Neuropathy, amyloidosis, and monoclonal …monoclonal gammopathies have been classified under the same nameas "plasma cell dyscrasias", on the basis of several observations. Monoclonal

Journal ofNeurology, Neurosurgery, and Psychiatry, 1979, 42, 193-202

Neuropathy, amyloidosis, and monoclonalgammopathyJ. W. FITTING, A. BISCHOFF, F. REGLI,AND G. DE CROUSAZ

From the Department of Neurology, CHUV, Lausanne, and the Department of Neurology,Berne University, Berne, Switzerland

S UMM ARY Three cases of neuropathy with monoclonal gammopathy and amyloid depositsin peripheral nerves are described. They appeared to present a benign gammopathy because ofthe duration of the neuropathy in the absence of any clinical or biological sign of myeloma ormacroglobulinaemia. The pathological abnormality found in the sural nerves of the threepatients was characterised by a marked loss of myelinated and unmyelinated nerve fibresbecause of active axonal degeneration with Wallerian degeneration. The most striking featurein all three cases was the finding of deposits identified as an accumulation of microfibrils.

Peripheral neuropathy is often associated withmalignant gammopathies, such as multiple myel-oma and Waldenstrom's macroglobulinaemia. Theassociation between neuropathy and generalisedamyloidosis, in the familial or sporadic form, isalso well known. We recently observed three casesof neuropathy with monoclonal gammopathy andamyloid deposits in peripheral nerve.

Case reports

CASE 1 (PB)In 1967, at the age of 60 years, this patient firstnoticed plantar paraesthesiae and slight weaknessof both legs. In 1968, an examination showed distalsensory loss in both legs and arms, and moderateweakness in both legs. In 1969, a monoclonal IgMwas found. In 1974, an examination showed distalsensory loss and weakness in upper and lowerlimbs. Sternal marrow was normal. Treatment withprednisone 60 mg/day, and later 15 mg/day wasgiven from May 1974 and stopped in November1974, without any clinical modification. In 1977,the patient complained of generalised weakness,pain in the legs, and tremor in action. He noticedno impotence, no orthostatic symptoms, but irregu-lar bowel movements, and absence of perspirationin the hands and feet.Examination showed total areflexia, wasting and

Address for reprint requests: Dr J. W. Fitting, Department ofNeurology, CHUV, 101 1 Lausanne, Switzerland.Accepted 13 July 1978

weakness of distal muscles in upper and lowerlimbs, and sensory loss in a glove and stockingdistribution. There was postural tremor of bothhands, exaggerated on movement, and ataxia ofgait. The skin was dry and there was no ortho-static hypotension.Electromyography in 1976 showed a median

nerve conduction velocity of 15 m/s. The lateraland medial popliteal nerves were inexcitable. Allthe muscles examined showed marked denervation.The ESR was 36 mm/hr, Hb 15.3 g/dl, white

blood cells 5500/mm3. Serum electrolytes, glucose,urea, creatinine, uric acid, alkaline phosphatase,cholesterol, total proteins, and bilirubin were inthe normal range. Electrophoresis showed a mono-clonal immunoglobulin component, shown to beIgM kappa by immunoelectrophoresis. The im-munoglobulin levels were: IgM 1045 mg/dl, IgG690 mg/dl, IgA 71 mg/dl (March, 1976) and IgM1400 mg/dl, IgG 800 mg/dl, IgA 70 mg/dl(November, 1977). Serum viscosity was 1.58. CSFprotein level was 0.47 g/l. The urine was nor-mal. Sternal marrow was normal, with 23%lymphocytes.A sural nerve biopsy was performed and speci-

mens prepared for light and electronmicroscopicexamination. Segments of the nerve were alsostained with Congo red, thioflavin T, and periodicacid-Schiff reagent (PAS)-in the Department ofNeurology, Berne University.

Light microscopy on 1 jum thick transversesections stained with methylene blue showed a

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severe reduction in the number of the myelinatednerve fibres with virtually complete loss of myel-inated nerve fibres of large diameter. The endo-neurial intercellular space appeared of increaseddensity, and around two of the endoneurial vesselsa cuff of a dark amorphous substance was verystriking (Fig. 1). The nerve did not react with theCongo red and thioflavine techniques.

Electron microscopy showed that most of thepreserved myelin sheaths had a normal lamellarstructure. Some features of myelin sheath break-down indicative of Wallerian degeneration werealso present. In about 20% of the axons, includingthose of unmyelinated nerve fibres, axonal de-generation was obvious. Many Schwann cell pro-

cesses depleted of axons showed a budded appear-ance. No onion bulb formation was discernible.In the extracellular space, disseminated accumu-lations of microfibrils, 10 nm in width, were seen.They were particularly striking in relation to endo-neurial vessels, where they were condensed to afelt-like mass (Fig. 2).

CASE 2 (MB)In 1969, at the age of 66 years, this patient noticedloss of sensation in his left hand and cramps andparaesthesiae in both hands. Neurological exam-ination was normal. In 1974, he began to complainof difficulties in walking, and pain and weaknessof the legs. In 1975 physical examination disclosed

G Fig. 1 Case 1. Left: sural nerve fromIgM gammopathy, stained with methyleneblue. In the transverse section severe

0 oc loss of myelinated nerve fibres is apparent.0 O Two intraneurial vessels show a cuff of

( an amorphous (dark) mass (arrows).C)i0 i Right: normal sural nerve. Original

C magnification X207... r

i'.- Fig. 2 Case 1. Electron micrograph of across-sectioned intrafascicular vessel.There is a cuff of a dense substance

X around the endothelial cells representingmicrofibrillar masses (right) indicated byarrows. Original magnification X3900

X (right) X36 500.

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Neuropathy, amyloidosis, and monoclonal gammopathy

almost total areflexia and diffuse weakness andsensory loss in the legs. During the next two years,the patient complained of progressive weakness,with inability to walk from April 1977. He noticedconstipation, impotence, and hoarseness of voice.Examination showed total areflexia and muscle

wasting of both hands and legs. There was mod-erate weakness in upper limbs, marked weaknessof the proximal muscles and almost total loss offunction of the distal muscles in lower limbs.Touch and pinprick sensation were impaired inglove and stocking distribution. Temperature sen-sation was absent in hands and legs. Vibratorysensation was reduced in the hands and absent atthe ankles. The skin was dry. There was no ortho-static hypotension on rising from supine to sittingposition. Six months later, examination showedfurther loss of function of proximal muscles of thelegs.At electromyography in 1975 conduction vel-

ocity of various nerves were: median 48 m/s,ulnar 49 m/s, right lateral popliteal 35 m/s, leftlateral popliteal 38 m/s. Subacute denervation ofmuscles of right leg and left hand was observed.In 1977 the conduction velocities were: mediannerve 32 m/s, ulnar nerve 49 m/s. Both lateralpopliteal nerves were inexcitable. Subacute tochronic denervation was detected in muscles of theright leg and left hand.The ESR was 20 mm/hr, Hb 13.1 g/dl, white

cells 4,500/mm3. Serum electrolytes, urea, creatin-ine, uric acid, alkaline phosphatase, and cholesterolwere in the normal range. Fasting blood glucoselevel was 104 mg/dl (5.2 mmol/l). Provoked hyper-glycaemia was in the normal range. Total serumproteins were 5.6 g/dl. Electrophoresis disclosed amonoclonal immunoglobulin component, shown tobe IgG lambda by immunoelectrophoresis. Im-munoglobulin levels were IgG 1900 mg/dl, IgA

100 mg/dl, IgM 90 mg/dl. Serum viscosity was 1.52.The CSF contained 1 white cell per mm3. The levelof protein was 0.94 g/l with monoclonal IgG. NoBence-Jones protein was found in the urine. Por-phobilinogen was elevated, uroporphyrin absent.and coproporphyrin was in the normal range.Sternal marrow was hypocellular, with normal cellsof all series; 20% were plasma cells, slightlypolymorphic.

Sural nerve biopsy was performed and preparedas in case 1. Histological examination showed asevere defect with almost complete loss of myel-inated nerve fibres. Endoneurial vessels alsoshowed striking changes with the presence of apoorly defined homogeneous clear substance ex-tending from the vessel wall into the adjacentneural tissue, where the normal fascicular struc-ture appeared more or less effaced (Fig. 3).

Electron microscopy clearly displayed the severeloss of myelinated and unmyelinated nerve fibres,with a reduction in number of Schwann cell pro-cesses. Many Schwann cell processes appearedbudded. Multiple deposits of a material consistingof accumulations of microfibrils typical of amy-loid were recognisable within the expanded inter-cellular spaces (Fig. 4).

CASE 3 (HF)In 1974, at the age of 47 years, this patient beganto complain of paraesthesiae and dysaesthesiae inboth legs. He noticed fatigue and cramps in thelegs during walking. These symptoms increasedprogressively until 1977. He complained also ofdecreased sexual potency.Examination showed a depressed left ankle re-

flex; other reflexes were present and symmetrical.There was wasting of distal muscles of lower limbs,predominantly on the left side. Muscular functionwas preserved in the upper limbs but reduced in

W.,

Fig. 3 Case 2. Sural nerve from IgGgammopathy showing the almost completeloss of myelinated nerve fibres. In thecentre a homogeneous clear mass

.4 represents a diseased vessel (*) fromwhich clear material is infiltrating theneural tissue. Methylene blue. Originalmagnification X720.

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the lower limbs, predominantly on the left side.Touch, pinprick, and temperature sensation werenormal in upper and lower limbs. Vibratory sen-sation was reduced at both ankles, predominantlyon the left side.At electromyography conduction velocities of

nerves were: median 62 m/s, right lateral popli-teal 59 m/s (with irregular potential, 0.5 mV), leftlateral popliteal 66 m/s (with prolonged potential,1 mV, 30 ms), left medial popliteal 48 m/s (withirregular potential, 0.5 mV). Chronic denervationwas observed in muscles of the lower limbs, pre-dominantly in the left tibialis anterior.The ESR was 6 mm/hr, Hb 16.3 g/dl, white

cells 8700/mm3. Serum electrolytes, glucose, urea,creatinine, uric acid, total proteins, cholesterol,bilirubin, alkaline phosphatase, T3 and T4 were inthe normal range. Electrophoresis disclosed amonoclonal immunoglobulin component, shown tobe IgG kappa by immunoelectrophoresis. Immuno-globulin levels were: IgG 1200 mg/dl, IgA 210mg/dl, IgM 110 mg/dl. Serum viscosity was 1.54.The urine was normal. Sternal marrow was normal,with 20% lymphocytes and 10% well differentiatedplasma cells.

Sural nerve biopsy showed a virtually completeabsence of myelinated nerve fibres. In a smallnumber of nerve fascicles a loosely structuredmaterial of moderate density was accumulatedcircumferentially in a subperineurial location.

Electron microscopic analysis revealed the pre-servation of only a few myelinated nerve fibres of

Fig. 4 Case 2. Electron micrographexhibiting the complete loss of myelinatedand unmyelinated axons. Schwann cellprocesses appear budded. There are fourdeposits of microfibrillar massesrepresenting amyloid (arrows). Originalmagnification X5900.

small calibre with a myelin sheath of normal ultra-structure (Fig. 5). Axonal degeneration was presentin myelinated and unmyelinated nerve fibres. TheSchwann cells were markedly reduced in number.rhe intercellular space appeared distended andfilled with accumulations of microfibrils in a patchydistribution (Figs. 5 and 6). This material was col-lected predominantly in the subperineurial space(Fig. 7).

Discussion

MALIGNANT AND BENIGN MONOCLONALGAMMOPATHIESApart from multiple myeloma and Waldenstrom'smacroglobulinaemia, production of monoclonalimmunoglobulin has been described in healthysubjects and in chronic inflammatory disease. Thiscondition was termed "benign monoclonal hyper-globulinaemia" and considered as a stable non-premyelomatous state by Waldenstrom (1964).During recent years, malignant and benign

monoclonal gammopathies have been classifiedunder the same name as "plasma cell dyscrasias",on the basis of several observations. Monoclonalimmunoglobulins of benign gammopathies maybelong to any of the immunoglobulin classes, andcannot be distinguished from immunoglobulins ofmalignant gammopathies (Wintrobe, 1974). Severalcases of apparently benign monoclonal gam-mopathies evolved to multiple myeloma or macro-globulinaemia after a number of years, even after

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Fig. 5 Case 3 Electron micrograph of the transversesectioned sural nerve showing a severe depletion ofnerve fibres and Schwann cells In the extracellularspace, a flaky infiltration by a poorly defined structureis visible Original magnification X5900.

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Fig. 6 Case 3. With high resolution thereappear patchy accumulations ofmicrofibrils consistent with amyloid.Original magnification X 178 000.

Fig. 7 Case 3. Electron micrograph ofthe subperineurial region displaying afinely dispersed infiltration by amyloidfibrils between some thin fibroblasticprocesses. Original magnification X 13 500.



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18 years of observation (Kyle and Bayrd, 1966;Wintrobe, 1974; Osserman, 1975).However, it is evident that not every benign

monoclonal gammopathy progresses to a malignantgammopathy, as the incidence of these two formsis different. The yearly incidence of multiple myel-oma is 0.002{0.004%, the incidence of benignmonoclonal gammopathies has been estimatedfrom 0.15-1.0% in adults, and at 3% in subjectsover the age of 70 (Wintrobe, 1974; Ameis andPruzanski, 1976).

It is not known whether benign monoclonalgammopathies are precursors of myeloma, whichwould all progress in this direction if they hadenough time, or if these conditions are distinct.For this reason Osserman (1975) does not speak ofbenign monoclonal gammopathy, but of "plasmacell dyscrasia of unknown significance."We are at the moment unable to predict the

evolution of individual cases of benign monoclonalgammopathy. Indeed, if malignant monoclonalgammopathies differ from benign forms in a seriesof parameters such as a higher level of the mono-clonal immunoglobulin, reduced level of otherimmunoglobulins, serum hyperviscosity, reducedhaemoglobin level, and an increased number ofplasma cells in the marrow, none of these criteriais absolute and of predictive value in an isolatedcase (Clauvel et al., 1971; Ritzmann et al., 1975).

AMYLOID)OSIS AND MONOCLONAL GAMMOPATHIESAmyloid substance is well known for Congo redstaining, polarisation birefringence, and its fibrillaraspect at electron microscopy. The different formsof amyloidosis were first classified according to thepresence or absence of associated pathology, andthe distribution of amyloid in the organism. In thenon-familial forms, amyloidosis may be either"primary" or "secondary" to another disease, suchas multiple myeloma, macroglobulinaemia, neo-plasms, chronic inflammatory and autoimmunediseases. Primary amyloidoses, and those associatedwith a myeloma or a macroglobulinaemia, havea predominantly mesenchymatous, or "pericolla-gen" distribution: heart, tongue, muscles, gastro-intestinal tract, nerves, skin (pattern 1). The othersecondary forms have a predominantly parenchy-matous, or "perireticular" distribution: liver,spleen, kidney, adrenals (pattern 2) (Wintrobe,1974; Osserman, 1975).Biochemical studies have shown that there are

at least two types of amyloid: one of immuno-globulin origin, with a pattern 1 distribution, andone of non-immunoglobulin origin with a pattern2 distribution. Analysis of amino-acid sequencesshowed that pattern I amyloid is composed of im-

munoglobulin light chains, and particularly of theirvariable fragment (Wintrobe, 1974; Glenner, 1975).This amyloid appears to be the result of productionof monoclonal immunoglobulin or immunoglobulinlight chains for three reasons. The amino-acidsequence was found to be homogeneous in differ-ent amyloid deposits in a given individual (Win-trobe, 1974). An M component, immunoglobulinor immunoglobulin light chain, was found in serumor urine of almost all cases of pattern 1 amyloidosis(Pruzanski and Katz, 1976). In contrast to theusual predominance of kappa light chains, a pre-dominance of lambda light chains was found inmonoclonal immunoglobulins associated withamyloidosis, corresponding to a predominance oflambda-type fibrils in amyloid (Glenner, 1975;Ameis and Pruzanski, 1976).Bone marrow examination showed another

analogy between "primary" amyloidosis andmonoclonal gammopathies. A moderate bonemarrow plasma cell infiltration was found in morethan 90% of cases of "primary" amyloidosis.These plasma cells even had an immature charac-ter in some cases (Pruzanski and Katz, 1976).Thus, pattern 1 (or "primary") amyloidosis is nowconsidered as a particular manifestation of plasmacell dyscrasias such as benign and malignant gam-mopathies (Wintrobe, 1974; Osserman, 1975).

PERIPHERAL NEUROPATHY AND MALIGNANTMONOCLONAL GAMMOPATHIESThe first case of peripheral neuropathy associatedwith a myeloma was described by Davison andBalser (1937). This sensorimotor neuropathy waspredominant in the upper limbs, and was charac-terised by intense pain, hypaesthesia, and distalmuscle wasting. Examination of the brachialplexuses showed swollen axons and disintegrationof myelin. In the absence of nerve compression orinfiltration, the neuropathy was considered to besecondary either to anaemia or to an unknowntoxic factor.Many similar observations were reported, and a

review of the literature mentioned a total of 44cases of neuropathy associated with myeloma, ex-cluding the cases with cellular infiltrate or amyloiddeposits (Davis and Drachman, 1972). Among 23cases of myeloma, Walsh (1971) found threeneuropathies on clinical examination (13%), andnine on electrophysiological study (39%). Theassociation between peripheral neuropathy andWaldenstrom's macroglobulinaemia is also wellknown, and more than 20 cases have beendescribed (McLeod and Walsh, 1975).The onset of clinical manifestations is generally

progressive but may be acute. This sensorimotor

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neuropathy begins in most cases in the lower limbs,is sometimes asymmetrical in macroglobulinaemia,and can progress to quadriplegia. Pain is a com-plaint frequently found in myeloma neuropathy-it is mentioned in 59% of cases in a review of theliterature. The signs of neuropathy generally pre-cede the diagnosis of myeloma, sometimes forseveral months, but may appear either before orafter the systemic manifestations of macro-globulinaemia (Davis and Drachman, 1972;McLeod and Walsh, 1975).Most studies indicate an axonal degeneration as

the primary process with secondary segmentaldemyelination. Hesselvik (1969), on the otherhand, found that demyelination was more im-portant than axonal degeneration, and another caseof diffuse demyelination without axonal degenera-tion, but with a plasma cell infiltration has beendescribed (Walsh, 1971; McLeod and Walsh, 1975).Though amyloidosis is often associated with

myeloma and macroglobulinaemia, deposits ofamyloid in peripheral nerves were rarely foundwhen neuropathy accompanied these conditions.In a pathological study of myeloma neuropathyHesselvik (1969) found amyloid deposits in periph-eral nerves in two cases from 17 necropsies andin none from 17 biopsies. Campbell and Halford(1964) described amyloid in the vasa nervorum ina myeloma case and Dayan et al. (1971) andDavies-Jones and Esiri (1971) reported the pres-ence of amyloid not only in vasa nervorum butin nerve interstitium. Nevertheless, these observa-tions remain isolated, and in most cases no amyloidhas been found in peripheral nerves in myelomaneuropathy. Likewise, in macroglobulinaemia onlyfour cases of amyloid deposits in peripheral nervesare known (McLeod and Walsh, 1975).According to a review of the literature concern-

ing 30 cases of myeloma, the neuropathy may de-crease under treatment, particularly in isolatedplasmocytoma if treated with radiotherapy. Im-provement of neuropathy after radiotherapy wasreported in two cases of plasmocytoma with afollow-up of one and a half and 10 years. Othertreatments, steroids and antimetabolites, have noeffect on neuropathy (Davis and Drachman, 1972).A therapeutic effect on macroglobulinaemia neuro-pathy has been described in some rare cases(McLeod and Walsh, 1975).

PERIPHERAL NEUROPATHY AND AMYLOIDOSIS

A hereditary neuropathy associated with familialamyloidosis was first described by Andrade (1952)in Portugal. The onset consists of autonomic andsensory dysfunction and is followed by loss of

motor function. The mode of transmission is auto-somal dominant. Several classes of hereditaryneuropathies were described with particularcharacters in each group.

In the non-familial forms of amyloidosis, neuro-pathy is found only in pattern 1 amyloidosis. AnM component was found in serum or urine in mostcases of neuropathy associated with pattern 1amyloidosis (Benson et al., 1973; Engel andAskanas, 1976; Trotter et al., 1977).The lower limbs are generally affected first with

hypaesthesiae, paraesthesiae, or constant pain.The sensory loss is distributed in a glove and stock-ing pattern. Loss of pain and temperature dis-crimination with preservation of touch has beennoted in the hereditary form and in some casesof sporadic amyloid neuropathy. Loss of motorfunction develops later, and frequently oedema andulceration in the lower limbs.Autonomic dysfunction is important and is

sometimes the sole manifestation in amyloidneuropathy. It is characterised by orthostatic hypo-tension, bowel dysfunction, loss of sweating, andimpotence. The carpal tunnel syndrome is fre-quent, and is caused by extrinsic compression ofnerve (Cohen and Benson, 1975).Cohen and Benson (1975) have described four

patterns of amyloid deposits. Amyloid substancemay be situated outside of the nerve and provokea compression neuropathy, particularly a carpaltunnel syndrome. Amyloid is also intravascularand can obstruct the vasa nervorum. Lastly, it isfound in the neural interstitial space, formingglobular deposits and diffuse infiltration.By electron microscopy, amyloid appears as

nodular masses extending tongues into the intra-fascicular space. Amyloid substance is composedof microfibrils with a diameter of 100 to 150 A(Bischoff, 1973).

Several authors have found a preferential lossof unmyelinated and small myelinated axons,which correlates well with the pain and tempera-ture sensory loss and the autonomic disturbances(Thomas and King, 1974). However, one groupmentioned a preferential degeneration of mye-linated fibres (Coimbra and Andrade, 1971).Biopsy samples from cases of amyloid neuropathy,however, show loss of both myelinated and un-myelinated fibres.At present, no treatment is effective in amyloid

neuropathy. Because of the relationship betweenpattern 1 amyloid and other plasma cell dyscrasias,amyloid neuropathies were treated as for myelomawith melphalan and prednisone, but without benefit(Cohen and Benson, 1975; Trotter et al., 1977).

B

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PERIPHERAL NEUROPATHY AND BENIGN MONOCLONAL

GAMMOPATHY WITHOUT AMYLOIDOSIS

Apart from neuropathy associated with a malig-nant gammopathy, almost always without amyloid,and apart from amyloid neuropathy, mostly associ-ated with a benign gammopathy, two cases were

reported concerning a neuropathy associated withbenign monoclonal gammopathy without amyloidat nerve biopsy.The patient of Forssman et al. (1973) com-

plained of subjective sensory disturbances in thelower limbs, without sensory loss at clinical ex-

amination. A monoclonal IgM was found, whiclhwas considered a benign gammopathy in theabsence of other signs of Waldenstrom's macro-

globulinaemia during six years. The nerve biopsydid not show amyloid, but revealed lymphocyticinfiltrates, and immunofluorescence showed IgMin connection with these infiltrates. With treatmentby chlorambucil, the symptoms disappeared withinthree weeks and a second nerve biopsy was normalsix months later.The case of Contamin et al. (1976) presented a

symmetrical sensorimotor neuropathy associatedwith a benign IgG monoclonal gammopathy.Nerve biopsy showed no amyloid deposits.These two isolated cases present unusual

features for plasma cell dyscrasia neuropathies-the absence of plasma cell infiltration of bonemarrow, and the favourable effect of treatment.

RELATIONSHIP BETWEEN AMYLOID NEUROPATHY ANI)

NEUROPATHY ASSOCIATED WITH MALIGNANT

MONOCLONAL GAMMOPATHIES

There are two main classes of neuropathy associ-ated with a monoclonal gammopathy: the neur-

opathy of myeloma and macroglobulinaemia,associated with a malignant monoclonal gammo-

pathy, and amyloid neuropathy associated with a

benign monoclonal gammopathy. At present,malignant and benign monoclonal gammopathiesand pattern 1 amyloidosis are considered to be dif-ferent manifestations of plasma cell dyscrasia. Apossible common cause for the neuropathies whichaccompany these conditions may be invoked.The pathogenesis of nerve damage is unknown

in these two types of neuropathy. In the case ofamyloid neuropathy, an ischaemic process hasbeen postulated, caused by the intravasculardeposits of amyloid. However, the obstruction ofvasa nervorum with amyloid is often confined toa minority of vessels and does not explain thediffuse degeneration of nerve fibres. Similarly, thehypothesis of nerve damage through amyloidnodule compression cannot be retained, becausethese nodular deposits are frequently absent. As

electron microscopy showed dissolution of base-ment membrane by amyloid (Coimbra andAndrade, 1971; Bischoff, 1973), it is possible thatthe loss of this diffusion barrier causes damage toSchwann cells of metabolic origin. The extensiveand symmetrical character of amyloid neuropathysuggested a "remote effect" of plasma celldyscrasia through the associated M component,either immunoglobulin or immunoglobulin frag-ment (Engel and Askanas, 1976; Trotter et al.,1977). Thus amyloid infiltration would representthe visible manifestation of an immune mechanismby an abnormal monoclonal IgM or IgG.The hypothesis of a "remote effect" through the

M component has also been applied to the neur-opathy associated with myeloma and macro-globulinaemia (Dayan et al., 1971; Davis andDrachman, 1972; Trotter et al., 1977). Indeed,amyloid deposits in peripheral nerves cannot beincriminated, as they are absent in most cases.Similarly, the plasma cell or lymphocytic infiltratesare rare. Serum hyperviscosity was also invoked,particularly in macroglobulinaemia neuropathy.but this hypothesis cannot be retained becauseseveral series of macroglobulinaemia neuropathyhave been described without hyperviscosity(Bigner et al., 1971).

Immunofluorescence studies provide supple-mentary arguments for participation of M com-ponent in peripheral nerve damage. Forssmanet al. (1973) described the presence of IgM in anerve biopsy sample in a case of neuropathyassociated with IgM monoclonal gammopathy. Thenerve biopsy showed a lymphocytic infiltrate, butno amyloid. Chazot et al. (1976) found monoclonalimmunoglobulin in nerve biopsy samples in eightof 10 cases of periplheral neuropathy associatedwith monoclonal gammopathy. In the two negativecases there was another possible cause for neur-opathy-alcoholism and diabetes. Finally, in threecases of monoclonal gammopathy without neur-opathy the nerve biopsy did not show any fluor-escence. Using the serum of three cases ofneuropathy with benign monoclonal gammopathy.Read et al. (1978) did not demonstrate any anti-body binding to peripheral nerves. However, thisobservation does not eliminate an immunologicalorigin, as these authors did not use autologousnerves, but homologous post-mortem nerves. In-deed a serum IgM M component has been demon-strated on the myelin of sural nerve in a case ofmacroglobulinaemia neuropathy, but this serumdid not show any binding to homologous controlnerve (Propp et al., 1975).

It is, therefore, possible that amyloid neuropathyand neuropathy associated with malignant mono-

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clonal gammopathies originate from a related orcommon immunological process. However, the roleof the M component remains unclear, and it is notknown whether the monoclonal immunoglobulinfound in peripheral nerve is responsible for nervedamage, or if it is only a bystander.

PRESENT CASESOur three cases presented a progressive sensori-motor neuropathy, with autonomic dysfunction(loss of sweating and irregular bowel movementsin two cases, partial or total loss of potency in twocases), in association with monoclonal gam-mopathy (IgM kappa, IgG lambda, IgG kappa).Though no absolute criterion distinguishes themalignant from the benign forms, we think thatthese three cases present a benign gammopathybecause of the duration of the neuropathy in theabsence of any clinical or biological sign ofmyeloma or macroglobulinaemia (10 years incase 1, at least three years in case 2, three years incase 3). In case 1, the bone marrow was normal atthe first examination and showed 23% well-dif-ferentiated lymphocytes at the second. It revealed20% slightly polymorphic plasma cells in case 2,and 10% well differentiated plasma cells in case 3.The pathological abnormality found in the sural

nerves of these three cases was characterised by amarked loss of myelinated and unmyelinated nervefibres because of active axonal degeneration withWallerian degeneration. The defect was particu-larly confined to the myelinated nerve fibres oflarge size in the case of IgM monoclonal gammo-pathy, whereas in the two cases with IgG mono-clonal gammopathy it was much more pronounced,comprising also many unmyelinated nerve fibresand resulting in a remarkable decrease in Schwanncells. There was no significant evidence of primarydemyelination as suggested by Propp et al. (1975),and in no case was lymphoid infiltration of thenerve fascicle observed, in contrast to the findingsof Chazot et al. (1976) and Contamin et al. (1976).The most striking feature in all three cases was

the finding of deposits of a material which by highresolution was identifiable as an accumulation ofmicrofibrils. In the case of IgM gammopathy, themicrofibrillar infiltration was most prominent inrelation to the endoneurial blood vessels, but it wasapparently unrelated to blood vessels in the thirdcase where it gave the intercellular intrafascicularspace a patchy appearance. In all three cases themicrofibrils were consistent with the ultrastructuralappearance of amyloid deposits. Since in the twocases with IgG gamniopathy, the severe defect ofthe neuiral structures is attributable to direct in-filtration by amyloid, an effect of a specific

antibody directed against neural tissue might besuggested.These cases appear similar to another recently

described by Neundorfer et al. (1977). Their casepresented a sensory, motor, and autonomic neuro-pathy with loss of pain discrimination and relativepreservation of touch sensation. There was an IgGmonoclonal gammopathy, and amyloid was dis-covered in a peripheral nerve biopsy. In spite ofthese features of amyloid neuropathy, the authorslabelled this case as myeloma because of a plasmacell infiltration of bone marrow. However, in mostcases of pattern 1 amyloidosis, a plasma cellinfiltration is found in bone marrow, sometimesexceeding 50% and occasionally presenting atypicalforms (Pruzanski and Katz, 1976).

In the presence of amyloid in peripheral nervein association with an apparently benign mono-clonal gammopathy and moderate infiltration ofthe bone marrow with differentiated plasma cellsor lymphocytes, there is a strong argument toconsider these three cases as pattern 1 amyloidosisneuropathy.

References

Ameis, A., and Pruzanski, W. (1976). M components-a review of 1,242 cases. Canadian Medical A ssocia-ation Journal, 114, 889-895.

Andrade, C. (1952). A peculiar form of peripheralneuropathy. Brain, 75, 408-427.

Benson, M. D., Brandt, K. D., Cathcart, E. S., andCohen, A. S. (1973). Neuropathy, M-componentsand amyloid. Arthritis and Rheumatism, 16, 535.

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Documents

Neuropathy, amyloidosis, and monoclonal …monoclonal gammopathies have been classified under the same nameas "plasma cell dyscrasias", on the basis of several observations. Monoclonal