Peripheral neuropathy associated with Castleman's disease

Journal of the Neurological Sciences, 1989, 89:253-267 Elsevier

253

JNS 03118

Peripheral neuropathy associated with Castleman's disease Michael Donaghy 1'2, P. Hall 3, J. Gawler 2, N.A. Gregson 4, S. Leibowitz 4, S. Jitpimolmard 1, R. H. M. King 1 and P. K. Thomas 1 Departments of 1Neurological Science, Royal Free Hospital School of Medicine, 2Neurology and 3Histopathology, St. Bartholomew's Hospital and 4Histopathology and Anatomy, United Medical School Guy's Hospital London (U.K.) (Received 18 August, 1988) (Revised, received 17 October, 1988) (Accepted 21 October, 1988)

SUMMARY

Four patients with polyneuropathy complicating the plasma cell variant of Castleman's disease (angiofoUicular lymph node hyperplasia) are described. The neuropathy was predominantly motor and severely disabling. Vasculopathy, papilloedema, organomegaly, endocrinopathy, oedema and paraproteinaemia were variably present in these patients. Sural nerve biopsy showed changes of both demyelination and axonal loss. Capillary proliferation and endothelial hypertrophy in the epineurium and endoneurium, similar to that seen in affected lymph nodes, suggested that a diffuse vasculopathy may contribute to the neuropathy. Serum antibody activity against a variety of neural antigen preparations was not detected in any of the patients. Two untreated patients died. Substantial improvement in the neuropathy occurred in the two patients treated with cyclophosphamide and prednisolone.

Key words: Castleman's disease; Peripheral neuropathy

Correspondence to: Dr. Michael Donaghy, University Department of Clinical Neurology, The Radcliffe Infirmary, Oxford, U.K. 0022-510X/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)

254 INTRODUCTION

Castleman's disease, or angiofollicular lymph node hyperplasia, is a lymphoproliferative disorder characterized histologically by lymphoid hyperplasia and marked lymphoid capillary proliferation (Castleman et al. 1956). It can occur in patients with the acquired immunodeficiency syndrome (AIDS) (Lachant et al. 1985) and in patients at risk for AIDS (Harris 1984) and, in view of the current epidemic of this infection, an increasing incidence of Castleman's disease may be anticipated. Two histological varieties of Castleman's disease are recognized, the hyaline vascular form and the less common plasma cell form. The plasma cell form is frequently multifocal and accompanied by systemic manifestations. There have been 5 single case reports of peripheral neuropathy complicating the plasma cell variant of Castleman's disease (Mallory and Spink 1968; Yu and Carson 1976; Hineman et al. 1982; Case Records of the Massachusetts General Hospital 1984, 1987). The pathogenetic mechanism responsible for this neuropathy is unclear although a preliminary finding indicated that serum from 1 patient contained antibodies reactive on immunoblotting with antigens derived from peripheral nerve (Case Records of the Massachusetts General Hospital 1984). We have studied 4 further patients with severely disabling neuropathy complicating the plasma cell variant of Castleman's disease. We discuss the pathogenesis of the neuropathy and report a satisfactory neurological response to immunosuppressive treatment. A separate report will deal with the histological and immunophenotypic features of lymph nodes in these same 4 patients (Hall et al. 1989).

CASE REPORTS Patient 1

In August 1981 this 24-year-old Sri Lankan man noticed painful thigh muscles and paraesthesiae in the soles of both feet. During the preceding 18 months he had developed diarrhoea, gynaecomastia, inferior myocardial infarction, lethargy, weight loss, conjunctivitis, arthralgia and inguinal lymphadenopathy. By September 1981 he had developed paraesthesiae in the fingers and leg weakness. Neurological examination in October 1981 revealed an areflexic tetraparesis with impaired vibration and joint position sense in the feet and reduced light touch and pin prick appreciation in the fingers and lower legs. The blood pressure was 130/80 mm Hg lying and 110/70 mm Hg standing. Inguinal lymph node biopsy showed the changes of Castleman's disease (plasma cell variant) and rectal biopsy did not demonstrate amyloid. In October 1981 an osteolytic lesion in the fight humerus was detected and biopsied, revealing a plasmacytoma. Melphelan (140mg/m 2 body surface area)was administered over 31 days. His strength continued to deteriorate and in December he could no longer walk or hold a pen. Examination then showed moderate weakness of facial and truncal muscles, severe diffuse weakness of limb muscles with distal wasting and complete paralysis of the ankle evertors and extensors of the toes. The first of 15 3-weekly cycles of cyclophosphamide (1 g over 4 days) was administered, accompanied by prednisolone 40 mg dally in January 1982. Four months later he became able to walk and write again. The prednisolone dosage was gradually reduced and stopped at the end of 1982. Strength continued to improve and in September 1982 sensation returned to the fingers and toes accompanied initially by pain and recurrence of the paraesthesiae. In March 1983 the only remaining neurological abnormalities were absent ankle tendon reflexes, only a flicker of movement in ankle and toe dorsiflexors and intrinsic foot muscles, and slight hyperaesthesia to pin prick below the knees; appreciation of joint position, vibration, temperature and light touch sensation had returned to normal. Neurological examination in June 1986 showed no further improvement.

255 Patient 2

This 52-year-old Iranian man noticed erectile failure in 1983 and mild diabetes mellitus was detected. In early 1984 he developed progressive leg weakness, burning sensations and tenderness in the soles of the feet, and numbness below the knees. By mid-1984 he was bedridden due to leg weakness. In mid 1985 paraesthesiae and numbness developed in the t'mger tips followed by progressive weakness of the arms such that by January 1986 they could no longer be raised from the bed. In late 1985 an abdominal mass appeared in the left iliac fossa. Neurological examination in January 1986 showed bilateral papilloedema, areflexia, a severe tetraparesis with complete paralysis of wrist extensors and ankle and toe dorsifiexors, contractures affecting wrist flexor muscles, prominent weakness of the trunk and proximal limb muscles, and wasted hand and lower leg muscles. The feet were hyperaesthetic to pin prick. Vibration and joint position sensation was absent from the toes but present at the ankles; pain and temperature sensation was preserved. At lumbar puncture the spinal fluid was under pressure of 9.5 cm H20 and contained 1.72 gfl of protein. CT brain scan was normal. Laparotomy and biopsy of enlarged retroperitoneal lymph nodes showed changes of Casfleman's disease (plasma cell variant). Following laparotomy he had to be artificially ventilated because of respiratory failure due to respiratory muscle weakness and developed fluctuations of heart rate and blood pressure typical of autonomic instability. He died in February 1986 a~er developing pneumonia. Permission for autopsy was not obtained. Patient 3

This 45-year-old Portuguese man first developed weakness of the legs and tingling and coldness in the feet in September 1984. At that time he underwent femoral-popliteal bypass surgery because of a 6 month history of intermittent claudication of the calves due to angiographically proven arterial occlusive disease. By November 1984 his gait was unsteady; by January 1985 he could no longer walk due to weakness, and paraesthesiae affected fingers and toes. Examination in May 1985 revealed a severe areflexic tetraparesis with inability to raise arms or legs from the bed, mild wasting of limb muscles and severe trunk weakness. Joint position sensation was absent from the toes and distal finger joints and pin prick and light touch sensations were impaired distally below midshins. Bilateral papilloedema was present. Visual acuity

Fig. 1. Light microscopic appearances of the cervical lymph node biopsy from patient 4. A central vessel is encompassed by concentric rings of small lymphocytes. Surrounding this are numerous plasma cells interspersed between high endothelial venules. (Haematoxytin and eosin, x 100.)

256 was normal. The protein concentration of spinal fluidwas 2.2 g/l; the pressure was not measured. CT brain scan was normal. Biopsy of enlarged cervical and inguinal lymph nodes showed changes of Castleman's disease (plasma cell variant). In June 1985,gangreneof the left forefoot developed,necessitatingamputation below the knee. His strength failed to improve despite treatment with 40 mg prednisolone daily for 4 weeks and he died in Portugal in July 1985. Cyclophosphamide therapy had been withheld because of the susceptibilityto infection posed by his gangrenous foot.

Patient4 This 41-year-old Caucasian English male developed right cervical lymphadenopathy in January 1985. Subsequent biopsy in October 1985 showed the histologicalpicture of Castleman's disease (plasma cell variant) (Fig. 1). During the previous 2 years he had been affected by coronary artery disease, pallor and cyanosis of fingers and toes, and erectile failure. Gynaecomastia and hepatosplenomegalywere noted. Tinglingand numbness first affected the toes in Autumn 1985and progressivediffuseweakness subsequently spread to all 4 limbs. In April 1986 his legs started to give way when he attempted to climb stairs and by May 1986 he was unable to walk. He could not hold his arms aloft or grip a pen. Examination revealed bilateral papilloedema,normal visual acuity,weak neck and trunk muscles, diffuseweakness of arms, worse proximally,and of the legs,maximal in the ankle evertors. The degree of muscle wasting was mild in relation to the severity of the weakness. All tendon reflexes were absent. Pin prick and temperature appreciation was reduced below the knees, vibration sense lost from the tips of the fingers and below the ankles and he made errors of joint position appreciation at the toes. Finger pad two point discrimination was 5 mm on the right and 3 mm on the left index finger. At lumbar puncture, the spinal fluid was under a pressure of 23 cm H20 , and contained 1.45g/l protein and I mononuclear cell/mm3. CT brain scan was normal. General examination revealed hepatosplenomegaly, diffuse lymphadenopathy, gynaecomastia, facial telangiectasia, ascites, leg oedema and normal peripheral pulses. Radioisotope bone scan was normal. His arterial blood oxygen tension was normal. Within 8 weeks of starting cyclophosphamide(2 mg/kg per day) and prednisolone (1 mg/kg per day) in May 1986 his strength improved and he became able to walk using sticks and get out of bed unaided. The lymphadenopathy had lessened and the hepatosplenomegalyand the digital cyanosis and facial telangiectasia had resolved. By 9 weeks after starting treatment he was able to walk usingonlyone stick; examinationat that time showed clear improvementin the strength of all muscle groups except the ankle dorsiflexors and intrinsic foot muscles. He remained areflexic.

METHODS

Sural nerve morphology Subtotal (patient 4) and total (patient 1) sural nerve biopsies were performed u n d e r local anaesthesia. The specimen from patient 4 was fixed for 3 h at 4 ° C in 3 ~o glutaraldehyde in Pipes buffer (Bauer and Stacey 1971), washed in buffer a n d postfixed in 2 ~o o s m i u m tetroxide in Pipes buffer. The specimen was embedded in Araldite using 1,2-epoxypropane as an intermediary after dehydration in ethanol. Semithin sections (1 # m ) for light microscopy were stained with thionin and acridine orange (Sievers 1971). Thin sections for electron microscopy were stained with 12.5~o methanolic uranyl acetate a n d lead citrate. Nerve fibre densities and size-frequency distributions were obtained using a K o n t r o n Videoplan image analysis system connected to a Leitz Ultraphot. Single fibre preparations were obtained by teasing in Araldite. The specimen from patient 1 was paraffin-embedded and stained with haematoxylin and eosin.

Immunostaining Acetone-fixed, cryostat-cut sections of sural nerve from patient 4 were examined by the direct immunoperoxidase method for deposits of IgG, IgM, IgA and C3 (Dako reagents).

257

Immunoassays Sera of all 4 patients, obtained prior to treatment and stored at - 20 °C, were tested by (a) complement fixation with human and rabbit sciatic nerve and human optic nerve antigens (Hughes et al. 1984); (b) indirect immunoperoxidase for antibody to human peripheral nerve components using negative control sera from a normal individual and a patient without neuropathy and positive control serum from a patient with a monoclonal IgM kappa-paraproteinaemia and neuropathy (Leibowitz et al. 1983); (c)immunoassay (ELISA) for antibody to myelin-associated glycoprotein (MAG); (d)Western blotting with human peripheral nerve antigens (using anti-IgG, IgM and IgA reagents); and (e)with human CNS myelin (anti-IgM). Myelin-associated glycoprotein for the ELISA assay was isolated from purified human CNS myelin by the method of Quarles et al. (1983). The phenol-extracted dialysed solution was concentrated, and then diluted in water to give a final concentration of approx. 1 #g/mg and used to coat microtitre ELISA plates (Titertek). After blocking with 5 ~o ox haemoglobin, the test sera were added to the wells (diluted 1 : 200 and 1 : 1000 in phosphate-buffered saline containing 0.05 ~o Tween and 0.19/0 bovine serum albumin) and incubated at room temperature for 1 h and at 4 ° C overnight. IgM and light chain binding were measured by incubating with anti-human # and x rabbit sera followed by an alkaline phosphatase conjugated goat anti-rabbit immunoglobulin serum. Western blotting was performed using nitrocellulose blots prepared from human CNS myelin and cauda equina proteins separated on 12~o polyacrylamide gels. Immunoglobulin binding was detected with an alkaline phosphatase conjugated antihuman immunoglobulin reagent (Blake et al. 1984).

RESULTS

Biochemical and serological investigations The results of relevant biochemical and serological tests in these 4 patients are shown in Table 1. Other routine investigations were noncontributory. Although fasting blood sugars were normal in all 4 patients, in patient 2 plasma glucose was 10.7 mmol/l 120 min after 75 g oral glucose load. IgA lambda-paraproteinaemia, too weak to quantify, was detected in the serum of patient 4 at the time of presentation with neuropathy. Serum protein electrophoresis in patient 1 was repeatedly normal until August 1985, 4 years after the onset of neuropathy, when a weak IgA lambda-paraprotein was detected. Blood lead and urinary porphyrin levels were normal in all 4 patients. Nerve conduction studies Concentric needle electrode sampling of muscles showed spontaneous fibrillation in each patient. Sensory nerve action potentials were generally reduced in amplitude and, to a relatively lesser extent, delayed (Table 2). Motor nerve conduction velocity was invariably slowed and often no response was obtained even with maximal stimulation of motor nerves in the legs. When motor nerve conduction velocity was greatly slowed

258 TABLE 1 R O U T I N E B L O O D A N D U R I N E TESTS AT T H E T I M E O F P R E S E N T A T I O N WITH N E U R O PATHY

VDRL Antibody to HIV Blood lead ~mol/1) Urine porphobilinogen Fasting blood sugar (mmol/1) Monoclonal gammopathy Antinuclear factor (IU/ml) Cryoglobulinaemia

Patient 1

Patient 2

Patient 3

Patient 4

0 0 0.2 0 5.0 0 100 NE

0 0 0.8 0 3.5 0 20 NE

0 NE 0.6 0 5.3 0 0 0

0 0 0.7 0 3.5 IgA2 0 0

NE = not estimated. TABLE 2 E L E C T R O D I A G N O S T I C STUDIES Patient 1 Date

Patient 2

Patient 3

9.81 (6.86)

Patient 4 4.86 (5.87)

Nerve conduction:

Motor studies Median

Ulnar

Peroneal

Tibial

MCV M A P (APB) DL F MCV M A P (ADM) DL MCV M A P (EDB) DL MCV

35

(58)

5.1 (3.6) 41

30 3.2 4 62

35 4.4

(62)

35

3.3 0 0 0 0

(2.8) (0) (0) (0)

3.8 23

10 3.6 5 3.3

(6) (2.7) (4) (2.1)

(25) (7)

23 0.1 5.6 13 0.025 0 0

6.5

Sensory studies Median Ulnar Radial Sural

SAP amp. lat. SAP amp. lat. SAP amp. lat. SAP amp. lat.

2.5 (0)

(26) (6.2)

0 0 0 0

4 4.2 1 4.1 10 4 1 6.8*

(o) (o) (o) (o) (o) (o)

Key: MCV = motor conduction velocity (m/sec); D L = distal latency (msec); F = F wave latency (msec); M A P = compound muscle action potential (mV); SAP = sensory action potential (#V, msec); APB = abductor pollicis brevis; A D M = abductor digiti minimi; EDB = extensor digitorum brevis; amp. = amplitude; lat. = latency; * = conduction distance 14 cm. Values in brackets for patients 1 and 4 were obtained after treatment.

259 (i.e. ulnar MCV of 23 m/sec in patient 3, peroneal MCV of 13 m/sec in patient 4), the compound muscle action potential amplitude was greatly diminished (0.1 and 0.025 mV, respectively). Motor nerve conduction was generally more severely affected than sensory nerve conduction. Nerve conduction was reassessed in patients 1 and 4 at intervals of 41/2 years and 1 year, respectively after commencing treatment with prednisolone and cyclophosphamide (Table 2). Motor nerve conduction was markedly improved in patient 1 in keeping with the clear clinical improvement in muscle power. The only electrophysiolo-

Fig. 2. Transverse section of sural nerve biopsy from patient 1 showing proliferation of epineurial blood vessels. (LM haematoxylin and eosin, x 210.).

260

gical improvement in patient 4 was an increase in the compound muscle action potential evoked in abductor pollicis brevis by supramaximal median nerve stimulation. Paradoxically, sensory nerve action potential amplitudes decreased in both patients during treatment. Sural nerve morphology

Light microscopy of both biopsied sural nerves revealed proliferation of capillaries within the epineurium (Fig. 2). Neither case showed evidence of vasculitic changes with inflammatory infiltrates or vessel walt destruction. Lymphoid or polymorphonuclear cell infiltrates were not encountered. Light microscopy of plastic embedded sural nerve sections from patient 4 showed a moderate loss of myelinated nerve fibres and active axonal degeneration with macrophage infiltration. Myelinated fibre density was reduced to 4982/mm 2 (normal 7460-9560/mm 2, age 35-44 years; Jacobs and Love 1985). The fibre size-frequency distribution showed a loss of fibres below 5 #m and above 9.5 #m diameter compared to the control (Fig. 3). Electron microscopy showed occasional myelinated fibres undergoing wallerian degeneration, bands of Btlngner, endoneurial macrophages ingesting myelin debris, and hypertrophied perineurial cells with intervening lipid debris consistent with ongoing Wallerian degeneration.

11001000e~

~9oo.

v

>,

o800 g 0~ a

0

5 Fibre Diameter

10 (pm)

Fig. 3. Myelinated fibre-size density distributions in the sural nerve biopsy of patient 4 (n = 1 6 2 9 ) compared with a normal control aged 38 years (n = 2 389). There was a loss of fibres from the extremes of the distribution. The increased density of fibres from 4.5 to 6 . 0 / ~ m diameter may be accounted for by the sprouts of regenerating large diameter myelinated fibres.

261

Fig. 4. Transverse section of sural nerve biopsy from Patient4 showing a hypertrophied endoneurial capillary. (LM thionin and acridine orange, x 810.) Clusters of regenerating myelinated axons were commonly seen. The myelin lamellae were normally spaced in surviving myelinated fibres. Unmyelinated fibre density was 29000/mm 2 (normal 35 700-36400/mm2; Jacobs and Love 1985) with a normal size distribution. Teased sural nerve fibres from Patient 4 showed 38~ undergoing axonal degeneration or regeneration, 27 ~ showed segmental demyelination or remyelination not clustered on individual fibres, 11 ~ had excessively wrinkled myelin and 2 2 ~ were normal (53 fibres). Both light and electron microscopy showed that the endoneurial capillaries were consistently hyperplastic with thickened walls, increased numbers of hypertrophied endothelial cells and increased numbers of pericytes (Figs. 4 and 5).

262

Fig. 5. Electron micrograph of an endoneurial capillary from patient 4 showing increased numbers of hypertrophied endothelial cells (E) containing numerous mitochondria surrounded by multiple layers of basal lamina (BL) and swollen pericytes(P). Bar = 1 #m.

Immunological studies The direct immunoperoxidase method showed no deposition of IgG, IgM or IgA in frozen sections of the sural nerve of patient 4. None of the sera showed antibody activity when tested by Western blotting with human peripheral and CNS antigen preparations, immunoassay (ELISA) for antibody to MAG, complement fixation with human and rabbit sciatic nerve and human optic nerve antigens, or indirect immunoperoxidase for antibody against peripheral nerve components.

263 DISCUSSION These 4 patients with the plasma cell variant of Castleman's disease all suffered from peripheral neuropathy involving severe motor disability in comparison to mild sensory loss. By the time of neurological investigation, neuropathic symptoms had been present for 2, 10, 15 and 18 months in the 4 patients and were relentlessly worsening without any sign of spontaneous remission. Clinically detectable lymph node enlargement preceded neuropathic symptoms in 3 of the patients; retroperitoneal lymph node enlargement was only detected 18 months after the onset of neuropathic symptoms in patient 2. Death occurred in the 2 patients who were not treated with prednisolone and cyclophosphamide. A similar neurological picture has been present in 5 previously reported patients with the plasma cell variant of angiofollicular lymph node hyperplasia although in 2 patients the neuropathy was clinically restricted to the legs (Mallory and Spink 1968; Yu and Carson 1976; Hineman etal. 1982; Case Records of the Massachusetts General Hospital 1984, 1987). Peripheral neuropathy has also been associated with the hyaline vascular form of Castleman's disease (Gaba et al. 1978). Angiofollicular lymph node hyperplasia without peripheral neuropathy has been reported in patients with AIDS (Lachant et al. 1985) and at risk for AIDS (Harris 1984); however, there were no antibodies to human immunodeficiencyvirus in the 3 of our patients who were tested. A number of systemic manifestations apart from peripheral neuropathy were present in these patients with Castleman's disease (Table 3). Of these features, papiUoedema, gynaecomastia, impotence, glucose intolerance, oedema, paraproteinaemia and hepatosplenomegaly are all variably present in the Crow-Fukase syndrome (Crow 1956; Fukase et al. 1969; Saihan et al. 1978; Nakanishi et al. 1984) and the POEMS syndrome of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (Shimpo 1968; Meshkinpour et al. 1977; Bardwick et al. 1980; Imawari et al. 1984). These systemic abnormalities have been described in asso-

TABLE 3 SYSTEMIC ABNORMALITIES

Patient 1

Papilloedema Gynaecomastia Impotence Glucose intolerance Coronary artery disease Peripheral vascular insufficiency Distal cyanosis Oedema Hepatosplenomegaly Paraproteinaemia Conjunctivitis

Patient 2

Patient 3

Patient 4

+

+

+ + +

+ + +

+ + + + +

+

264 ciation with osteosclerotic myeloma (Crow 1956; Aguayo et al. 1964; Morley and Schweiger 1967; Iwashita et al. 1977; WaldenstrOm et al. 1978; Talerman and Bateson 1979; Driedger and Pruzanski 1980; Kelly et al. 1983), reactive lymph node hyperplasia (Bardwick et al. 1980; Nakanishi et al. 1984) or angiofollicular lymph node hyperplasia (Nakanishi et al. 1984; Case Records of the Massachusetts General Hospital 1987). In a series of 30 patients with the Crow-Fukase syndrome, 19 out of 32 biopsied lymph nodes showed angiofollicular hyperplasia typical of Castleman's disease (Nakanishi et al. 1984). Although enlarged lymph nodes have been encountered in the POEMS syndrome, they showed reactive changes only; angiofollicular hyperplasia was not noted (Bardwick et al. 1980). The polyneuropathy that occurs in the Crow-Fukase and POEMS syndromes and in osteosclerotic myeloma is usually predominantly motor, often severely disabling and chronically progressive (Bardwick et al. 1980; Kelly et al. 1983; Nakanishi et al. 1984). It is closely similar to the neuropathy encountered in our own and other cases of Castleman's disease (Mallory and Spink 1968; Yu and Carson 1976; Hineman et al. 1982; Case Records of the Massachusetts General Hospital 1984, 1987). Since all these lymphoproliferative disorders, ranging from osteosclerotic myeloma to angiofoUicular lymph node hyperplasia, include overlapping elements from a constellation of systemic symptoms, it seems likely that they share common underlying pathogenetic mechanisms. However, it is noteworthy that angiofollicular lymph node hyperplasia is usually not associated with neuropathy (Castleman et al. 1956) and when it is, oedema, impaired peripheral circulation or paraproteinaemia may be the only systemic abnormalities (Mallory and Spink 1968; Yu and Carson 1976; Hineman et al. 1982; Case Records of the Massachusetts General Hospital 1984). Our patients with Castleman's disease showed moderate slowing of motor nerve conduction, reduced amplitude sensory action potentials and electromyographic evidence of denervation. Similar electrophysiological findings were present in another patient with Castleman's disease (Case Records of the Massachusetts General Hospital 1984). Teased sural nerve fibre preparations from our Patient 4 and a previously reported patient with Castleman's disease (Case Records of the Massachusetts General Hospital 1984) showed a mixture of demyelination and axonal degeneration. Electron microscopy ofmyelinated fibres in both these cases showed normal myelin spacing. The widely spaced myelin described in chronic demyelinating neuropathy associated with IgM paraproteinaemia (Smith et al. 1983) was not observed. The electrophysiological and pathological data available so far suggest that the neuropathy associated with Castleman's disease involves a combination of demyelination and axonal degeneration. In patients with peripheral neuropathy complicating the closely related Crow-Fukase and POEMS syndromes and osteosclerotic myeloma, variable degrees of slowing of nerve conduction were encountered and nerve biopsies also showed a mixture of axonal degeneration and demyelination (Bardwick et al. 1980; Driedger and Pruzanski 1980; Kelly et al. 1983; Nakanishi et al. 1984; Berkovic et al. 1986). Our immunological studies provided no evidence that antibody is deposited in peripheral nerve of these patients or that their serum reacts with peripheral nerve antigens. In particular we were unable to confirm the suggestion, based upon one reported case of Castleman's disease (Case Records of the Massachusetts General

265 Hospital 1984), that antibody activity to peripheral nerve antigens can be detected in the serum by immunoblotting. There was evidence of abnormal capillary proliferation, similar to that seen in the affected lymph nodes, in the two peripheral nerve biopsies which we examined. Neither biopsy showed any features of an inflammatory vasculitis. Epineurial capillary proliferation was present in both biopsies. It has been suggested that this finding indicates compensatory hypervascularization subsequent to peripheral nerve ischaemia (Schr6der 1986). Thus it is of interest that light and electron microscope studies of the endoneurial capillaries of patient 4 also showed proliferative changes. Capillary endothelial cells were hypertrophied and increased in number so as nearly to occlude the vessel ~men. They were surrounded by thickened walls comprised of increased numbers of pericytes and layers of basal lamina. These changes in endoneurial vessels resemble those described in human diabetic neuropathy (Dyck et al. 1985; Powell et al. 1985). Interestingly, 3 of our 4 patients had either ischaemic heart disease or peripheral arterial disease and patient 4 had cyanosis of the hands and feet despite normal peripheral pulses and normal arterial blood oxygen tension. This suggests that a systemic vasculopathy was present which was not due to an inflammatory vasculitis. It is possible that such a diffuse vasculopathy affecting the vasa nervorum contributed to the widespread peripheral nerve damage in our patients. It is of interest that noninflammatory vasculopathy has been reported in patients with polyneuropathy in whom angiofollicular lymph node hyperplasia was not detected but who exhibited elements of the POEMS syndrome (Amid et al. 1975; Trentham et al. 1976). The association of a generalized vasculopathy with Castleman's disease, or angiofollicular lymph node hyperplasia, suggests the presence of a circulating angioproliferative factor. Evidence that such a factor is implicated in Castleman's disease is provided by the striking vascular proliferation present in affected lymph nodes (Castleman et al. 1956). Without treatment the combination of polyneuropathy and the plasma cell variant of Castleman's disease has a poor prognosis; our 2 untreated patients both died. The other 2 patients received prednisolone and cyclophosphamide and their disability due to neuropathy and their nerve conduction studies improved over the 12-month period following the introduction of therapy. In view of the vasculopathy hypothesis for the neuropathy advanced earlier, it was of interest that the marked distal limb cyanosis in patient 4 also resolved on therapy. A similar striking improvement in peripheral neuropathy with prednisolone and cyclophosphamide therapy has been noted in the Crow-Fukase and POEMS syndromes both of which are related to Castleman's disease (Nakanishi et al. 1984; Berkovic et al. 1986). It is thus important to recognize the systemic disorder which underlies these disabling neuropathies since they respond well to treatment with prednisolone and cyclophosphamide. Treatment with prednisolone alone does not improve the neuropathy judging from our experience in patient 3 and that of Nakanishi et al. (1984) in the Crow-Fukase syndrome.

266 ACKNOWLEDGEMENTS We thank Professors G.M.

B e s s e r a n d T . A . Lister for allowing us to r e p o r t

p a t i e n t s 2 a n d 3, J a n e W o r k m a n for histological a n d p h o t o g r a p h i c a s s i s t a n c e a n d K i e r a n Price for secretarial assistance. T h e electron m i c r o s c o p e w a s p r o v i d e d by the Medical Research Council.

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