Article abstract
A 61-year-old man had osteosclerotic myeloma that was localized in the eleventh thoracic vertebral body and associated with sensorimotor polyneuropathy, skin hyperpigmentation, edema, hypertrichosis, gynecomastia, and white nails. Cases of osteosclerotic myeloma with and without polyneuropathy in the literature were reviewed with special reference to accompanying dermatologic and endocrinologic signs and symptoms. We assume that the polyneuropathy, cutaneous hyperpigmentation, edema, hypertrichosis, gynecomastia, and white nails are causally related to each other and are a remote effect of osteosclerotic myeloma. Quantitative histologic analysis of two sural nerves biopsied within 2 years of each other during the course of the disease indicatedthat both large and small myelinated fibers degenerated progressively, with relative preservation of unmyelinated fibers. NEUROLOGY 27: 675-681, July I977
Polyneuropathy, skin hyperpigmentation, edema, and hypertrichosis in localized osteosclerotic myeloma HlROSHl IWASHITA, M.D., AKlO OHNISHI, M.D., MASAHIRO ASADA, M.D., YASUHISA KANAZAWA, M.D., and YOSHIGORO KUROIWA, M.D.
I
n 1938 Scheinker’ reported an autopsy case of solitary osteosclerotic myeloma in a 39-year-old man in the sternum associated with sensorimotor polyneuropathy . The patient had localized patches of thickened and deeply pigmented skin on the anterior chest. In 1956, Crow2 described two cases of osteosclerotic myeloma associated with polyneuropathy and diffuse skin hyperpigmentation. More recently, cases of sensorimotor polyneuropathy , diffuse cutaneous hyperpigmentation, edema, and dysglobulinemia associated with or without myeloma have been increasingly repo~-ted.~-~ However, the pathogenetic mechanism of polyneuropathy and skin and endocrine manifestations in dysglobulinemia and/or myeloma still remains to be solved. In this paper we report a case of localized osteosclerotic myeloma associated with sensorimotor polyneuropathy,
From the Departmentsof Neurobgy (Drs. Iwashita, Asada, Kanazawa, and Kuroiwa) and Neuropathobgy (Dr. Ohnishi), Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka City 812, Japan. Received for publication June 8, 1976. Dr. Iwashita’s address is Department of Neurology, Neurological Institute, Faculty of Medicine, Kyushu University, Fukwka City 812, Japan.
diffuse skin hyperpigmentation, edema, hypertrichosis, gynecomastia, white nails, and hepatomegaly, all of which improved after irradiation of the myeloma site and steroid therapy. Case report. A 61-year-old Japanese man was admitted to the
Department of Neurology, Kyushu University Hospital in August 1973 because of weakness and tingling sensation of upper and lower limbs. In November 1972, he began to have a tingling sensation and numbness in the feet, with occasional edema. The feet later were constantly edematous. In March 1973, weakness of the feet and difficulty in walking up and down stairs appeared. When he was admitted in August 1973, he was diagnosed as having a polyneuropathy of unknown etiology. At that time, there was no abnormal pattern of the serum proteins by electrophoresis, and Bence Jones protein was negative in urine by a routine boiling method. However, an immunoelectrophoretic analysis of serum proteins and an extensive skeletal survey were not done. In January 1974, the face, upper limbs, and back became increasingly darkly pigmented. He began to have tingling and weakness in the hands. The fingers became semiflexed and, in cold weather, became purplish. Weakness in lower limbs was progressively worse, so that he could not walk at the time of the second admission in September 1974. He drank about half a liter of Japanese sake (alcohol 16 to 17 percent) daily for nearly 40 years before neurologic symptoms
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Osteosclerotic myeloma
Figure 1. Right: control. Left: patient. The patient shows diffuse cutaneous hyperpigmentation.
Figure 2. Marked pitting edema on the dorsum of the foot.
Figure 3. Hypertrichosis on the anterior surface of the upper parts of legs and knees.
began. He had no history of exposure to any other neurotoxic agents. He had been impotent for 10 years. No neurologic findings similar to those noted in this patient were present in the family or among his neighbors. On the second admission, his skin showed dark brownish skin pigmentation over his whole body. His mammary areola were black (figure 1). Breasts were slightly swollen with induration (gynecomastia). The skin of his fingers and forearms was thickened, and fingernails and toenails were white. There was marked pitting edema, especially in distal parts of the upper and lower limbs (figure 2). The face skin was somewhat reddish and thickened. Hyperhidrosis was seen on the face, neck, and back, There was an unusual hypertrichosis (rough hair) on upper portion of the legs and knees (figure 3), which had not been present a few years ago. The abdomen was swollen and the liver was palpable four fingerbreadths below the costal margin. The spleen and lymph nodes were not palpable. There were a few dark reddish verrucous eruptions of millet-size to pea-size over the chest, abdomen, and back. Blood pressure was 150 mm Hg systolic and 90 mm Hg diastolic. Neurologically, he was alert and well oriented. Slight venous engorgement a n d arteriosclerosis in the retina, but no papilledema, was seen. The pupils were miotic and not responsive to light, but reacted well to accommodation (Argyll Robertson pupil). Muscle weakness of moderate to severe degree was present in the hands and below the knees, especially in the anterior tibia1 and peroneal muscles. The weak muscles were slightly to moderately atrophic. He could not pick up small objects with his fingers. Deep tendon reflexes in the four limbs were absent with no pathologic
reflexes. Standing was difficult, and he could not walk even with canes. Moderate to severe impaired touch and temperature sensations as well as dysalgesia and delayed pain were found in the hands and below the knees in a glove-stocking fashion. Vibration sensation was totally absent below the neck; so was position sensation in the fingers and toes. There was no abnormality in coordination, and sphincter function was normal. Laboratory data on the second admission (figures in parentheses show normal values) follow: Erythrocyte sedimentation rate was 11 mm in 1 hour, 33 mm in 2 hours. Usually proteinuria was not found. When trace amounts of protein were present no Bence Jones protein by boiling methods with buffer was found. However, an immunoelectrophoretic analysis of 100-fold concentrated urine showed lambda type Bence Jones protein with a clear M-bow formation (figure 4). There was no glucosuria. Serum total protein was 6.0 gm per 100 ml (6.5 to 8.5) and its cellulose-acetate electrophoresis showed albumin 53.3 percent (54.0 to 62.0). a1-globulin 4.2 percent (3.0 to 6.0),az-globulin 10.2 percent (8.0 to 12.0), J-globulin 8.5 percent (8.0 to 12.0) and gamma globulin 23.3 percent (14.0 to 21.0). Immunoglobulin quantitation was IgG 2,120mgper 100ml(1,160to2,080),IgA304mgper100ml (140 to 350), and IgM 250 mg per 100 ml (60 to 380). There was no monoclonal pattern in the gamma globulin region, but a slight polyclonal increase of IgG was seen. Immunoelectrophoresis of serum protein revealed an M-bow-forming precipitating line of Bence Jones protein of lambda type. There was no M-bow formation in IgG, IgA, or IgM precipitating lines. Bone marrow puncture of the sternum
676
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Figure 4. lmmunoelectrophoresis of urine. P: patient, C: control, WHS: whole humanserum. The arrow indicates an M-bow formation. showed 2.4 percent plasma cells (less than 1.9) without other abnormalities. Serum estrogen (estradiol) was 12.5, 17.5, and 50.0 pg per ml (17 to 41) on three occasions. The following laboratory tests were negative or within normal limits: serologic tests for syphilis in serum and cerebrospinal fluid (CSF), numbers of red blood cells, hemoglobin, white blood cells and differential counts, electrocardiogram, serum icterus index, serum electrolytes (potassium, sodium, and chloride), glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, serum phospholipids, glucose tolerance test, anti-streptolysin 0, lupus erythematosus test, antinuclear antibody test, urinary 17-ketosteroids, urinary 17-hydroxysteroids1 basal metabolic rate, and measles and rubella virus antibody titers in serum. Roentgenologic examinations of the whole skeleton revealed a solitary osteosclerotic lesion of the eleventh thoracic vertebral body as shown (figure 5). A biopsy specimen of this sclerotic lesion contained a nest of immature plasma cells (figure 6). On cerebrospinal fluid examination opening pressure was 170 mm HzO with normal dynamics. The fluid contained no cells but its protein content was 167.5 mg per 100 ml (normal 10 to 40). Mastix reaction showed a deep middle curve. Electrophoresis of CSF protein showed prealbumin 2.1 percent (2.8 to 6.0), albumin 57.5 percent (55.9 to 65.3). a I-globulin 5.3 percent (3.5 to 8.3), a 2-globulin 5.9 percent (4.3 to 6.3),J-globulin 10.6 percent (12.1 to 15.1) and gamma globulin 18.6 percent (7.6to9.8).CSFIgGwas29.6mgper100m1(0.4to4.2), IgA2.8 mgper100mI(OSto l.O),andIgM l.Omgper100ml(Oto0.5); on electmmyography denervation of involved muscles was found. Conduction velocity of motor fibers of the left ulnar nerve was
Figure 5. Tomography of the spine. There is a localized osteosclerotic lesion in the eleventh thoracic vertebral body (arrow).
Figure 6. Biopsy of the osteosclerotic lesion in the eleventh thoracic vertebral body. There is a nest of immatureplasma cells (hematoxylin-eosin, x400). 18.0 m/sec, which is a markedly low value. Measurement of conduction velocity of the left tibia1 nerve and sural nerve was not possible because an electrical response could not be obtained. Electroencephalography showed a small amount of diffuse theta-waves without other abnormalities. Biopsy of a verrucous eruption over the abdomen showed a hemangioma.
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Osteosclerotic myeloma Table 1. Numbers* of nerve fibers and denervated Schwann cell clusters in sural nerves
Histologic studies of sural nerves. Method. Fascicular biopsy of the right sural nerve was done at the ankle level at the time of the first admission (August 17, 1973). Two years later, a fascicular biopsy of the left sural nerve was performed at ankle level (April 14, 1975). The sural nerves were fixed for 2 hours with 4 percent glutaraldehyde in 0.1 M cacodylate buffer (pH 7.38). The tissue was washed in the same buffer, postfixed in 1 percent osmium tetroxide in the same buffer for 2 hours, dehydrated, and embedded in epoxy. Photographic enlargement ( X 1,000) of transverse sections of sural nerves were used to measure the number of myelinated fibers per square millimeter of fascicular area and the frequency distribution of the diameters of myelinated fibers.I0 The number of myelinated fibers was divided into large (diameter > 5 pm) and small (diameter S 5 p m ) myelinated fibers (table 1). These values were obtained in this case and six controls between the ages of 26 and 68 years. The numbers of unmyelinated fibers and of clusters of Schwann cells or their processes without any unmyelinated fibers (denervated Schwann cell clusters) per square millimeter of fascicular area and the frequency distribution of the diameters of
fibers was markedly decreased compared with the number of fibers in controls and in the nerve of the first biopsy. The number of unmyelinated fibers per square millimeter of fascicular area was within the range of control values, probably due to the occurrence of sprouted axons. The frequency distribution of the diameters of unmyelinated fibers was similar to that of controls. The number of denervated Schwann cell clusters per square millimeterof fasciculararea was similarto that ofthe first biopsy specimen. Light microscopic observation of transverse sections of sural nerves on both first and second biopsy showed the occasional presence of myelin ovoids. No onion bulb formation was found. Electron microscopic observation confirmed the presence of 678
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150q L
4
t E u loo0 .0
d
5
10
15
MyeliMted Fiber Diameters (urn) Figure 7.Frequencydistribution of diameters of myelinated fibers of healthy sural nerves (top) and of the sural nerve on the first biopsy (middle) and on the second biopsy (bottom). Note the moderate decrease of both large and small myelinated fibers on the first biopsy, and the almost total loss of myelinated fibers of the sural nerve on the second biopsy.
gynecomastia, and cutaneous hyperpigmentation improved. Liver swelling decreased, and the hair on the legs and knees became softer. Edema also decreased. Foot drop, however, remained without improvement. Prednisolone dosage was gradually decreased to 25 mg every other day. The roentgenologic finding of the eleventh thoracic vertebral body remained unchanged. Bence Jones protein of the lambda type was still present in urine by immunoelectrophoresis. He is followed monthly at the Out Patient Department, Kyushu University Hospital. He continues to take 20 to 25 mg of prednisolone every other day. As of April 1976, he still shows the above-mentioned improved medical and neurologic findings.
Figure 8. Schwann cell cytoplasm containing myelin figures and membranous bodies, indicating the previous degeneration of myelinated fibers ( x 10,500). myelin ovoids in the cytoplasm of Schwann cells (figure 8). No amyloid deposit was found on light and electron microscopy. Treatment and clinical course during and after the second admission. Sixty mg of prednisolone was administered orally every other day for 2 weeks without noticeable decrease of edema and skin hyperpigmentation. There was no change in muscle weakness of the upper and lower limbs. After irradiation using a total dosage of 3,000 rad of cobalt to the eleventh thoracic vertebral body (myeloma site) for 17 days with continued prednisolone therapy, his grasping power increased and he became able to pick up small objects with fingers and walk with canes by himself. The thickened skin, white nails,
Discussion. We have accounts of 59 cases (including the present case) of osteosclerotic myeloma (table 2) in the literature. Myeloma cases without clear description of osteosclerotic lesion were excluded. Thirty cases (50.8 percent)ly29l were associated with polyneuropathy and 29 cases (49.2 percent)3w9 were not. An unusually high association of polyneuropathy and osteosclerotic 2 3 ~ 2 6 (53.3 ~50 myeloma has been n o t e d . 6 ~ 7 ~ 1 2 ~ 1 3 ~Sixteen percent) of 30 cases with polyneuropathy had “solitary” osteosclerotic lesion. Thirteen (81.3 percent) of these 16 were males. Most cases without polyneuropathy had multiple osteosclerotic lesions. Mean age (48.8 years) of cases with polyneuropathy is younger than that (57.7 years) of those without polyneuropathy. There is a clear male preponderance in cases with polyneuropathy (especially “solitary” osteosclerotic myeloma), while women seem to be more often affected than men in cases without polyneuropathy. Table 3 shows the frequency of occurrence of skin hyperpigmentation, edema, and other signs in
Table 2. Clinical analysis of cases of osteosclerotic myeloma
Table 3. The frequency of skin hyperpigmentation, edema, and some other signs in osteosclerotic myeloma
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Osteosclerotic myeloma
osteosclerotic myeloma with and without polyneuropathy. These signs have been described in 13.3 to 36.7 percent of cases with polyneuropathy, while they have not been observed in cases without polyneuropathy except for hepatomegaly (17.2 percent) and edema (one case). This may indicate that skin hyperpigmentation and other signs are more closely related to cases with polyneuropathy than to cases without polyneuropathy. Because we find a high frequency of Japanese patients with osteosclerotic myeloma with polyneuropathy, skin hyperpigmentation, edema, and other signs, frequency of Japanese patients for each sign are also included in the table. Reported cases with hypertrichosis and gynecomastia are all Japanese. Non-Japanese cases of osteosclerotic myeloma associated with polyneuropathy and skin hyperpigmentation were reported only by Scheinkerl from Austria and Crow2 from England. Gupta and PrabhakerS1from India reported gynecomastia and clubbed fingers in a c a s e with m y e l o m a and polyneuropathy. However, because it is not clear whether the myeloma in this case was osteosclerotic or not, it was not included in the above series. Whether the frequent occurrence of skin hyperpigmentation and of other signs in Japanese cases with osteosclerotic myeloma and polyneuropathy is due to a racial factor or some other environmental (exogenic) factor(s) needs further study. However, because of the reports of Scheinkerl and Crow,2 it is known that the syndrome also occurs in races other than the Japanese. From J a p a n c a s e s o f p o l y n e u r o p a t h y , s k i n hyperpigmentation, edema, hypertrichosis, and dysglobulinemia in which myeloma (osteosclerotic or osteolytic) was not found hematologically, roentgenologically, and pathologically also have been we- reported the first such case r e p ~ r t e d . ~ In - ~1971 ~~~ ~~ with autopsy finding^.^ Recently Trentham, Masi, and Markers reported a 44-year-old black woman with polyneuropathy, papilledema, anasarca, lymph node swelling, hepatosplenomegaly, amenorrhea, and polyclonal gammopathy. The patient had no evidence of myeloma. They suggested that ‘‘vasculopathic process” accounted for the multiplicity of t h e clinical manifestation. Although there is, as was discussed e l ~ e w h e r eno , ~ clear difference in clinical manifestations between myeloma and nonmyeloma cases presenting with polyneuropathy, skin hyperpigmentation, and edema, it would be appropriate at present to classify the cases of polyneuropathy,skin hyperpigmentation, and edema into two groups from an etiologic point of view: (1) myeloma cases and (2) nonmyeloma cases. The etiology of the association of pigmentation, edema, and other signs seen in the present case of osteosclerotic myeloma with polyneuropathy is not known. There is no evidence that protein abnormality (in the present case Bence Jones protein of lambda type) plays an essential role in causing these signs. We found no evidence of amyloid deposition. Fukase and co-workers3 reported a case of solitary plasmacytoma in the abdomen presenting with polyneuropathy,skin hyperpigmentation, and edema in which a surgical removal of the tumor 680
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brought a remarkable improvement in weakness of the limbs, skin hyperpigmentation, and edema. Shimomori and Kusumoto5’ and Nishitani and associatesss reported similar cases. Davis and Drachman have reported effectiveness of irradiation for polyneuropathy in solitary rnye10ma.l~ Oda and associatess reported that in a case of polyneuropathy, skin hyperpigmentation, and edema, cobalt irradiation of an osteosclerotic lesion in the fourth thoracic vertebral body brought a remarkable improvement in symptoms and signs. Because steroid was used at the same time in our case, there is no definite evidence that cobalt irradiation of the site of localized osteosclerotic myeloma brought about the improvement in symptoms and signs. However, from the daily clinical observation that the improvement of symptoms and signs of our case became apparent after cobalt irradiation, we believe radiotherapy did result in improvement. The above literature and our experience may support the hypothesis that not only polyneuropathy but also skin hyperpigmentation, edema, hepatomegaly, hypertrichosis, while nails, and gynecomastia are caused by so-called “remote effect’’ of osteosclerotic myeloma. The results of the quantitative histologic analysis of the sural nerves biopsied demonstrated that myelinated fibers degenerated relentlessly between the time of the first and second biopsy. These quantitative histologic data are similar to those reported by Walsh60 in cases of multiple myeloma with polyneuropathy. REFERENCES 1. Scheinker I: Myelom und Nervensystem: Uber eine bisher nicht
beschriebene mit eingentumlichenHautveranderungeneinhergehende Polyneuritis bei einem plasmazellulBren Myelom des Sternums. 2 Neurol 147247-273, 1938 2. Crow RS: Peripheral neuritis in myelomatosis. Br Med J 2:802-804, 1956 3. Fukase M, Kakimatsu T, Nishitani H, et al: Report of a case of solitary plasmacytoma in the abdomen presenting polyneuropathy and endocrinological disorders. (Abstr) Clin Neurol (Tokyo) 9:657, 1969 4. lwashita H, lnoue N, Nagamatsu K: Polyneuropathy, pigmentation, diabetes mellitus and monoclonal gammopathy: Report of an autopsy case. Clin Neurol (Tokyo) 1 1 :492-499, 1971 5. lmawari M, Akatsuka N, lshibashi M, et al: Syndrome of plasma cell dyscrasia, polyneuropathy and endocrine disturbances: Report of a case. Ann Intern Med 81:490-493, 1974 6. Nishitani H, Noguchi S, Fukase M: Immunoglobulin and neuropathy: Myelomatous polyneuropathy associated with pigmentation. Neurol Med (Tokyo) 2:325-337, 1975 7. lwashita H: Polyneuropathy associated with dermatoendocrinological changes and dysglobulinemia. Adv Neurol Sci (Tokyo) 20:709-726, 1976 8. Trentham DE, Masi AT, Marker HW: Polyneuropathy and anasarca: Evidence for a new connective tissue syndrome and vasculopathic contribution. Ann Intern Med 84:271-274, 1976 9. Dyck PJ, Gutrecht JA, Bastron JA, et al: Histologic and teased-fiber measurements of sural nerve in disorders of lower motor and primary sensory neurons. Mayo Clin Proc 43:81-123, 1968 10. Ohnishi A, Dyck PJ: Loss of small peripheral sensory neurons in Fabry disease: Histologic and morphometric evaluation of cutaneous nerves, spinal ganglia and posterior column. Arch Neurol 31:120127, 1974 11. Victor M, Banker BQ, Adams RD. The neuropathyof multiple myeloma. J Neurol Neurosurg Pyschiatry 21:73-68, 1958 12. Morley JB, Schwieger AC: The relation between chronic polyneuropathy and osteosclerotic myeloma. J Neurol Neurosurg Psychiatry 30:432-442, 1987 13. Davis LE, DrachmanDB: Myebmaneuropathy. Successfultreatment of two cases and review of cases. Arch Neurol27:507-511,1972 14. Waldenstram J: Diagnosis and treatment of multiple myeloma. New York, Grune & Stratton, 1970, p 58
15. Odelberg-Johnson0:Osteosclerotic changes in myelomatosis: Report of a case. Acta Radiol 52:139-144, 1959 16.Small JM, Moxon CP, Woolf AL: Report on a clinicopathological conference. Birmingham Med Rev 20546-552,1961 17.Aguayo A, Thompson DW, Humphry JB: Multiple myeloma with polyneuropathy and osteosclerotic lesion. J Neurol Neurosurg Psychiatry 27:562-566, 1964 18.Rushton DI: Peripheral sensorimotor neuropathy associated with a localized myeloma. Br Med J 2:203-205,1965 19. Mayo CM, Daniels A, Barron KD: Polyneuropathy in the osteosclerotic form of multiple myeloma. Trans Am Neurol Assoc 93:240-242, 1968 20.Lowbeer L Multiple myeloma with osteosclerosis. Am J Clin Pathol 52:757,1969 21.Osuntokun BO, Akinjughe FM, McFarlane H: Multiple myeloma: Osteosclerosis and neuromyopathy. West Afr Med J April:43-46, 1969 22.Taleman A, Bateson EM: Multiple myeloma associated with bone sclerosis and peripheral neuropathy. Br J Radiol 43:698700,1970 23. Mangalik A, Veliath AJ: Osteosclerotic myeloma and peripheral 1971 neuropathy: A case report. Cancer 28:1040-1045, 24.Courey RW: Osteosclerotic lesions of unusual nature. JAMA 21237-378,1972 25.Case records of the Massachusetts General Hospital: Osteoblastic myelomawith peripheralneuropathy. N Engl J Med 267:138-143,1972 26.Getaz P, Handler L, Jacobs P, et al: Osteosclerotic myeloma with peripheral neuropathy. South Afr Med J 151246-1250, 1974 27.Yodoi J, Takatsuki K, Wakisaka K: Association of plasmacytoma, polyneuropathy, pigmentation and gynecomastia. (Abstr) Acta Haematol Jap 36363,1973 28.Yodoi J, Takatsuki K, Wakisaka K, et al: Plasma cell dyscrasia with polyneuropathy and high serum estrogen level: Report of a case with severe skin changes over the osteosclerotic lesion. (Abstr) J Jap Soc Intern Med 64:187,1975 29.Shimizu T, Fujimura K, Taketomi Y, et al: A case of plasma cell dyscrasia with polyneuritisand endocrine disorders. (Abstr) Clin Neurol (Tokyo) 15:398,1975 30.Rypins E L An unusual roentgenologic finding in multiple myeloma. Am J Roengenol30:56-58, 1933 31. Bailey CO: Plasma cell myeloma of humerus treated by roentgen radiation. Report of a case followed seven years. Am J Roentgenol 36:980.962,1936 32.Krainin P, Dangio CJ, Smellin A: Multiple myeloma with new bone formation. Arch Intern Med 84:976-982,1949 33. Kohler LM, Laur A Osteosklerose bei Plasmazytom: Bericht Ober einen Fall. Fortschr R(lntgenstr 72:714-717,1950 34.Galgano AR: Unusual features of multiple myeloma. Am J Roentgenol 74304-314,1955 35.Videbaek A: Unusual cases of osteomyelosclerosis. Acta Med Scand 153:459-465, 1956 36. H o d l e r J : U b e r d a s V o r k o m m e n o s t e o p l a s t i s c h e r Knochenverllnderungenbei der KLlhlerschen Krankheit. Schweiz Med Wochenschr 42:1085-1067,1956 37.Lewin H, Stein JM: Solitary plasma cell myeloma with new bone formation. Am J Roentgenol 79:WO-637,1958 38. Engels EP, Smith RC, Krants S: Bone sclerosis in multiple myeloma. Radiology 75:242-247,1960 39.Porter EC: Osteogenesis in multiple myeloma: Report of a case.
Radiology 76:457-458,1961 40.Tuboku-Metzger A F Case reports: Plasmacytoma with unusual radiological findings in the bones. Br J Radiol 34529-530,1961 41.Fairley HG, Oxon DM, Jackson DC, et al: Case reports:Osteosclerosis 1964 in myebmatosis. Br J Radiol 37:852-855, 42.Langley OR, Sabean HB: Sclerotic lesions of bone in myeloma. Can Med Assoc J 94:940-946,1966 43.Degnan TJ, Feinberg A, Basset E: Osteosclerosis and plasma cell leukemia. JAMA 201 :780-781,1967 44. Evison G, Evans KT: Bone sclerosis in multiple myebma. Br J Radiol 40:81-89,1967 45. Myers RW, Nichols R L Osteosclerosis in multiple myeloma. J Tenn Med Assoc 63755757,1970 46.Clarisse PDT, Staple Tw. Diffuse bone sclerosis in multiple myeloma. Radiology 99:327-328,1971 47.Brown TS, Paterson CR: Osteosclerosis in myeloma. J Bone Surg 55:621-623.1973 48. Roberts M, Rinaudo PA, Vilinskas J, et al: Solitary sclerosing plasma-cell myebma of the spine. J Neurosurg 40:125-129,1974 49.Sultan C, Varet B, Gouault M, et al: Mydlome et osttlocondensation (Discussion anatomo-clinique). Nouv Rev Franc Hemat 9:435-446, 1969 50. Mcleod JG, Walsh JC: Neuropathies associatedwith paraproteinemias
and dysproteinemias. In Dyck PJ. Thomas PK, Lambert ED (Editors): Peripheral Neuropathy. Philadelphia, London, Toronto, WB Saunders Company, 1975,voI2, pp 1012-1029 51. Gupta SP, Prabhaker BR: Peripheralneuropathyand solitary myeloma. Br Med J 2:1004.1965 52.Baba S,Kobayashi T. Hasegawa K, et al: Three cases of obscure diagnosis with main symptoms of generalized lymphadenopathy,skin pigmentation, paresthesia. and muscular atrophy of lower limbs and papilledema. lgaku No Ayumi 87431-432,1973 53.Shimizu T Myeloma and nervous system. Naika 34:18&193, 1974 54.Akihama T, Miura A, Shibata A: A case of plasma cell dyscrasia associated with polyneuropathy and hormonal disturbance. Clin Haematol (Tokyo) 16:744756,1975 55. NagashimaT, Yamane I,KamizumaK, et al: A case of 31-year-oldman with skin pigmentation, hypertrichosis, gynecomastia, papilledema, Guillain-Barr6 type polyneuritis and generalized lymphadenopathy. J Jap Soc lntem Med 64:615616,1975 56.Saikawa S,Nagamatsu K, lgata A: Polyneuropathy with monoclonal gammopathy, papilledema, skin pigmentation and diabetes mellitus. Neurol Med (Tokyo) 2384-386,1975 57.Shimomori T, Kusumoto M: A case of solitary plasmacytoma with polyneuropathy, pigmentation and gynecomastia. (Abstr) J Jap SOC lntem Med 59:1016,1970 58.Nishitani H, Konishi T, Noguchi S, et al: Malignant tumors and nervous system with special reference to peripheralnerves and muscles. Naika
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1971
Erratum: A word substitution was inadvertently made in the abstract “Fasting-associated fatal rhabdomyolysis (familial),” W.K. Engel and R.T. Shebert (NEUROLOGY 27:347-348, 1977). The original sentence read: “EMG 2 mo after an episode showed a BSAP pattern with some fibrillations.”
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Polyneuropathy, skin hyperpigmentation, edema, and hypertrichosis in localized osteosclerotic myeloma HlROSHl IWASHITA, AKlO OHNISHI, MASAHIRO ASADA, et al. Neurology 1977;27;675 DOI 10.1212/WNL.27.7.675 This information is current as of July 1, 1977 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1977 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
A 61-year-old man had osteosclerotic myeloma that was localized in the eleventh thoracic vertebral body and associated with sensorimotor polyneuropathy, skin hyperpigmentation, edema, hypertrichosis, gynecomastia, and white nails. Cases of osteosclerotic myeloma with and without polyneuropathy in the literature were reviewed with special reference to accompanying dermatologic and endocrinologic signs and symptoms. We assume that the polyneuropathy, cutaneous hyperpigmentation, edema, hypertrichosis, gynecomastia, and white nails are causally related to each other and are a remote effect of osteosclerotic myeloma. Quantitative histologic analysis of two sural nerves biopsied within 2 years of each other during the course of the disease indicatedthat both large and small myelinated fibers degenerated progressively, with relative preservation of unmyelinated fibers. NEUROLOGY 27: 675-681, July I977
Polyneuropathy, skin hyperpigmentation, edema, and hypertrichosis in localized osteosclerotic myeloma HlROSHl IWASHITA, M.D., AKlO OHNISHI, M.D., MASAHIRO ASADA, M.D., YASUHISA KANAZAWA, M.D., and YOSHIGORO KUROIWA, M.D.
I
n 1938 Scheinker’ reported an autopsy case of solitary osteosclerotic myeloma in a 39-year-old man in the sternum associated with sensorimotor polyneuropathy . The patient had localized patches of thickened and deeply pigmented skin on the anterior chest. In 1956, Crow2 described two cases of osteosclerotic myeloma associated with polyneuropathy and diffuse skin hyperpigmentation. More recently, cases of sensorimotor polyneuropathy , diffuse cutaneous hyperpigmentation, edema, and dysglobulinemia associated with or without myeloma have been increasingly repo~-ted.~-~ However, the pathogenetic mechanism of polyneuropathy and skin and endocrine manifestations in dysglobulinemia and/or myeloma still remains to be solved. In this paper we report a case of localized osteosclerotic myeloma associated with sensorimotor polyneuropathy,
From the Departmentsof Neurobgy (Drs. Iwashita, Asada, Kanazawa, and Kuroiwa) and Neuropathobgy (Dr. Ohnishi), Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka City 812, Japan. Received for publication June 8, 1976. Dr. Iwashita’s address is Department of Neurology, Neurological Institute, Faculty of Medicine, Kyushu University, Fukwka City 812, Japan.
diffuse skin hyperpigmentation, edema, hypertrichosis, gynecomastia, white nails, and hepatomegaly, all of which improved after irradiation of the myeloma site and steroid therapy. Case report. A 61-year-old Japanese man was admitted to the
Department of Neurology, Kyushu University Hospital in August 1973 because of weakness and tingling sensation of upper and lower limbs. In November 1972, he began to have a tingling sensation and numbness in the feet, with occasional edema. The feet later were constantly edematous. In March 1973, weakness of the feet and difficulty in walking up and down stairs appeared. When he was admitted in August 1973, he was diagnosed as having a polyneuropathy of unknown etiology. At that time, there was no abnormal pattern of the serum proteins by electrophoresis, and Bence Jones protein was negative in urine by a routine boiling method. However, an immunoelectrophoretic analysis of serum proteins and an extensive skeletal survey were not done. In January 1974, the face, upper limbs, and back became increasingly darkly pigmented. He began to have tingling and weakness in the hands. The fingers became semiflexed and, in cold weather, became purplish. Weakness in lower limbs was progressively worse, so that he could not walk at the time of the second admission in September 1974. He drank about half a liter of Japanese sake (alcohol 16 to 17 percent) daily for nearly 40 years before neurologic symptoms
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Osteosclerotic myeloma
Figure 1. Right: control. Left: patient. The patient shows diffuse cutaneous hyperpigmentation.
Figure 2. Marked pitting edema on the dorsum of the foot.
Figure 3. Hypertrichosis on the anterior surface of the upper parts of legs and knees.
began. He had no history of exposure to any other neurotoxic agents. He had been impotent for 10 years. No neurologic findings similar to those noted in this patient were present in the family or among his neighbors. On the second admission, his skin showed dark brownish skin pigmentation over his whole body. His mammary areola were black (figure 1). Breasts were slightly swollen with induration (gynecomastia). The skin of his fingers and forearms was thickened, and fingernails and toenails were white. There was marked pitting edema, especially in distal parts of the upper and lower limbs (figure 2). The face skin was somewhat reddish and thickened. Hyperhidrosis was seen on the face, neck, and back, There was an unusual hypertrichosis (rough hair) on upper portion of the legs and knees (figure 3), which had not been present a few years ago. The abdomen was swollen and the liver was palpable four fingerbreadths below the costal margin. The spleen and lymph nodes were not palpable. There were a few dark reddish verrucous eruptions of millet-size to pea-size over the chest, abdomen, and back. Blood pressure was 150 mm Hg systolic and 90 mm Hg diastolic. Neurologically, he was alert and well oriented. Slight venous engorgement a n d arteriosclerosis in the retina, but no papilledema, was seen. The pupils were miotic and not responsive to light, but reacted well to accommodation (Argyll Robertson pupil). Muscle weakness of moderate to severe degree was present in the hands and below the knees, especially in the anterior tibia1 and peroneal muscles. The weak muscles were slightly to moderately atrophic. He could not pick up small objects with his fingers. Deep tendon reflexes in the four limbs were absent with no pathologic
reflexes. Standing was difficult, and he could not walk even with canes. Moderate to severe impaired touch and temperature sensations as well as dysalgesia and delayed pain were found in the hands and below the knees in a glove-stocking fashion. Vibration sensation was totally absent below the neck; so was position sensation in the fingers and toes. There was no abnormality in coordination, and sphincter function was normal. Laboratory data on the second admission (figures in parentheses show normal values) follow: Erythrocyte sedimentation rate was 11 mm in 1 hour, 33 mm in 2 hours. Usually proteinuria was not found. When trace amounts of protein were present no Bence Jones protein by boiling methods with buffer was found. However, an immunoelectrophoretic analysis of 100-fold concentrated urine showed lambda type Bence Jones protein with a clear M-bow formation (figure 4). There was no glucosuria. Serum total protein was 6.0 gm per 100 ml (6.5 to 8.5) and its cellulose-acetate electrophoresis showed albumin 53.3 percent (54.0 to 62.0). a1-globulin 4.2 percent (3.0 to 6.0),az-globulin 10.2 percent (8.0 to 12.0), J-globulin 8.5 percent (8.0 to 12.0) and gamma globulin 23.3 percent (14.0 to 21.0). Immunoglobulin quantitation was IgG 2,120mgper 100ml(1,160to2,080),IgA304mgper100ml (140 to 350), and IgM 250 mg per 100 ml (60 to 380). There was no monoclonal pattern in the gamma globulin region, but a slight polyclonal increase of IgG was seen. Immunoelectrophoresis of serum protein revealed an M-bow-forming precipitating line of Bence Jones protein of lambda type. There was no M-bow formation in IgG, IgA, or IgM precipitating lines. Bone marrow puncture of the sternum
676
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Figure 4. lmmunoelectrophoresis of urine. P: patient, C: control, WHS: whole humanserum. The arrow indicates an M-bow formation. showed 2.4 percent plasma cells (less than 1.9) without other abnormalities. Serum estrogen (estradiol) was 12.5, 17.5, and 50.0 pg per ml (17 to 41) on three occasions. The following laboratory tests were negative or within normal limits: serologic tests for syphilis in serum and cerebrospinal fluid (CSF), numbers of red blood cells, hemoglobin, white blood cells and differential counts, electrocardiogram, serum icterus index, serum electrolytes (potassium, sodium, and chloride), glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, serum phospholipids, glucose tolerance test, anti-streptolysin 0, lupus erythematosus test, antinuclear antibody test, urinary 17-ketosteroids, urinary 17-hydroxysteroids1 basal metabolic rate, and measles and rubella virus antibody titers in serum. Roentgenologic examinations of the whole skeleton revealed a solitary osteosclerotic lesion of the eleventh thoracic vertebral body as shown (figure 5). A biopsy specimen of this sclerotic lesion contained a nest of immature plasma cells (figure 6). On cerebrospinal fluid examination opening pressure was 170 mm HzO with normal dynamics. The fluid contained no cells but its protein content was 167.5 mg per 100 ml (normal 10 to 40). Mastix reaction showed a deep middle curve. Electrophoresis of CSF protein showed prealbumin 2.1 percent (2.8 to 6.0), albumin 57.5 percent (55.9 to 65.3). a I-globulin 5.3 percent (3.5 to 8.3), a 2-globulin 5.9 percent (4.3 to 6.3),J-globulin 10.6 percent (12.1 to 15.1) and gamma globulin 18.6 percent (7.6to9.8).CSFIgGwas29.6mgper100m1(0.4to4.2), IgA2.8 mgper100mI(OSto l.O),andIgM l.Omgper100ml(Oto0.5); on electmmyography denervation of involved muscles was found. Conduction velocity of motor fibers of the left ulnar nerve was
Figure 5. Tomography of the spine. There is a localized osteosclerotic lesion in the eleventh thoracic vertebral body (arrow).
Figure 6. Biopsy of the osteosclerotic lesion in the eleventh thoracic vertebral body. There is a nest of immatureplasma cells (hematoxylin-eosin, x400). 18.0 m/sec, which is a markedly low value. Measurement of conduction velocity of the left tibia1 nerve and sural nerve was not possible because an electrical response could not be obtained. Electroencephalography showed a small amount of diffuse theta-waves without other abnormalities. Biopsy of a verrucous eruption over the abdomen showed a hemangioma.
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Osteosclerotic myeloma Table 1. Numbers* of nerve fibers and denervated Schwann cell clusters in sural nerves
Histologic studies of sural nerves. Method. Fascicular biopsy of the right sural nerve was done at the ankle level at the time of the first admission (August 17, 1973). Two years later, a fascicular biopsy of the left sural nerve was performed at ankle level (April 14, 1975). The sural nerves were fixed for 2 hours with 4 percent glutaraldehyde in 0.1 M cacodylate buffer (pH 7.38). The tissue was washed in the same buffer, postfixed in 1 percent osmium tetroxide in the same buffer for 2 hours, dehydrated, and embedded in epoxy. Photographic enlargement ( X 1,000) of transverse sections of sural nerves were used to measure the number of myelinated fibers per square millimeter of fascicular area and the frequency distribution of the diameters of myelinated fibers.I0 The number of myelinated fibers was divided into large (diameter > 5 pm) and small (diameter S 5 p m ) myelinated fibers (table 1). These values were obtained in this case and six controls between the ages of 26 and 68 years. The numbers of unmyelinated fibers and of clusters of Schwann cells or their processes without any unmyelinated fibers (denervated Schwann cell clusters) per square millimeter of fascicular area and the frequency distribution of the diameters of
fibers was markedly decreased compared with the number of fibers in controls and in the nerve of the first biopsy. The number of unmyelinated fibers per square millimeter of fascicular area was within the range of control values, probably due to the occurrence of sprouted axons. The frequency distribution of the diameters of unmyelinated fibers was similar to that of controls. The number of denervated Schwann cell clusters per square millimeterof fasciculararea was similarto that ofthe first biopsy specimen. Light microscopic observation of transverse sections of sural nerves on both first and second biopsy showed the occasional presence of myelin ovoids. No onion bulb formation was found. Electron microscopic observation confirmed the presence of 678
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150q L
4
t E u loo0 .0
d
5
10
15
MyeliMted Fiber Diameters (urn) Figure 7.Frequencydistribution of diameters of myelinated fibers of healthy sural nerves (top) and of the sural nerve on the first biopsy (middle) and on the second biopsy (bottom). Note the moderate decrease of both large and small myelinated fibers on the first biopsy, and the almost total loss of myelinated fibers of the sural nerve on the second biopsy.
gynecomastia, and cutaneous hyperpigmentation improved. Liver swelling decreased, and the hair on the legs and knees became softer. Edema also decreased. Foot drop, however, remained without improvement. Prednisolone dosage was gradually decreased to 25 mg every other day. The roentgenologic finding of the eleventh thoracic vertebral body remained unchanged. Bence Jones protein of the lambda type was still present in urine by immunoelectrophoresis. He is followed monthly at the Out Patient Department, Kyushu University Hospital. He continues to take 20 to 25 mg of prednisolone every other day. As of April 1976, he still shows the above-mentioned improved medical and neurologic findings.
Figure 8. Schwann cell cytoplasm containing myelin figures and membranous bodies, indicating the previous degeneration of myelinated fibers ( x 10,500). myelin ovoids in the cytoplasm of Schwann cells (figure 8). No amyloid deposit was found on light and electron microscopy. Treatment and clinical course during and after the second admission. Sixty mg of prednisolone was administered orally every other day for 2 weeks without noticeable decrease of edema and skin hyperpigmentation. There was no change in muscle weakness of the upper and lower limbs. After irradiation using a total dosage of 3,000 rad of cobalt to the eleventh thoracic vertebral body (myeloma site) for 17 days with continued prednisolone therapy, his grasping power increased and he became able to pick up small objects with fingers and walk with canes by himself. The thickened skin, white nails,
Discussion. We have accounts of 59 cases (including the present case) of osteosclerotic myeloma (table 2) in the literature. Myeloma cases without clear description of osteosclerotic lesion were excluded. Thirty cases (50.8 percent)ly29l were associated with polyneuropathy and 29 cases (49.2 percent)3w9 were not. An unusually high association of polyneuropathy and osteosclerotic 2 3 ~ 2 6 (53.3 ~50 myeloma has been n o t e d . 6 ~ 7 ~ 1 2 ~ 1 3 ~Sixteen percent) of 30 cases with polyneuropathy had “solitary” osteosclerotic lesion. Thirteen (81.3 percent) of these 16 were males. Most cases without polyneuropathy had multiple osteosclerotic lesions. Mean age (48.8 years) of cases with polyneuropathy is younger than that (57.7 years) of those without polyneuropathy. There is a clear male preponderance in cases with polyneuropathy (especially “solitary” osteosclerotic myeloma), while women seem to be more often affected than men in cases without polyneuropathy. Table 3 shows the frequency of occurrence of skin hyperpigmentation, edema, and other signs in
Table 2. Clinical analysis of cases of osteosclerotic myeloma
Table 3. The frequency of skin hyperpigmentation, edema, and some other signs in osteosclerotic myeloma
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osteosclerotic myeloma with and without polyneuropathy. These signs have been described in 13.3 to 36.7 percent of cases with polyneuropathy, while they have not been observed in cases without polyneuropathy except for hepatomegaly (17.2 percent) and edema (one case). This may indicate that skin hyperpigmentation and other signs are more closely related to cases with polyneuropathy than to cases without polyneuropathy. Because we find a high frequency of Japanese patients with osteosclerotic myeloma with polyneuropathy, skin hyperpigmentation, edema, and other signs, frequency of Japanese patients for each sign are also included in the table. Reported cases with hypertrichosis and gynecomastia are all Japanese. Non-Japanese cases of osteosclerotic myeloma associated with polyneuropathy and skin hyperpigmentation were reported only by Scheinkerl from Austria and Crow2 from England. Gupta and PrabhakerS1from India reported gynecomastia and clubbed fingers in a c a s e with m y e l o m a and polyneuropathy. However, because it is not clear whether the myeloma in this case was osteosclerotic or not, it was not included in the above series. Whether the frequent occurrence of skin hyperpigmentation and of other signs in Japanese cases with osteosclerotic myeloma and polyneuropathy is due to a racial factor or some other environmental (exogenic) factor(s) needs further study. However, because of the reports of Scheinkerl and Crow,2 it is known that the syndrome also occurs in races other than the Japanese. From J a p a n c a s e s o f p o l y n e u r o p a t h y , s k i n hyperpigmentation, edema, hypertrichosis, and dysglobulinemia in which myeloma (osteosclerotic or osteolytic) was not found hematologically, roentgenologically, and pathologically also have been we- reported the first such case r e p ~ r t e d . ~ In - ~1971 ~~~ ~~ with autopsy finding^.^ Recently Trentham, Masi, and Markers reported a 44-year-old black woman with polyneuropathy, papilledema, anasarca, lymph node swelling, hepatosplenomegaly, amenorrhea, and polyclonal gammopathy. The patient had no evidence of myeloma. They suggested that ‘‘vasculopathic process” accounted for the multiplicity of t h e clinical manifestation. Although there is, as was discussed e l ~ e w h e r eno , ~ clear difference in clinical manifestations between myeloma and nonmyeloma cases presenting with polyneuropathy, skin hyperpigmentation, and edema, it would be appropriate at present to classify the cases of polyneuropathy,skin hyperpigmentation, and edema into two groups from an etiologic point of view: (1) myeloma cases and (2) nonmyeloma cases. The etiology of the association of pigmentation, edema, and other signs seen in the present case of osteosclerotic myeloma with polyneuropathy is not known. There is no evidence that protein abnormality (in the present case Bence Jones protein of lambda type) plays an essential role in causing these signs. We found no evidence of amyloid deposition. Fukase and co-workers3 reported a case of solitary plasmacytoma in the abdomen presenting with polyneuropathy,skin hyperpigmentation, and edema in which a surgical removal of the tumor 680
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brought a remarkable improvement in weakness of the limbs, skin hyperpigmentation, and edema. Shimomori and Kusumoto5’ and Nishitani and associatesss reported similar cases. Davis and Drachman have reported effectiveness of irradiation for polyneuropathy in solitary rnye10ma.l~ Oda and associatess reported that in a case of polyneuropathy, skin hyperpigmentation, and edema, cobalt irradiation of an osteosclerotic lesion in the fourth thoracic vertebral body brought a remarkable improvement in symptoms and signs. Because steroid was used at the same time in our case, there is no definite evidence that cobalt irradiation of the site of localized osteosclerotic myeloma brought about the improvement in symptoms and signs. However, from the daily clinical observation that the improvement of symptoms and signs of our case became apparent after cobalt irradiation, we believe radiotherapy did result in improvement. The above literature and our experience may support the hypothesis that not only polyneuropathy but also skin hyperpigmentation, edema, hepatomegaly, hypertrichosis, while nails, and gynecomastia are caused by so-called “remote effect’’ of osteosclerotic myeloma. The results of the quantitative histologic analysis of the sural nerves biopsied demonstrated that myelinated fibers degenerated relentlessly between the time of the first and second biopsy. These quantitative histologic data are similar to those reported by Walsh60 in cases of multiple myeloma with polyneuropathy. REFERENCES 1. Scheinker I: Myelom und Nervensystem: Uber eine bisher nicht
beschriebene mit eingentumlichenHautveranderungeneinhergehende Polyneuritis bei einem plasmazellulBren Myelom des Sternums. 2 Neurol 147247-273, 1938 2. Crow RS: Peripheral neuritis in myelomatosis. Br Med J 2:802-804, 1956 3. Fukase M, Kakimatsu T, Nishitani H, et al: Report of a case of solitary plasmacytoma in the abdomen presenting polyneuropathy and endocrinological disorders. (Abstr) Clin Neurol (Tokyo) 9:657, 1969 4. lwashita H, lnoue N, Nagamatsu K: Polyneuropathy, pigmentation, diabetes mellitus and monoclonal gammopathy: Report of an autopsy case. Clin Neurol (Tokyo) 1 1 :492-499, 1971 5. lmawari M, Akatsuka N, lshibashi M, et al: Syndrome of plasma cell dyscrasia, polyneuropathy and endocrine disturbances: Report of a case. Ann Intern Med 81:490-493, 1974 6. Nishitani H, Noguchi S, Fukase M: Immunoglobulin and neuropathy: Myelomatous polyneuropathy associated with pigmentation. Neurol Med (Tokyo) 2:325-337, 1975 7. lwashita H: Polyneuropathy associated with dermatoendocrinological changes and dysglobulinemia. Adv Neurol Sci (Tokyo) 20:709-726, 1976 8. Trentham DE, Masi AT, Marker HW: Polyneuropathy and anasarca: Evidence for a new connective tissue syndrome and vasculopathic contribution. Ann Intern Med 84:271-274, 1976 9. Dyck PJ, Gutrecht JA, Bastron JA, et al: Histologic and teased-fiber measurements of sural nerve in disorders of lower motor and primary sensory neurons. Mayo Clin Proc 43:81-123, 1968 10. Ohnishi A, Dyck PJ: Loss of small peripheral sensory neurons in Fabry disease: Histologic and morphometric evaluation of cutaneous nerves, spinal ganglia and posterior column. Arch Neurol 31:120127, 1974 11. Victor M, Banker BQ, Adams RD. The neuropathyof multiple myeloma. J Neurol Neurosurg Pyschiatry 21:73-68, 1958 12. Morley JB, Schwieger AC: The relation between chronic polyneuropathy and osteosclerotic myeloma. J Neurol Neurosurg Psychiatry 30:432-442, 1987 13. Davis LE, DrachmanDB: Myebmaneuropathy. Successfultreatment of two cases and review of cases. Arch Neurol27:507-511,1972 14. Waldenstram J: Diagnosis and treatment of multiple myeloma. New York, Grune & Stratton, 1970, p 58
15. Odelberg-Johnson0:Osteosclerotic changes in myelomatosis: Report of a case. Acta Radiol 52:139-144, 1959 16.Small JM, Moxon CP, Woolf AL: Report on a clinicopathological conference. Birmingham Med Rev 20546-552,1961 17.Aguayo A, Thompson DW, Humphry JB: Multiple myeloma with polyneuropathy and osteosclerotic lesion. J Neurol Neurosurg Psychiatry 27:562-566, 1964 18.Rushton DI: Peripheral sensorimotor neuropathy associated with a localized myeloma. Br Med J 2:203-205,1965 19. Mayo CM, Daniels A, Barron KD: Polyneuropathy in the osteosclerotic form of multiple myeloma. Trans Am Neurol Assoc 93:240-242, 1968 20.Lowbeer L Multiple myeloma with osteosclerosis. Am J Clin Pathol 52:757,1969 21.Osuntokun BO, Akinjughe FM, McFarlane H: Multiple myeloma: Osteosclerosis and neuromyopathy. West Afr Med J April:43-46, 1969 22.Taleman A, Bateson EM: Multiple myeloma associated with bone sclerosis and peripheral neuropathy. Br J Radiol 43:698700,1970 23. Mangalik A, Veliath AJ: Osteosclerotic myeloma and peripheral 1971 neuropathy: A case report. Cancer 28:1040-1045, 24.Courey RW: Osteosclerotic lesions of unusual nature. JAMA 21237-378,1972 25.Case records of the Massachusetts General Hospital: Osteoblastic myelomawith peripheralneuropathy. N Engl J Med 267:138-143,1972 26.Getaz P, Handler L, Jacobs P, et al: Osteosclerotic myeloma with peripheral neuropathy. South Afr Med J 151246-1250, 1974 27.Yodoi J, Takatsuki K, Wakisaka K: Association of plasmacytoma, polyneuropathy, pigmentation and gynecomastia. (Abstr) Acta Haematol Jap 36363,1973 28.Yodoi J, Takatsuki K, Wakisaka K, et al: Plasma cell dyscrasia with polyneuropathy and high serum estrogen level: Report of a case with severe skin changes over the osteosclerotic lesion. (Abstr) J Jap Soc Intern Med 64:187,1975 29.Shimizu T, Fujimura K, Taketomi Y, et al: A case of plasma cell dyscrasia with polyneuritisand endocrine disorders. (Abstr) Clin Neurol (Tokyo) 15:398,1975 30.Rypins E L An unusual roentgenologic finding in multiple myeloma. Am J Roengenol30:56-58, 1933 31. Bailey CO: Plasma cell myeloma of humerus treated by roentgen radiation. Report of a case followed seven years. Am J Roentgenol 36:980.962,1936 32.Krainin P, Dangio CJ, Smellin A: Multiple myeloma with new bone formation. Arch Intern Med 84:976-982,1949 33. Kohler LM, Laur A Osteosklerose bei Plasmazytom: Bericht Ober einen Fall. Fortschr R(lntgenstr 72:714-717,1950 34.Galgano AR: Unusual features of multiple myeloma. Am J Roentgenol 74304-314,1955 35.Videbaek A: Unusual cases of osteomyelosclerosis. Acta Med Scand 153:459-465, 1956 36. H o d l e r J : U b e r d a s V o r k o m m e n o s t e o p l a s t i s c h e r Knochenverllnderungenbei der KLlhlerschen Krankheit. Schweiz Med Wochenschr 42:1085-1067,1956 37.Lewin H, Stein JM: Solitary plasma cell myeloma with new bone formation. Am J Roentgenol 79:WO-637,1958 38. Engels EP, Smith RC, Krants S: Bone sclerosis in multiple myeloma. Radiology 75:242-247,1960 39.Porter EC: Osteogenesis in multiple myeloma: Report of a case.
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and dysproteinemias. In Dyck PJ. Thomas PK, Lambert ED (Editors): Peripheral Neuropathy. Philadelphia, London, Toronto, WB Saunders Company, 1975,voI2, pp 1012-1029 51. Gupta SP, Prabhaker BR: Peripheralneuropathyand solitary myeloma. Br Med J 2:1004.1965 52.Baba S,Kobayashi T. Hasegawa K, et al: Three cases of obscure diagnosis with main symptoms of generalized lymphadenopathy,skin pigmentation, paresthesia. and muscular atrophy of lower limbs and papilledema. lgaku No Ayumi 87431-432,1973 53.Shimizu T Myeloma and nervous system. Naika 34:18&193, 1974 54.Akihama T, Miura A, Shibata A: A case of plasma cell dyscrasia associated with polyneuropathy and hormonal disturbance. Clin Haematol (Tokyo) 16:744756,1975 55. NagashimaT, Yamane I,KamizumaK, et al: A case of 31-year-oldman with skin pigmentation, hypertrichosis, gynecomastia, papilledema, Guillain-Barr6 type polyneuritis and generalized lymphadenopathy. J Jap Soc lntem Med 64:615616,1975 56.Saikawa S,Nagamatsu K, lgata A: Polyneuropathy with monoclonal gammopathy, papilledema, skin pigmentation and diabetes mellitus. Neurol Med (Tokyo) 2384-386,1975 57.Shimomori T, Kusumoto M: A case of solitary plasmacytoma with polyneuropathy, pigmentation and gynecomastia. (Abstr) J Jap SOC lntem Med 59:1016,1970 58.Nishitani H, Konishi T, Noguchi S, et al: Malignant tumors and nervous system with special reference to peripheralnerves and muscles. Naika
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1971
Erratum: A word substitution was inadvertently made in the abstract “Fasting-associated fatal rhabdomyolysis (familial),” W.K. Engel and R.T. Shebert (NEUROLOGY 27:347-348, 1977). The original sentence read: “EMG 2 mo after an episode showed a BSAP pattern with some fibrillations.”
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Polyneuropathy, skin hyperpigmentation, edema, and hypertrichosis in localized osteosclerotic myeloma HlROSHl IWASHITA, AKlO OHNISHI, MASAHIRO ASADA, et al. Neurology 1977;27;675 DOI 10.1212/WNL.27.7.675 This information is current as of July 1, 1977 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1977 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
