Clinical
0
Neurology
und Neurosurgery,
1992 Elsevier Science Publishers
CLINEU
94 (I 992) 65-68 B.V. All rights reserved
65 0303-8467192:s
05.00
00172
Case report
POEMS syndrome: follow-up study of a case C. Crisci”, F. Barbierib, D. Parented, N. Pappone” and G. Carusoc “Fondazione Clinica de1 Lavoro, Medical Center ofCampoli. Departments of bNeurology and ‘Cliniwi Neurophysiology, II School of Medicine, University of Naples, Naples, Italy and ‘Ospedale Sacro Cuore di Gesti, Benevento, Italy (Received (Revised.
(Accepted
Key words:
POEMS; CIDP; Polyneuropathy;
26 August,
received
1991)
10 October.
I I October,
Cyclophosphamide;
1991)
1991)
Nerve conduction velocity
Summary
We report here the case of a 20-year-old man with POEMS syndrome @olyneuropathy, organomegaly, endocrinopathy, M proteins, skin changes). This rare syndrome followed a 3-year history of a syndrome that mimicks a chronic inflammatory demyelinating polyneuropathy (CIDP). Treatment with cyclophosphamide induced regression of the syndrome and improved peripheral nerve conduction.
Introduction
POEMS syndrome is a rare disease, mostly described in Asian patients. It is characterized by a peculiar “symptom complex” [l] (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), first described by Crow in 1956 and later reported with different eponyms: Crow-Fukase syndrome, Shimpo’s syndrome, Takatsuki’s syndrome. A skeletal myeloma (plasmacytoma) is found in most cases and a paraneoplastic etiology is frequently recognized [2]. The case described here has some peculiarities that deserve attention.
Case report
In 1986, after an episode of flu, a 20-year-old Italian male suffered acute weakness in the limbs (more prominent in the legs); there was areflexia, bilateral foot drop. Correspondence
Napoli.
Italy.
to: Dr. Claudio
Crisci,
Via Terracina
381. I-80125
mild “glove-stocking” hypoesthesia and hypopallesthesia. Motor and sensory conduction velocities, orthodromically tested with needle electrodes, were irregular but definitely slowed in the arms (Table 1) and undetectable in the legs. Cerebrospinal fluid (CSF) analysis revealed 2/mm3 cells and 209 mgi dl protein. The patient was diagnosed to have a Guillain-Barre syndrome. Clinical improvement was obtained within 2 months of steroid therapy but he suffered a relapse of the illness each of the following 2 summers, with severe weakness in the limbs and marked muscle wasting. He recovered partially after each episode, though he did not comply fully with the therapy prescribed. In these 2 years, nerve conduction velocities became absent to severely decreased (Table 1). A diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was considered according to the currently accepted criteria [3]. At the 4th relapse, in 1988, in addition to marked worsening of the neuropathy with severe tetraparesis and distal hypoesthesia and apallesthesia, the patient had diffuse hyperpigmentation and thickening of the skin.
T.4BLE MEDIAN Date
I NERVE
CONDUCTION
VELOCIT)’
Sensory
Motor
__.____ Velocity
Amplitude
Dig. 3-
Wrist-
wrist (m/set)
elbow (m/set)
I l/86 3187
44.2 39.8
39.7 33.2
8.1 6.1
1.9 6.3
12187
0 0 0
0 0 0 29.2
0 0 0 0.75
0 0 0 0.50
1O/89 6190 519 I
27.7
hepato- and splenomegaly, lymphadenopathy, peripheral and finger clubbing.
Wrist
Amplitude Elbow
Lat.
(msec)
Elbowwrist
Wrist
El bo\v
(mV)
(mVt
(mkec)
gynecomastia, generalized edema, slight papilledema
On CT scan, the spleen.
liver and
kidneys were markedly enlarged. An oesteolytic area was present in the right ileum. A needle biopsy in that point showed plasmacellular infiltrates (7%). The lesion was
4.1 5.9 0 6.4 6.5 5.5
-
treated
25.9 22.7 0 6.3 7.0 21.2
by local irradiation
14.8 10.9 0
8.4
0.48 0.60 0.65
6.0 0 0.24 0.30 0.20
(3500 rad). A second
needle
biopsy in the same area a year later showed no evidence of plasmacytoma
or osteosclerotic
myeloma.
Total body
bone scintigraphy was normal. There was evidence of thyroid malfunction: TSH was elevated to 6.6 mg/ml (normal 0.2-3.1). Hyperglyceridemia (250 mg%/ml; nor-
Fig. 1. Transverse semithin epoxy section of a fascicle of the sural nerve of the patient (a) and of a control nerve (b). The striking reduction of the myelinated fibres is evident (glutaraldehyde and osmium tetroxide; toluidine blue stain. x 680).
67
Fig. 2. Electron micrography (x21 000; bar = 1pm) of the sural nerve showing a myelinated fibre with uncompacted
lamellar strut ture
in the inner layers of the myelin sheath.
ma1 70-l 70) and
hypercholesterolemia
(450 mg%/ml;
normal 150- 220) were present. Monoclonal proteins were absent in serum while a monoclonal lambda band together with IgG. IgA and kappa-polyclonal chains were detected in concentrated urine. Bone marrow aspiration showed a moderately increased count of plasma cells ( 10%). An enlarged axillary showed angiofollicular hyperplasia
lymphnode biopsy as described by
involved mainly giant dystrophic No myelinated Unmyelinated
the inner layers of the myelin sheath. A axon devoid of myelin was also seen. fibres could be isolated fibres were quantitatively
for teasing. and qualita-
tively spared. Six months therapy with cyclophosphamide (250 mg daily for 7 days a month) was followed by an evident though partial clinical improvement. with an almost
Castleman [4]. All signs and symptoms were consistent with the diagnosis of POEMS syndrome [5]. A sural
complete regression of the skin abnormalities organomegaly. In the urine only a small
and of the monoclonal
nerve biopsy was performed and the nerve specimen was processed according to Dyck et al. [6]. On light micros-
band of kappa chains persisted, while the lambda monoclonal and polyclonal chains disappeared. All laboratory
copy a severe loss of both large and small myelinated tibres (MFs) was evident (Fig. l), with prominent axonal degeneration and features suggesting demyelination. On
tests returned to normal. Conduction velocities u’ere mild but clearly improved in the upper limbs suggesting a peripheral nerve fibre regeneration: they were still un-
electron microscopy, a loose myelin sheath was present due to the opening of the major dense line into flattened islands of Schwann cell cytoplasm (Fig. 2). This abnormality, previously described by Bergouignan et al. [7] was observed in about 3% of the myelinated fibers and
detectable in the lower limbs. Denervation potentials were still present on EMG. At present, muscle strength and trophism are improving with an intensive rehabilitation program, and the patient is able to walk and lead an almost normal and productive life.
Discussion
POEMS syndrome is rare in the Western world and difficult to diagnose, particularly in cases with unusual presentation like ours. This syndrome usually affects patients in their forties with an average duration of 3 years and a generally poor prognosis [2]. Neoplastic bone lesions, mainly plasmacytoma, are present in 70% of the Asiatic and in more than 80% of the European patients. It has been suggested that this finding may account for the multiple clinical manifestations, as plasma cells may secrete an abnormal immunoglobulin, toxic for many involved organs [2]. Sural nerve biopsy shows severe loss of peripheral nerve fibres with both degenerative and demyelinating features. In our case the age of onset was much younger than usual: the outcome seems favourable, and the typical clinical signs appeared after a 3-year history of a CIDPlike syndrome. This modality of onset is quite unusual, although a remittent clinical course has been described by Kelly et al. [8] in cases of polyneuropathy associated with myeloma. This could support the hypothesis of an autoimmune pathogenesis, as no definite neoplastic lesion or plasma cell dyscrasia could be found. The lymphadenopathy resembling Castleman’s disease as found in our case is common in paraproteinaemias associated with monoclonal proteins and has been described in the POEMS syndrome [9, lo]. The widening of the myelin lamellae is of particular interest: it affected the inner layers, and in an irregular way. This pattern is similar, but not identical, to that described in polyneuropathies associated with monoclonal gammopathy [1 l] in which the widening affects the outer part of the myelin sheath. In both cases the alteration is probably due to the location of an antimyelinassociated protein within the intraperiod line [12], but the differences in location may be due to the heterogeneity of such proteins. Choice of therapy in this disease is generally dependent on the cause: regression of the clinical signs and symptoms is conditioned by the treatment of the myeloma or plasmacytoma. In cases without a recognized neoplastic lesion, cytotoxic drugs have been tried with inconstant or transient results (melphalan, steroids, cyclophosphamide, tamoxifen). In our case, the treatment with cyclophosphamide triggered a regression of almost all the clinical signs, which supports the hypothesis of an autoimmune pathogenesis.
References
A. (1984) Geographical patterns of neuropathy: Japan. In: Asbury, A.K. and Gilliatt, R.W. (Eds.), Peripheral Nerve Disorders, Butterworth, London, pp. 303--319. Nakanishi, T., Sobue, I., Toyokura, Y. et al. (1984) The Crow-Fukase Syndrome: a study of 102 cases in Japan. Neurology 34: 712-720. Dyck, P.J. and Arnason, B. (1984) Chronic inflammatory demyelinating polyradiculoneuropathy. In: Dyck. P.J.. Thomas, P.K., Lambert, E.H. and Bunge, R. (Eds.), Peripheral Neuropathy, vol. 2, W.B. Saunders, Philadelphia, PA. pp. 2101- 2114. Castleman, B., Iverson, L. and Menendez, V.P. (1956) Localised mediastinal lymph-node hyperplasia resembling thymoma. Cancer, 9: 822-830. Bardwick, P.A., Zvaifler, N.J., Gill, G.N., Newman, D., Greenway, G.D. and Resnick, K.L. (1980) Plasma cell neoplasia with polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes: the POEMS syndrome. Report of two cases and a review of the literature. Medicine (Baltimore), 59: 3 1l-322. Dyck, P.J., Karnes, J., Lais, A., Lofren, E.P. and Stevens, J.C. (1984) Pathological alterations of the peripheral nervous system in humans. In: Dyck, P.J., Thomas, P.K., Lambert, E.H. and Bunge, R. (Eds.), Peripheral Neuropathy, Vol. 1, W.B. Saunders, Philadelphia, PA, pp. 760-870. Bergouignan, F.X., Massonnat, R., Vital, C. et al. (1987) Uncompacted lamellae in three patients with POEMS syndrome. Eur. Neurol. 2713: 1733 I8 1. Kelly. J.J., Kyle, R.A., Miles, J.M., O’Brien, P.C. and Dyck, P.J. ( 198 1) The spectrum of peripheral neuropathy in myeloma. Neurology, 3 1: 243 I. Thajeb, P., Chee, Y., Lo, S.F. and Lee, N. (1989) The POEMS syndrome among Chinese: association with Castleman’s disease and some immunological abnormalities. Acta Neurol. Stand., 80(6): 492-500. Donaghy, M., Hall, P.. Gawler, J. et al. (1989) Peripheral neuropathy associated with Castleman’s disease. J. Neurol. Sci., 89: 253-267. Julien, J., Vital, C.: Vallat, J.M., Lagueny, A., Ferrer, X. and Leboutet, M.J. (1984) Chronic demyelinating neuropathy with IgM-producing lymphocytes in peripheral nerve and delayed appearance of “benign” monoclonal gammopathy. Neurology, 34: 1387-1389. McLeod, J.G. and Pollard, J.D. (1984) Neuropathies in systemic diseases: hidden and overt. In: Asbury, A.K. and Gilliatt, R.W. (Eds.), Peripheral Nerve Disorders, Butterworth, London, pp. 92-- 125.
1 Ohnishi,
2
3
4
5
6
7
8
9
10
11
12
0
Neurology
und Neurosurgery,
1992 Elsevier Science Publishers
CLINEU
94 (I 992) 65-68 B.V. All rights reserved
65 0303-8467192:s
05.00
00172
Case report
POEMS syndrome: follow-up study of a case C. Crisci”, F. Barbierib, D. Parented, N. Pappone” and G. Carusoc “Fondazione Clinica de1 Lavoro, Medical Center ofCampoli. Departments of bNeurology and ‘Cliniwi Neurophysiology, II School of Medicine, University of Naples, Naples, Italy and ‘Ospedale Sacro Cuore di Gesti, Benevento, Italy (Received (Revised.
(Accepted
Key words:
POEMS; CIDP; Polyneuropathy;
26 August,
received
1991)
10 October.
I I October,
Cyclophosphamide;
1991)
1991)
Nerve conduction velocity
Summary
We report here the case of a 20-year-old man with POEMS syndrome @olyneuropathy, organomegaly, endocrinopathy, M proteins, skin changes). This rare syndrome followed a 3-year history of a syndrome that mimicks a chronic inflammatory demyelinating polyneuropathy (CIDP). Treatment with cyclophosphamide induced regression of the syndrome and improved peripheral nerve conduction.
Introduction
POEMS syndrome is a rare disease, mostly described in Asian patients. It is characterized by a peculiar “symptom complex” [l] (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), first described by Crow in 1956 and later reported with different eponyms: Crow-Fukase syndrome, Shimpo’s syndrome, Takatsuki’s syndrome. A skeletal myeloma (plasmacytoma) is found in most cases and a paraneoplastic etiology is frequently recognized [2]. The case described here has some peculiarities that deserve attention.
Case report
In 1986, after an episode of flu, a 20-year-old Italian male suffered acute weakness in the limbs (more prominent in the legs); there was areflexia, bilateral foot drop. Correspondence
Napoli.
Italy.
to: Dr. Claudio
Crisci,
Via Terracina
381. I-80125
mild “glove-stocking” hypoesthesia and hypopallesthesia. Motor and sensory conduction velocities, orthodromically tested with needle electrodes, were irregular but definitely slowed in the arms (Table 1) and undetectable in the legs. Cerebrospinal fluid (CSF) analysis revealed 2/mm3 cells and 209 mgi dl protein. The patient was diagnosed to have a Guillain-Barre syndrome. Clinical improvement was obtained within 2 months of steroid therapy but he suffered a relapse of the illness each of the following 2 summers, with severe weakness in the limbs and marked muscle wasting. He recovered partially after each episode, though he did not comply fully with the therapy prescribed. In these 2 years, nerve conduction velocities became absent to severely decreased (Table 1). A diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was considered according to the currently accepted criteria [3]. At the 4th relapse, in 1988, in addition to marked worsening of the neuropathy with severe tetraparesis and distal hypoesthesia and apallesthesia, the patient had diffuse hyperpigmentation and thickening of the skin.
T.4BLE MEDIAN Date
I NERVE
CONDUCTION
VELOCIT)’
Sensory
Motor
__.____ Velocity
Amplitude
Dig. 3-
Wrist-
wrist (m/set)
elbow (m/set)
I l/86 3187
44.2 39.8
39.7 33.2
8.1 6.1
1.9 6.3
12187
0 0 0
0 0 0 29.2
0 0 0 0.75
0 0 0 0.50
1O/89 6190 519 I
27.7
hepato- and splenomegaly, lymphadenopathy, peripheral and finger clubbing.
Wrist
Amplitude Elbow
Lat.
(msec)
Elbowwrist
Wrist
El bo\v
(mV)
(mVt
(mkec)
gynecomastia, generalized edema, slight papilledema
On CT scan, the spleen.
liver and
kidneys were markedly enlarged. An oesteolytic area was present in the right ileum. A needle biopsy in that point showed plasmacellular infiltrates (7%). The lesion was
4.1 5.9 0 6.4 6.5 5.5
-
treated
25.9 22.7 0 6.3 7.0 21.2
by local irradiation
14.8 10.9 0
8.4
0.48 0.60 0.65
6.0 0 0.24 0.30 0.20
(3500 rad). A second
needle
biopsy in the same area a year later showed no evidence of plasmacytoma
or osteosclerotic
myeloma.
Total body
bone scintigraphy was normal. There was evidence of thyroid malfunction: TSH was elevated to 6.6 mg/ml (normal 0.2-3.1). Hyperglyceridemia (250 mg%/ml; nor-
Fig. 1. Transverse semithin epoxy section of a fascicle of the sural nerve of the patient (a) and of a control nerve (b). The striking reduction of the myelinated fibres is evident (glutaraldehyde and osmium tetroxide; toluidine blue stain. x 680).
67
Fig. 2. Electron micrography (x21 000; bar = 1pm) of the sural nerve showing a myelinated fibre with uncompacted
lamellar strut ture
in the inner layers of the myelin sheath.
ma1 70-l 70) and
hypercholesterolemia
(450 mg%/ml;
normal 150- 220) were present. Monoclonal proteins were absent in serum while a monoclonal lambda band together with IgG. IgA and kappa-polyclonal chains were detected in concentrated urine. Bone marrow aspiration showed a moderately increased count of plasma cells ( 10%). An enlarged axillary showed angiofollicular hyperplasia
lymphnode biopsy as described by
involved mainly giant dystrophic No myelinated Unmyelinated
the inner layers of the myelin sheath. A axon devoid of myelin was also seen. fibres could be isolated fibres were quantitatively
for teasing. and qualita-
tively spared. Six months therapy with cyclophosphamide (250 mg daily for 7 days a month) was followed by an evident though partial clinical improvement. with an almost
Castleman [4]. All signs and symptoms were consistent with the diagnosis of POEMS syndrome [5]. A sural
complete regression of the skin abnormalities organomegaly. In the urine only a small
and of the monoclonal
nerve biopsy was performed and the nerve specimen was processed according to Dyck et al. [6]. On light micros-
band of kappa chains persisted, while the lambda monoclonal and polyclonal chains disappeared. All laboratory
copy a severe loss of both large and small myelinated tibres (MFs) was evident (Fig. l), with prominent axonal degeneration and features suggesting demyelination. On
tests returned to normal. Conduction velocities u’ere mild but clearly improved in the upper limbs suggesting a peripheral nerve fibre regeneration: they were still un-
electron microscopy, a loose myelin sheath was present due to the opening of the major dense line into flattened islands of Schwann cell cytoplasm (Fig. 2). This abnormality, previously described by Bergouignan et al. [7] was observed in about 3% of the myelinated fibers and
detectable in the lower limbs. Denervation potentials were still present on EMG. At present, muscle strength and trophism are improving with an intensive rehabilitation program, and the patient is able to walk and lead an almost normal and productive life.
Discussion
POEMS syndrome is rare in the Western world and difficult to diagnose, particularly in cases with unusual presentation like ours. This syndrome usually affects patients in their forties with an average duration of 3 years and a generally poor prognosis [2]. Neoplastic bone lesions, mainly plasmacytoma, are present in 70% of the Asiatic and in more than 80% of the European patients. It has been suggested that this finding may account for the multiple clinical manifestations, as plasma cells may secrete an abnormal immunoglobulin, toxic for many involved organs [2]. Sural nerve biopsy shows severe loss of peripheral nerve fibres with both degenerative and demyelinating features. In our case the age of onset was much younger than usual: the outcome seems favourable, and the typical clinical signs appeared after a 3-year history of a CIDPlike syndrome. This modality of onset is quite unusual, although a remittent clinical course has been described by Kelly et al. [8] in cases of polyneuropathy associated with myeloma. This could support the hypothesis of an autoimmune pathogenesis, as no definite neoplastic lesion or plasma cell dyscrasia could be found. The lymphadenopathy resembling Castleman’s disease as found in our case is common in paraproteinaemias associated with monoclonal proteins and has been described in the POEMS syndrome [9, lo]. The widening of the myelin lamellae is of particular interest: it affected the inner layers, and in an irregular way. This pattern is similar, but not identical, to that described in polyneuropathies associated with monoclonal gammopathy [1 l] in which the widening affects the outer part of the myelin sheath. In both cases the alteration is probably due to the location of an antimyelinassociated protein within the intraperiod line [12], but the differences in location may be due to the heterogeneity of such proteins. Choice of therapy in this disease is generally dependent on the cause: regression of the clinical signs and symptoms is conditioned by the treatment of the myeloma or plasmacytoma. In cases without a recognized neoplastic lesion, cytotoxic drugs have been tried with inconstant or transient results (melphalan, steroids, cyclophosphamide, tamoxifen). In our case, the treatment with cyclophosphamide triggered a regression of almost all the clinical signs, which supports the hypothesis of an autoimmune pathogenesis.
References
A. (1984) Geographical patterns of neuropathy: Japan. In: Asbury, A.K. and Gilliatt, R.W. (Eds.), Peripheral Nerve Disorders, Butterworth, London, pp. 303--319. Nakanishi, T., Sobue, I., Toyokura, Y. et al. (1984) The Crow-Fukase Syndrome: a study of 102 cases in Japan. Neurology 34: 712-720. Dyck, P.J. and Arnason, B. (1984) Chronic inflammatory demyelinating polyradiculoneuropathy. In: Dyck. P.J.. Thomas, P.K., Lambert, E.H. and Bunge, R. (Eds.), Peripheral Neuropathy, vol. 2, W.B. Saunders, Philadelphia, PA. pp. 2101- 2114. Castleman, B., Iverson, L. and Menendez, V.P. (1956) Localised mediastinal lymph-node hyperplasia resembling thymoma. Cancer, 9: 822-830. Bardwick, P.A., Zvaifler, N.J., Gill, G.N., Newman, D., Greenway, G.D. and Resnick, K.L. (1980) Plasma cell neoplasia with polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes: the POEMS syndrome. Report of two cases and a review of the literature. Medicine (Baltimore), 59: 3 1l-322. Dyck, P.J., Karnes, J., Lais, A., Lofren, E.P. and Stevens, J.C. (1984) Pathological alterations of the peripheral nervous system in humans. In: Dyck, P.J., Thomas, P.K., Lambert, E.H. and Bunge, R. (Eds.), Peripheral Neuropathy, Vol. 1, W.B. Saunders, Philadelphia, PA, pp. 760-870. Bergouignan, F.X., Massonnat, R., Vital, C. et al. (1987) Uncompacted lamellae in three patients with POEMS syndrome. Eur. Neurol. 2713: 1733 I8 1. Kelly. J.J., Kyle, R.A., Miles, J.M., O’Brien, P.C. and Dyck, P.J. ( 198 1) The spectrum of peripheral neuropathy in myeloma. Neurology, 3 1: 243 I. Thajeb, P., Chee, Y., Lo, S.F. and Lee, N. (1989) The POEMS syndrome among Chinese: association with Castleman’s disease and some immunological abnormalities. Acta Neurol. Stand., 80(6): 492-500. Donaghy, M., Hall, P.. Gawler, J. et al. (1989) Peripheral neuropathy associated with Castleman’s disease. J. Neurol. Sci., 89: 253-267. Julien, J., Vital, C.: Vallat, J.M., Lagueny, A., Ferrer, X. and Leboutet, M.J. (1984) Chronic demyelinating neuropathy with IgM-producing lymphocytes in peripheral nerve and delayed appearance of “benign” monoclonal gammopathy. Neurology, 34: 1387-1389. McLeod, J.G. and Pollard, J.D. (1984) Neuropathies in systemic diseases: hidden and overt. In: Asbury, A.K. and Gilliatt, R.W. (Eds.), Peripheral Nerve Disorders, Butterworth, London, pp. 92-- 125.
1 Ohnishi,
2
3
4
5
6
7
8
9
10
11
12
