POEMS Syndrome Associated with Ischemic Stroke

ORIGINAL CONTRIBUTION 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

Background: A syndrome variously combining periph- Methods: Three patients with an acute cerebral infarc- eral neuropathy, visceromegaly, endocrinopathy, mono- tion associated with POEMS syndrome underwent mag- clonal gammopathy, and skin changes (POEMS syn- netic resonance imaging, diffusion-weighted imaging, drome) is a rare variant of plasma cell dyscrasia with magnetic resonance angiography, transcranial Doppler multisystemic manifestations. Acute ischemic strokes in ultrasonography, and serum fibrinogen level and serum patients with POEMS syndrome have rarely been re- C-reactive protein level analysis. The serum fibrinogen ported, and the pathophysiologic mechanism of this dis- level before the stroke was collected retrospectively from ease is unknown. Fibrinogen is reported to be an inde- the hospital medical records. pendent risk factor for cerebrovascular disease and is correlated with the interleukin 6 level in the plasma. The Results: There was an elevated fibrinogen level in all of serum level of interleukin 6 is high in the active stage of the patients. In 2 patients, unilateral or bilateral end ar- POEMS syndrome. tery border-zone infarcts were observed on the brain magnetic resonance imaging scan. The serum fibrinogen level Objective: To describe the neuroimaging findings was high before the stroke in 2 patients. and fibrinogen levels in patients with POEMS syndrome. Conclusions: The POEMS syndrome can be associated with stroke, particularly end artery border-zone infarc- Design: Case series. tions. We suggest that an elevated fibrinogen level might play a role in the pathogenesis of stroke. Setting: The neurology department of a tertiary refer- ral center. Arch Neurol. 2003;60:745-749

HE ACRONYM POEMS was rienced an acute ischemic stroke underwent brain first suggested by Bard- magnetic resonance imaging (MRI) and diffu- wick and colleagues1 to de- sion-weighted imaging (DWI) using previ- 4 scribe a syndrome variously described methods. Magnetic resonance ously combining peripheral angiography of the intracranial and extracra- nial vessels and/or transcranial Doppler ultra- neuropathy,T visceromegaly, endocrinopa- sonography was used to document the pres- thy, monoclonal gammopathy, and skin ence of large-artery disease. All subjects changes. Ischemic diseases of the coro- underwent a structured clinical interview, physi- From the Department of nary and lower limb arteries have often cal and neurologic examinations, electrocardio- Neurology and the Clinical been reported in patients with POEMS syn- graphy, echocardiography, and laboratory test- Research Institute, Seoul 2,3 ing, including serum fibrinogen level and National University Hospital, drome. However, acute ischemic strokes C-reactive protein (CRP) level analysis. The se- Neuroscience Research Institute in patients with POEMS syndrome have rum fibrinogen level from before the onset of the of Seoul National University rarely been reported, and the pathophysi- stroke, if available, was collected retrospec- Medical Research Center, Seoul ologic mechanism of this disease is un- tively from the hospital medical records. The epi- (Drs Kang, Chu, Jeong, and known. We report 3 cases of acute cere- demiologic and clinical characteristics of the pa- Roh), and the Department of bral ischemic stroke associated with tients are summarized in the Table. Neurology, College of Medicine, POEMS syndrome, and suggest a pos- Kwandong University, sible pathologic mechanism. Kangwon-do (Dr Lee), South RESULTS Korea; and the Center for Molecular Imaging Research, METHODS PATIENT 1 Massachusetts General Hospital, Harvard Medical From June 1, 2000, to May 31, 2001, 3 consecu- This patient was a 42-year-old man with School, Boston (Dr Kim). tive patients with POEMS syndrome who expe- a history of sensorimotor polyneuropa-

(REPRINTED) ARCH NEUROL / VOL 60, MAY 2003 WWW.ARCHNEUROL.COM 745

Patient

Characteristic 123 Clinical symptoms Slurred speech, right-sided facial palsy, Tetraparesis Slurred speech and monoparesis of the right arm Visceromegaly Hepatosplenomegaly and Castleman Hepatosplenomegaly and Hepatomegaly and lymphadenopathy disease Castleman disease Monoclonal gammopathy Absent Present Present Risk factors for stroke Old myocardial infarction History of smoking Hypertension Brain MRI and DWI findings BZI in the left ACA-MCA and MCA-PCA Bilateral end artery BZIs and BZI in the left MCA-PCA territory, left territories and a left MCA infarction bilateral PCA infarctions end artery BZI, and stenosis of the left intracranial ICA MRA findings Hypoplastic right precommunicating Stenosis of the left MCA Not performed ACA segment and fetal type circulation in the right PCA TCD findings Increased MFV of the left ACA, the Not performed Increased MFV in the left ICA siphon, MCA, and the right ICA siphon the right MCA, both VAs, and the basilar artery Serum fibrinogen level, before/after 0.557/0.603 0.706/0.594 Not obtained/0.361 the stroke, g/dL† CRP level, mg/dL‡ 1.1 0.9 1.6 Hemoglobin, g/dL 12.2 12.8 11.7 Platelet count, ϫ103/µL§ 695 232 280 LA Absent Absent Not performed APL Absent Absent Not performed APC Absent Absent Not performed Echocardiographic findings Akinesia of the anterior, anterolateral, Mildly decreased systolic function Pulmonary hypertension and and inferolateral wall of the left ventricle and pericardial effusion pericardial effusion

Abbreviations: ACA, anterior cerebral artery; APC, activated protein C resistance; APL, anti−phospholipid antibody; BZI, border-zone infarction; CRP, C-reactive protein; DWI, diffusion-weighted imaging; ICA, internal carotid artery; LA, lupus anticoagulant; MCA, middle cerebral artery; MFV, mean flow velocity; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; PCA, posterior cerebral artery; TCD, transcranial Doppler ultrasonography; VA, vertebral artery. SI units: To convert fibrinogen level to micromoles per liter, multiply by 29.41. *All patients had a peripheral neuropathy, endocrinopathy (hypothyroidism), and skin changes (hyperpigmentation). †The reference range for serum fibrinogen level in our laboratory is 0.17 to 0.35 g/dL. ‡The reference range for CRP level in our laboratory is 0 to 0.5 mg/dL. §The reference range for platelet count in our laboratory is 130 ϫ 103/µL to 400 ϫ 103/µL.

thy, splenomegaly, lymphadenopathy, hypothyroid- anterior cerebral artery, the left MCA, and the right ism, hyperpigmentation, and myocardial infarction. internal carotid artery siphon. He was admitted to the hospital with weakness of the right arm. A neurologic examination revealed right- PATIENT 2 sided central type facial palsy, dysarthria, and monoparesis of the right arm. Deep tendon reflexes were This patient was a 48-year-old woman with a history of diminished in all limbs, and sensation was impaired in polyneuropathy, hepatomegaly, hypothyroidism, M pro- both legs. The serum fibrinogen and CRP levels were tein, hyperpigmentation, gangrene of the left foot, and 0.603 g/dL (17.7 µmol/L) and 1.1 mg/dL, respectively, human herpesvirus 8–associated Castleman disease. She on day 3. Four months before onset, the serum had a 5 pack-year history of smoking. She was admitted fibrinogen level had been 0.557 g/dL (16.4 µmol/L). to the hospital because of acute weakness in all limbs. This patient did not have polycythemia. Lupus antico- The findings on physical examination included quad- agulant, anti–phospholipid antibody, and activated riplegia, hypoesthesia involving the distal parts of both protein C resistance were not detected. This patient legs, and areflexia in all extremities. Her fibrinogen level had mild thrombocythemia. Echocardiography was 0.594 g/dL (17.5 µmol/L) on day 3. It had been 0.706 showed akinesia of the anterior, anterolateral, and g/dL (20.8 µmol/L) 1 month before admission. Her CRP inferolateral wall. On the MRI and DWI scans, there level was 0.9 mg/dL on day 10. Polycythemia, thrombo- were left anterior cerebral artery–middle cerebral cythemia, lupus anticoagulant, anti–phospholipid anti- artery (MCA) border-zone infarctions (BZIs) and body, and activated protein C resistance were not ob- MCA–posterior cerebral artery BZIs (Figure 1). Mag- served. Echocardiography showed a mildly decreased netic resonance angiography showed a hypoplastic systolic function of the left ventricle and a small amount right precommunicating anterior cerebral artery seg- of pericardial effusion. An MRI scan revealed bilateral pos- ment and fetal type circulation in the right posterior terior cerebral artery infarcts and bilateral end artery BZIs cerebral artery. Transcranial Doppler ultrasonography (Figure 2). On magnetic resonance angiography, there revealed increased mean flow velocities of the left was stenosis of the left proximal MCA.

(REPRINTED) ARCH NEUROL / VOL 60, MAY 2003 WWW.ARCHNEUROL.COM 746

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).

A B

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).

PATIENT 3 She was admitted to the hospital because of sudden slurred speech. Physical examination findings revealed hyper- This patient was a 52-year-old woman with a 2-year his- pigmentation, hepatomegaly, lymphadenopathy, asci- tory of uncontrolled hypertension. Six months before hos- tes, dysarthria, tetraparesis, and areflexia of both legs. The pital admission, she insidiously developed numbness and fibrinogen level was 0.361 g/dL (10.6 µmol/L) on day 12, weakness in 4 limbs. Two weeks before admission, she and the CRP level was 1.6 mg/dL on day 16. Neither poly- experienced abdominal distention and edema of both legs. cythemia nor thrombocythemia was detected. Echocar-

(REPRINTED) ARCH NEUROL / VOL 60, MAY 2003 WWW.ARCHNEUROL.COM 747

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.

diography showed pulmonary hypertension and a small central role in the formation of thrombi.6 A previous DWI amount of pericardial effusion. The MRI and DWI scans study,7 involving 329 consecutive patients who experi- showed a left end artery BZI, a left MCA–posterior ce- enced an ischemic stroke, showed that an elevated fi- rebral artery BZI, and narrowing of the left intracranial brinogen level was significantly associated with bilat- internal carotid artery (Figure 3). A transcranial Dop- eral multiple cerebral infarcts. All 3 patients in the present pler ultrasonographic examination revealed an in- study had multiple infarcts on DWI. This may support creased mean flow velocity in the left internal carotid ar- the hypothesis that a high fibrinogen level is related to tery siphon, the right MCA, both vertebral arteries, and the pathogenesis of cerebrovascular disease in patients the basilar artery. with POEMS syndrome. Fibrinogen is an acute-phase reactant, and its level COMMENT increases in cases of tissue damage, such as ischemic injury to the brain.8 This raises the question as to whether All 3 patients had BZIs on the MRI scan, and patients 2 the high plasma fibrinogen levels in our patients might and 3 had evidence of end artery BZIs on the MRI scan. be the epiphenomenon of the acute vascular events and In the first 2 patients, the lesions on magnetic resonance the associated inflammatory processes. Our patients’ lev- angiography did not explain the infarcts on the MRI scan. els of CRP, another acute-phase protein, were lower than Patient 1 had a history of coronary heart disease. Theo- the median CRP level (13 mg/dL) of patients with first- retically, it is possible that POEMS syndrome causes heart ever ischemic stroke, as determined in a previous study.9 disease,2 and that the ensuing cardioembolism gives rise In contrast, the fibrinogen levels of 2 patients (patients to ischemic stroke. However, it is also possible that POEMS 1 and 2) were higher than the mean fibrinogen level (0.476 syndrome contributes to ischemic disease involving the g/dL [14.0 µmol/L]) of a previous study.9 Patient 3 had coronary and cerebral arteries. Patient 2 had no definite a slightly lower level of fibrinogen than the mean fibrino- risk factors for stroke except for a negligible 5 pack-year gen level of the previous report, but it was higher than history of smoking. Thrombophilic test results revealed the upper normal limit of the reference value used at Seoul no abnormalities, except hyperfibrinogenemia. A hema- National University Hospital (0.17-0.35 g/dL [5.0-10.3 tologic problem, such as an elevated hematocrit, was re- µmol/L]). Hyperfibrinogenemia was present before the ported to be associated with the occurrence of BZIs.5 These stroke in 2 patients, whose serum fibrinogen levels had findings suggest that fibrinogen may play a role as a pro- been measured before the current episode. Thus, we as- coagulant or a rheostatic agent in the pathogenesis of stroke sume that the observed hyperfibrinogenemia was not just associated with POEMS syndrome. a marker of the inflammatory process, but should in fact Fibrinogen is an independent risk factor for cere- be regarded as an actual participant in the development brovascular disease. Fibrinogen is involved in cell pro- of the stroke. liferation and in mechanisms (platelet aggregation, en- It was reported that aberrant interleukin 6 activity dothelial cell injury, and plasma viscosity) that play a might play an important role in the various manifesta-

(REPRINTED) ARCH NEUROL / VOL 60, MAY 2003 WWW.ARCHNEUROL.COM 748

©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 tions of POEMS syndrome. The serum level of interleu- Hospital, 28 Yongon-Dong, Chongro-Gu, Seoul 110-744, kin 6 is abnormally high in the active stage of POEMS South Korea (e-mail: [email protected]). syndrome, and is typically normalized with corticoste- roids and plasmapheresis.10 Interleukin 6 is also known to stimulate the synthesis of fibrinogen in the liver.11 Al- REFERENCES though speculative, our hypothesis is that interleukin 6 might contribute to the development of stroke in patients with POEMS syndrome by inducing hyperfibrino- 1. Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, genemia. and skin changes: the POEMS syndrome: report on two cases and a review of In summary, we studied 3 patients with POEMS syn- the literature. Medicine. 1980;59:311-322. drome who experienced an acute cerebral ischemic stroke. 2. Manning WJ, Goldberger AL, Drews RE, et al. POEMS syndrome with myocar- We suggest that an elevated fibrinogen level may play a dial infarction: observations concerning pathogenesis and review of the litera- role in the pathogenesis of ischemic stroke associated with ture. Semin Arthritis Rheum. 1992;22:151-161. 3. Lesprit P, Authier FJ, Gherardi R, et al. Acute arterial obliteration: a new feature POEMS syndrome. However, because we studied only 3 of the POEMS syndrome? Medicine. 1996;75:226-232. patients, there may be a possibility of coincidence. Fur- 4. Chu K, Kang DW, Kim HJ, Lee YS, Park SH. Diffusion-weighted imaging abnor- ther studies, including a large population of patients with malities in Wernicke encephalopathy: reversible cytotoxic edema? Arch Neurol. POEMS syndrome, are required. 2002;59:123-127. 5. Bogousslavsky J, Regli F. Borderzone infarctions distal to internal carotid artery occlusion: prognostic implications. Ann Neurol. 1986;20:346-350. Accepted for publication December 9, 2002. 6. Di Minno G, Mancini M. Measuring plasma fibrinogen to predict stroke and myo- Author contributions: Study concept and design (Drs cardial infarction. Arteriosclerosis. 1990;10:1-7. Kang and Roh); acquisition of data (Drs Chu and Lee); 7. Roh JK, Kang DW, Lee SH, Yoon BW, Chang KH. Significance of acute multiple analysis and interpretation of data (Drs Kim and Jeong); brain infarction on diffusion-weighted imaging. Stroke. 2000;31:688-694. 8. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis drafting of the manuscript (Drs Kang, Chu, Kim, and and review of literature. Ann Intern Med. 1993;118:956-963. Jeong); critical revision of the manuscript for important in- 9. Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive pro- tellectual content (Drs Lee and Roh); statistical expertise tein and fibrinogen levels in ischemic stroke. Stroke. 2001;32:133-138. (Drs Kang and Kim); administrative, technical, and ma- 10. Feinberg L, Temple D, de Marchena E, Patarca R, Mitrani A. Soluble immune me- terial support (Drs Jeong and Lee); study supervision (Drs diators in POEMS syndrome with pulmonary hypertension: case report and review of the literature. Crit Rev Oncog. 1999;10:293-302. Chu and Roh). 11. Margaglione M, Grandone E, Mancini FP, Di Minno G. Genetic modulation of plasma Corresponding author and reprints: Jae-Kyu Roh, MD, fibrinogen concentrations: possible importance of interleukin-6. J Thromb Throm- PhD, Department of Neurology, Seoul National University bolysis. 1996;3:51-56.

Correction

Incorrect Insertion Nucleotides. In the Observation by Salviati et al titled “Cy- tochrome c Oxidase Deficiency Due to Novel SCO2 Mutation Mimics Werdnig- Hoffmann Disease,” published in the May issue of the ARCHIVES (2002;59:862- 865), the nucleotides were incorrect. In the “Results” section, on page 864, left- hand column, second complete paragraph, the third sentence should have read as follows: “Negative clones were sequenced and revealed a 10–base pair du- plication of nt-1302 to nt-1311 (Figure 2B) that disrupts the reading frame of the messenger RNA and gives rise to a truncated 83 amino acid polypeptide in which the 21 amino acids at the C-terminus are abnormal (Figure 2C).”

(REPRINTED) ARCH NEUROL / VOL 60, MAY 2003 WWW.ARCHNEUROL.COM 749