, she insidiously developed numbness and weakness in 4 limbs. Two weeks before admission, she experienced abdominal distention and edema of both legs. She was admitted to the hospital because of sudden slurred speech. Physical examination findings revealed hyperpigmentation, hepatomegaly, lymphadenopathy, ascites, dysarthria, tetraparesis, and areflexia of both legs. The fibrinogen level was 0.361 g/dL (10.6 µmol/L) on day 12, and the CRP level was 1.6 mg/dL on day 16. Neither polycythemia nor thrombocythemia was detected. Echocardiography showed pulmonary hypertension and a small amount of pericardial effusion. The MRI and DWI scans showed a left end artery BZI, a left MCA–posterior cerebral artery BZI, and narrowing of the left intracranial internal carotid artery (Figure 3). A transcranial Doppler ultrasonographic examination revealed an increased mean flow velocity in the left internal carotid artery siphon, the right MCA, both vertebral arteries, and the basilar artery.
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Figure 3. Brain magnetic resonance imaging scan of patient 3. A, A T2-weighted axial image shows narrowing of the left intracranial internal carotid artery. B, A fluid-attenuated inversion recovery image shows left end artery and left posterior border-zone infarctions.
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COMMENT
All 3 patients had BZIs on the MRI scan, and patients 2 and 3 had evidence of end artery BZIs on the MRI scan. In the first 2 patients, the lesions on magnetic resonance angiography did not explain the infarcts on the MRI scan. Patient 1 had a history of coronary heart disease. Theoretically, it is possible that POEMS syndrome causes heart disease,2 and that the ensuing cardioembolism gives rise to ischemic stroke. However, it is also possible that POEMS syndrome contributes to ischemic disease involving the coronary and cerebral arteries. Patient 2 had no definite risk factors for stroke except for a negligible 5 pack-year history of smoking. Thrombophilic test results revealed no abnormalities, except hyperfibrinogenemia. A hematologic problem, such as an elevated hematocrit, was reported to be associated with the occurrence of BZIs.5 These findings suggest that fibrinogen may play a role as a procoagulant or a rheostatic agent in the pathogenesis of stroke associated with POEMS syndrome.
Fibrinogen is an independent risk factor for cerebrovascular disease. Fibrinogen is involved in cell proliferation and in mechanisms (platelet aggregation, endothelial cell injury, and plasma viscosity) that play a central role in the formation of thrombi.6 A previous DWI study,7 involving 329 consecutive patients who experienced an ischemic stroke, showed that an elevated fibrinogen level was significantly associated with bilateral multiple cerebral infarcts. All 3 patients in the present study had multiple infarcts on DWI. This may support the hypothesis that a high fibrinogen level is related to the pathogenesis of cerebrovascular disease in patients with POEMS syndrome.
Fibrinogen is an acute-phase reactant, and its level increases in cases of tissue damage, such as ischemic injury to the brain.8 This raises the question as to whether the high plasma fibrinogen levels in our patients might be the epiphenomenon of the acute vascular events and the associated inflammatory processes. Our patients' levels of CRP, another acute-phase protein, were lower than the median CRP level (13 mg/dL) of patients with first-ever ischemic stroke, as determined in a previous study.9 In contrast, the fibrinogen levels of 2 patients (patients 1 and 2) were higher than the mean fibrinogen level (0.476 g/dL [14.0 µmol/L]) of a previous study.9 Patient 3 had a slightly lower level of fibrinogen than the mean fibrinogen level of the previous report, but it was higher than the upper normal limit of the reference value used at Seoul National University Hospital (0.17-0.35 g/dL [5.0-10.3 µmol/L]). Hyperfibrinogenemia was present before the stroke in 2 patients, whose serum fibrinogen levels had been measured before the current episode. Thus, we assume that the observed hyperfibrinogenemia was not just a marker of the inflammatory process, but should in fact be regarded as an actual participant in the development of the stroke.
It was reported that aberrant interleukin 6 activity might play an important role in the various manifestations of POEMS syndrome. The serum level of interleukin 6 is abnormally high in the active stage of POEMS syndrome, and is typically normalized with corticosteroids and plasmapheresis.10 Interleukin 6 is also known to stimulate the synthesis of fibrinogen in the liver.11 Although speculative, our hypothesis is that interleukin 6 might contribute to the development of stroke in patients with POEMS syndrome by inducing hyperfibrinogenemia.
In summary, we studied 3 patients with POEMS syndrome who experienced an acute cerebral ischemic stroke. We suggest that an elevated fibrinogen level may play a role in the pathogenesis of ischemic stroke associated with POEMS syndrome. However, because we studied only 3 patients, there may be a possibility of coincidence. Further studies, including a large population of patients with POEMS syndrome, are required.
AUTHOR INFORMATION
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Corresponding author and reprints: Jae-Kyu Roh, MD, PhD, Department of Neurology, Seoul National University Hospital, 28 Yongon-Dong, Chongro-Gu, Seoul 110-744, South Korea (e-mail: rohjk{at}snu.ac.kr).
Accepted for publication December 9, 2002.
Author contributions: Study concept and design (Drs Kang and Roh); acquisition of data (Drs Chu and Lee); analysis and interpretation of data (Drs Kim and Jeong); drafting of the manuscript (Drs Kang, Chu, Kim, and Jeong); critical revision of the manuscript for important intellectual content (Drs Lee and Roh); statistical expertise (Drs Kang and Kim); administrative, technical, and material support (Drs Jeong and Lee); study supervision (Drs Chu and Roh).
From the Department of Neurology and the Clinical Research Institute, Seoul National University Hospital, Neuroscience Research Institute of Seoul National University Medical Research Center, Seoul (Drs Kang, Chu, Jeong, and Roh), and the Department of Neurology, College of Medicine, Kwandong University, Kangwon-do (Dr Lee), South Korea; and the Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Kim).
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