J Neurol (2013) 260:3178–3181 DOI 10.1007/s00415-013-7180-z
LETTER TO THE EDITORS
Ischemic stroke as clinical onset of POEMS syndrome P. Dacci • F. Lessi • E. Dalla Bella • M. Morbin • C. Briani • G. Lauria
Received: 4 October 2013 / Revised: 28 October 2013 / Accepted: 30 October 2013 / Published online: 13 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Dear Sirs, Peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare, multisystemic disorder associated with plasma cell dyscrasia. Ischemic stroke can complicate the clinical picture, with an overall 5-year risk of 13.4 % [1]. In recent studies, nine cases of recurrent stroke have been reported [2–4]. We describe the unique case of two patients in whom stroke was the presenting feature of POEMS syndrome. One of them experienced a recurrent stroke. A 49-year-old man complained of acute aphasia and right-side hemiparesis that recovered in 2 days, due to multiple ischemic lesions (Fig. 1). He did not have any risk factors for cerebrovascular diseases except for cigarette smoking (20 daily). Hematological exams were normal except for hyperhomocysteinemia (20 mmol/L; n.v. 5–15 mmol/L), thrombocytosis (511 9 109/L; n.v. 150–450) and IgA-k paraproteinemia. Electrocardiograms and carotid, vertebral, and transcranial Doppler ultrasonography findings were negative. Transesophageal P. Dacci E. Dalla Bella G. Lauria (&) Headache and Neuroalgology Unit, IRCCS Foundation, ‘‘Carlo Besta’’ Neurological Institute, Via Celoria 11, 20133 Milan, Italy e-mail: [email protected] F. Lessi Hematology Unit, Department of Medicine, University of Padua, Padua, Italy M. Morbin Neuropathology Units, IRCCS Foundation, ‘‘Carlo Besta’’ Neurological Institute, Milan, Italy C. Briani Department of Neurosciences, University of Padua, Padua, Italy
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echocardiogram disclosed a patent foramen ovale and the patient underwent percutaneous closure. One year later, he complained of progressive tingling, spontaneous pain, acrocyanosis, distal limb weakness and dysautonomic symptoms (erectile dysfunction, increased sweating and orthostatic dizzness). Hematological exams were unchanged. Screenings for systemic vasculitis, viral infections, malabsorption, and connective tissue disorders were negative. Based on cerebrospinal fluid (CSF) examination (protein 99 mg/dL; n.v. \45 mg/dL) and nerve conduction study (NCS) findings, he was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy. Oral prednisone and monthly intravenous immunoglobulin (IVIG) treatment for 6 months were both unsuccessful. When referred to us, the neurological examination showed decreased proprioception at the first metatarsal joints (3/8, Rydel-Seiffer 64 Hz tuning fork), hand weakness, impaired walking on the heels, lower limb areflexia, acrocyanosis and hyperkeratosis of hypothenar eminences. NCS showed an axonal sensorimotor neuropathy, confirmed by sural nerve biopsy that demonstrated intense vascular endothelial growth factor (VEGF) deposition (Fig. 2). Abdominal echography revealed hepato-splenomegaly. As a result, he was diagnosed with POEMS syndrome. A bone marrow biopsy demonstrated lymphoid aggregates with rimmings of k-restricted monoclonal Ig and plasma cells. At a 12-month follow-up, evaluations indicated that an autologous stem cell transplant had successfully reduced neuropathy symptoms. A 46-yr-old man presented with facio-brachial left palsy caused by right temporal-parietal ischemic stroke (Fig. 1) that fully recovered in 2 weeks. Secondary prevention with acetylsalicylic acid was started. One month later, he complained of paraesthesia and progressive
J Neurol (2013) 260:3178–3181
3179
Fig. 1 a Diffusion-weighted magnetic resonance imaging showing acute multiple ischemic lesions in the cortical-subcortical left frontal, parietal and occipital lobes in patient 1. b FLAIR axial magnetic
resonance imaging showing subacute right parietal-occipital ischemic stroke in patient 2
weakness at the lower limbs. Based on CSF analysis (protein 116 mg/dL) and NCS findings, he was diagnosed with Guillain Barre` syndrome. Plasma-exchange and IVIG treatment were unsuccessful and the patient worsened to flaccid tetraparesis. When referred to us, the hematological exams showed IgG-k paraprotein (4.54 g/ L), thrombocytosis (483 9 109/L) and increased VEGF level ([2,000 ng/L). Screenings for systemic vasculitis, viral infections, malabsorption, and connective tissue disorders were negative. Bone marrow biopsy revealed 30 % clonal plasmacellular infiltrate. A whole-body CT scan showed sclerotic bone lesions, splenomegaly and bilateral pleural effusion. NCS showed severe axonal sensorimotor neuropathy. He was diagnosed with POEMS syndrome. After refusing an autologous stem cell transplant, the patient underwent lenalidomide and dexamethasone treatment, which improved VEGF levels and his overall clinical picture. Six months later, he experienced a recurrent right temporal-parietal ischemic stroke. After
satisfactory recovery, an autologous stem cell transplant was successfully performed. POEMS syndrome is a life-threatening condition. The diagnosis is often challenging and treatment may be delayed. The pathophysiological mechanisms underlying ischemic stroke in POEMS syndrome remain speculative. Thrombocytosis, polyglobulia, hyperfibrinogenemia [2] and high levels of circulating pro-inflammatory cytokines are believed to trigger the procoagulatory state [5–7]. Among the latter, interleukin-6, which was demonstrated to be elevated in POEMS syndrome, is known to stimulate the synthesis of fibrinogen, a known risk factor for stroke [8]. POEMS syndrome may also cause heart disease [9] and cardioembolic stroke, also due to atrial thrombosis [10]. Moreover, arterial and venous thromboses were detected in some patients [5, 11–14]. We emphasize that ischemic stroke can precede the occurrence of neuropathy in POEMS syndrome, which should be suspected in the presence of typical
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J Neurol (2013) 260:3178–3181
Fig. 2 Sural nerve biopsy in patient 1. a Slight reduction in myelinated fiber density with occasional images of Wallerian-like degeneration, and some groups of small fibers organized in clusters of regeneration. (Semithin sections stained with Toluidine blue). About 8–10 % of the myelinated fibers disclose altered myelin lamellae compaction, mainly of the inner layers. These alterations sometimes affects the entire area of contact between the myelin and axon (b), while other times it is focal (c; electron microscopy). d Nerve fascicles, regular in morphology and size, in the absence of
inflammatory infiltrates or vasculitis. Histochemical staining of amyloid with Congo red showed no deposits (data not shown). (Paraffin, serial sections stained with hematoxylin-eosin). Deposits of VEGF on endothelial cells (f, arrows) and some endoneural (f, arrowheads) GFAP-positive cells (e, arrowheads). Immunofluorescence staining with antibodies against light and heavy chains of immunoglobulins and complement C3d showed no immunodeposition (data not shown)
hematological abnormalities, mainly if they occur in young patients.
incidence, risk factors, and imaging characteristics. Neurology 73(16):1308–1312 Kang K, Chu K, Kim DE, Jeong SW, Lee JW, Roh JK (2003) POEMS syndrome associated with ischemic stroke. Arch Neurol 60(5):745–749 Garcia T, Dafer R, Hocker S, Schneck M, Barton K, Biller J (2007) Recurrent strokes in two patients with POEMS syndrome and Castleman’s disease. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 16(6):278–284 Sommer B, Schaumberg J (2012) Therapeutic challenges in a patient with POEMS syndrome and recurrent stroke: presentation of a case and review of the literature. Acta Neurol Belg 112(1):9–13 Zenone T, Bastion Y, Salles G, Rieux C, Morel D, Felman P, Espinouse D, Bryon PA, Coiffier B (1996) POEMS syndrome, arterial thrombosis and thrombocythaemia. J Intern Med 240(2):107–109 Scarlato M, Previtali SC, Carpo M, Pareyson D, Briani C, Del Bo R, Nobile-Orazio E, Quattrini A, Comi GP (2005) Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis. Brain 128(Pt 8):1911–1920
Conflicts of interest of interest.
The authors declare that they have no conflict
Ethical standard This study describes activities performed in patients during the course of appropriate diagnostic examinations and therapy in clinical practice. It is not a clinical study or trial and therefore did not require submission to the Ethic Committee. All activities have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. The authors hereby declare that the research documented in the submitted manuscript has been carried out in accordance with the above stated ethical standards.
References 1. Dupont SA, Dispenzieri A, Mauermann ML, Rabinstein AA, Brown RD Jr (2009) Cerebral infarction in POEMS syndrome:
123
2.
3.
4.
5.
6.
J Neurol (2013) 260:3178–3181 7. Scarlato M, Previtali SC (2011) POEMS syndrome: the matterof-fact approach. Curr Opin Neurol 24(5):491–496 8. Margaglione M, Grandone E, Mancini FP, Di Minno G (1996) Genetic modulation of plasma fibrinogen concentrations: possible importance of interleukin-6. J Thromb Thrombolysis 3(1):51–56 9. Manning WJ, Goldberger AL, Drews RE, Goldstein BJ, Matheson JK, Rabinowe SL, Trentham DE, Landsberg L (1992) POEMS syndrome with myocardial infarction: observations concerning pathogenesis and review of the literature. Semin Arthr Rheum 22(3):151–161 10. Lee MR, Choi HJ, Lee EB, Baek HJ (2007) POEMS syndrome complicated by extensive arterial thromboses. Clin Rheumatol 26(11):1989–1992 11. Lesprit P, Authier FJ, Gherardi R, Belec L, Paris D, Melliere D, Schaeffer A, Godeau B (1996) Acute arterial obliteration: a new feature of the POEMS syndrome? Medicine 75(4):226–232
3181 12. Huth M, Gordon D, Verrier ED, Otto CM (1991) Aortic valvular fibroma as a source of systemic emboli in POEMS syndrome. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr 4(4):401–404 13. Bova G, Pasqui AL, Saletti M, Bruni F, Auteri A (1998) POEMS syndrome with vascular lesions: a role for interleukin-1beta and interleukin-6 increase—a case report. Angiology 49(11):937–940 14. Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, Greipp PR, Witzig TE, Basu R, Suarez GA et al (2003) POEMS syndrome: definitions and long-term outcome. Blood 101(7):2496–2506
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LETTER TO THE EDITORS
Ischemic stroke as clinical onset of POEMS syndrome P. Dacci • F. Lessi • E. Dalla Bella • M. Morbin • C. Briani • G. Lauria
Received: 4 October 2013 / Revised: 28 October 2013 / Accepted: 30 October 2013 / Published online: 13 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Dear Sirs, Peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare, multisystemic disorder associated with plasma cell dyscrasia. Ischemic stroke can complicate the clinical picture, with an overall 5-year risk of 13.4 % [1]. In recent studies, nine cases of recurrent stroke have been reported [2–4]. We describe the unique case of two patients in whom stroke was the presenting feature of POEMS syndrome. One of them experienced a recurrent stroke. A 49-year-old man complained of acute aphasia and right-side hemiparesis that recovered in 2 days, due to multiple ischemic lesions (Fig. 1). He did not have any risk factors for cerebrovascular diseases except for cigarette smoking (20 daily). Hematological exams were normal except for hyperhomocysteinemia (20 mmol/L; n.v. 5–15 mmol/L), thrombocytosis (511 9 109/L; n.v. 150–450) and IgA-k paraproteinemia. Electrocardiograms and carotid, vertebral, and transcranial Doppler ultrasonography findings were negative. Transesophageal P. Dacci E. Dalla Bella G. Lauria (&) Headache and Neuroalgology Unit, IRCCS Foundation, ‘‘Carlo Besta’’ Neurological Institute, Via Celoria 11, 20133 Milan, Italy e-mail: [email protected] F. Lessi Hematology Unit, Department of Medicine, University of Padua, Padua, Italy M. Morbin Neuropathology Units, IRCCS Foundation, ‘‘Carlo Besta’’ Neurological Institute, Milan, Italy C. Briani Department of Neurosciences, University of Padua, Padua, Italy
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echocardiogram disclosed a patent foramen ovale and the patient underwent percutaneous closure. One year later, he complained of progressive tingling, spontaneous pain, acrocyanosis, distal limb weakness and dysautonomic symptoms (erectile dysfunction, increased sweating and orthostatic dizzness). Hematological exams were unchanged. Screenings for systemic vasculitis, viral infections, malabsorption, and connective tissue disorders were negative. Based on cerebrospinal fluid (CSF) examination (protein 99 mg/dL; n.v. \45 mg/dL) and nerve conduction study (NCS) findings, he was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy. Oral prednisone and monthly intravenous immunoglobulin (IVIG) treatment for 6 months were both unsuccessful. When referred to us, the neurological examination showed decreased proprioception at the first metatarsal joints (3/8, Rydel-Seiffer 64 Hz tuning fork), hand weakness, impaired walking on the heels, lower limb areflexia, acrocyanosis and hyperkeratosis of hypothenar eminences. NCS showed an axonal sensorimotor neuropathy, confirmed by sural nerve biopsy that demonstrated intense vascular endothelial growth factor (VEGF) deposition (Fig. 2). Abdominal echography revealed hepato-splenomegaly. As a result, he was diagnosed with POEMS syndrome. A bone marrow biopsy demonstrated lymphoid aggregates with rimmings of k-restricted monoclonal Ig and plasma cells. At a 12-month follow-up, evaluations indicated that an autologous stem cell transplant had successfully reduced neuropathy symptoms. A 46-yr-old man presented with facio-brachial left palsy caused by right temporal-parietal ischemic stroke (Fig. 1) that fully recovered in 2 weeks. Secondary prevention with acetylsalicylic acid was started. One month later, he complained of paraesthesia and progressive
J Neurol (2013) 260:3178–3181
3179
Fig. 1 a Diffusion-weighted magnetic resonance imaging showing acute multiple ischemic lesions in the cortical-subcortical left frontal, parietal and occipital lobes in patient 1. b FLAIR axial magnetic
resonance imaging showing subacute right parietal-occipital ischemic stroke in patient 2
weakness at the lower limbs. Based on CSF analysis (protein 116 mg/dL) and NCS findings, he was diagnosed with Guillain Barre` syndrome. Plasma-exchange and IVIG treatment were unsuccessful and the patient worsened to flaccid tetraparesis. When referred to us, the hematological exams showed IgG-k paraprotein (4.54 g/ L), thrombocytosis (483 9 109/L) and increased VEGF level ([2,000 ng/L). Screenings for systemic vasculitis, viral infections, malabsorption, and connective tissue disorders were negative. Bone marrow biopsy revealed 30 % clonal plasmacellular infiltrate. A whole-body CT scan showed sclerotic bone lesions, splenomegaly and bilateral pleural effusion. NCS showed severe axonal sensorimotor neuropathy. He was diagnosed with POEMS syndrome. After refusing an autologous stem cell transplant, the patient underwent lenalidomide and dexamethasone treatment, which improved VEGF levels and his overall clinical picture. Six months later, he experienced a recurrent right temporal-parietal ischemic stroke. After
satisfactory recovery, an autologous stem cell transplant was successfully performed. POEMS syndrome is a life-threatening condition. The diagnosis is often challenging and treatment may be delayed. The pathophysiological mechanisms underlying ischemic stroke in POEMS syndrome remain speculative. Thrombocytosis, polyglobulia, hyperfibrinogenemia [2] and high levels of circulating pro-inflammatory cytokines are believed to trigger the procoagulatory state [5–7]. Among the latter, interleukin-6, which was demonstrated to be elevated in POEMS syndrome, is known to stimulate the synthesis of fibrinogen, a known risk factor for stroke [8]. POEMS syndrome may also cause heart disease [9] and cardioembolic stroke, also due to atrial thrombosis [10]. Moreover, arterial and venous thromboses were detected in some patients [5, 11–14]. We emphasize that ischemic stroke can precede the occurrence of neuropathy in POEMS syndrome, which should be suspected in the presence of typical
123
3180
J Neurol (2013) 260:3178–3181
Fig. 2 Sural nerve biopsy in patient 1. a Slight reduction in myelinated fiber density with occasional images of Wallerian-like degeneration, and some groups of small fibers organized in clusters of regeneration. (Semithin sections stained with Toluidine blue). About 8–10 % of the myelinated fibers disclose altered myelin lamellae compaction, mainly of the inner layers. These alterations sometimes affects the entire area of contact between the myelin and axon (b), while other times it is focal (c; electron microscopy). d Nerve fascicles, regular in morphology and size, in the absence of
inflammatory infiltrates or vasculitis. Histochemical staining of amyloid with Congo red showed no deposits (data not shown). (Paraffin, serial sections stained with hematoxylin-eosin). Deposits of VEGF on endothelial cells (f, arrows) and some endoneural (f, arrowheads) GFAP-positive cells (e, arrowheads). Immunofluorescence staining with antibodies against light and heavy chains of immunoglobulins and complement C3d showed no immunodeposition (data not shown)
hematological abnormalities, mainly if they occur in young patients.
incidence, risk factors, and imaging characteristics. Neurology 73(16):1308–1312 Kang K, Chu K, Kim DE, Jeong SW, Lee JW, Roh JK (2003) POEMS syndrome associated with ischemic stroke. Arch Neurol 60(5):745–749 Garcia T, Dafer R, Hocker S, Schneck M, Barton K, Biller J (2007) Recurrent strokes in two patients with POEMS syndrome and Castleman’s disease. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 16(6):278–284 Sommer B, Schaumberg J (2012) Therapeutic challenges in a patient with POEMS syndrome and recurrent stroke: presentation of a case and review of the literature. Acta Neurol Belg 112(1):9–13 Zenone T, Bastion Y, Salles G, Rieux C, Morel D, Felman P, Espinouse D, Bryon PA, Coiffier B (1996) POEMS syndrome, arterial thrombosis and thrombocythaemia. J Intern Med 240(2):107–109 Scarlato M, Previtali SC, Carpo M, Pareyson D, Briani C, Del Bo R, Nobile-Orazio E, Quattrini A, Comi GP (2005) Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis. Brain 128(Pt 8):1911–1920
Conflicts of interest of interest.
The authors declare that they have no conflict
Ethical standard This study describes activities performed in patients during the course of appropriate diagnostic examinations and therapy in clinical practice. It is not a clinical study or trial and therefore did not require submission to the Ethic Committee. All activities have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. The authors hereby declare that the research documented in the submitted manuscript has been carried out in accordance with the above stated ethical standards.
References 1. Dupont SA, Dispenzieri A, Mauermann ML, Rabinstein AA, Brown RD Jr (2009) Cerebral infarction in POEMS syndrome:
123
2.
3.
4.
5.
6.
J Neurol (2013) 260:3178–3181 7. Scarlato M, Previtali SC (2011) POEMS syndrome: the matterof-fact approach. Curr Opin Neurol 24(5):491–496 8. Margaglione M, Grandone E, Mancini FP, Di Minno G (1996) Genetic modulation of plasma fibrinogen concentrations: possible importance of interleukin-6. J Thromb Thrombolysis 3(1):51–56 9. Manning WJ, Goldberger AL, Drews RE, Goldstein BJ, Matheson JK, Rabinowe SL, Trentham DE, Landsberg L (1992) POEMS syndrome with myocardial infarction: observations concerning pathogenesis and review of the literature. Semin Arthr Rheum 22(3):151–161 10. Lee MR, Choi HJ, Lee EB, Baek HJ (2007) POEMS syndrome complicated by extensive arterial thromboses. Clin Rheumatol 26(11):1989–1992 11. Lesprit P, Authier FJ, Gherardi R, Belec L, Paris D, Melliere D, Schaeffer A, Godeau B (1996) Acute arterial obliteration: a new feature of the POEMS syndrome? Medicine 75(4):226–232
3181 12. Huth M, Gordon D, Verrier ED, Otto CM (1991) Aortic valvular fibroma as a source of systemic emboli in POEMS syndrome. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr 4(4):401–404 13. Bova G, Pasqui AL, Saletti M, Bruni F, Auteri A (1998) POEMS syndrome with vascular lesions: a role for interleukin-1beta and interleukin-6 increase—a case report. Angiology 49(11):937–940 14. Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, Greipp PR, Witzig TE, Basu R, Suarez GA et al (2003) POEMS syndrome: definitions and long-term outcome. Blood 101(7):2496–2506
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![[Budd-Chiari syndrome as clinical expression of POEMS syndrome].](/assets/img/hold.png)
