68464ournal ofNeurology, Neurosurgery, and Psychiatry 1996;60:684-689 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.684 on 1 June 1996. Downloaded from CLINICOPATHOLOGICAL CASE CONFERENCE

Lymphoma, paraproteinaemia, and neuropathy

John H J Wokke, James H Morris, Michael Donaghy

Case presentation latency 53 ms. Right sural nerve biopsy In 1984 a 55 year old former nurse developed showed myelinated fibre loss, no vasculitis. anaemia (haemoglobin 6-4 g/dl), palpitation, Congo red staining was negative. The ECG haemoglobinuria, and splenomegaly. Investi- RR interval ratio (inspiration/expiration) was gations showed an erythrocyte sedimentation 1-08. Blood glucose, vitamin B12, antinuclear rate (ESR) > 140 mm/h, white blood cell factor, and chest radiography were normal. count 4 x 109g/l, platelets 97 x 109g/l, retic- A diagnostic investigation was performed. ulocytes 2-2%, direct Coombs test negative, anti-S antibody present; IgG 4-9 (7-19) g/l, IgA 0-6 (0 8-5) g/l, IgM 14-5 (0 5-2) g/l, IgM Discussion lambda paraprotein. Bone marrow biopsy Dr John HJ Wokke showed a non-Hodgkin's lymphoma predomi- This patient had a raised ESR, low white nantly composed of B cells. A chest radi- blood cells and platelets, and an IgM lambda ograph and abdominal CT showed no paraprotein. These abnormalities are in favour lymphadenopathy. Her lymphoma was treated of a gammopathy and therefore the first diag- with prednisolone and chlorambucil (4 mg nostic procedure is a bone marrow biopsy to daily) and she received blood transfusions. analyse the nature of the gammopathy. May Despite this treatment, her haematological we review the pathological studies of this indices worsened and in February 1985 she biopsy? received one cycle of cyclophosphamide, vin- cristine (2 mg/mm2), and prednisolone. In DrJ_ Moris June 1985, steroids were replaced with aza- The bone marrow trephine (fig 1) showed thioprine and she was maintaining a haemo- marrow diffusely infiltrated by tumour com- globin of 11 g/dl. posed largely of lymphoplasmacytoid cells that In January 1985 she developed "sciatica marked immunocytochemically as B cells. pains" down her right leg followed by a numb Many of the tumour cells also marked with patch on the dorsum of her right foot. In June IgM and lambda light chain. A diagnosis of 1986 she developed "needle pains" in her right non-Hodgkin's lymphoma, B cell type was thumb, index, and middle fingers followed by made. gradual numbness and coldness of these fin- http://jnnp.bmj.com/ gers. In May 1987 a numb patch appeared Dr Wokke suddenly on her right lower lip and submental In 1984 a B cell non-Hodgkin's lymphoma region. In August 1987 a right carpal tunnel was diagnosed and the patient received decompression failed to relieve the finger immunosuppressive and cytostatic therapy. Division of pains. Right T8 dermatome devel- However, during this treatment her neurologi- Neuromuscular oped in October 1987. In 1988 she developed cal condition gradually worsened as she devel-

Diseases, University burning sensations and loss of and sciatica of the which resulted in on September 23, 2021 by guest. Protected copyright. Hospital Utrecht, patchy pain oped right leg Heidelberglaan 100, temperature sensation in both hands and feet, numbness of the right foot in January 1985; in 3584 CX Utrecht, The worse on the right side. She noted that pain- June disturbance of sensation of fingers of the Netherlands less burns had affected her right index finger, right hand developed. Two years later distur- J H J Wokke and had to wear a glove because of hypersensi- bance of sensation in an area of the right Departments of Neuropathology and tive skin on the right hand. Her bowel habit mandibular nerve occurred. She had an inter- Clinical Neurology, became erratic and she developed nocturia. current reinfection with the Varicella zoster The Radcliffe The neurological examination in 1988 virus in 1987. In 1988 symptoms of a small Infirmary, Oxford, that muscle tendon fibre became manifest with a OX2 6HE, UK showed bulk, power, neuropathy J H Morris reflexes, vibration, and joint position sensa- somewhat asymmetric distribution. In addi- M Donaghy tions were normal. There was impaired pin tion, orthostatic hypotension and erratic bowel Presented at the Conference prick and temperature sensation in the left habit pointed to failure of the autonomic ner- of the Association of British Neurologists and submental region, the first to third fingers of vous system. The neurological examination Nederlandse Vereniging voor the right hand, and the dorsum of the right was inconclusive as there was no proof of sym- Neurologie, Aviemore, 4-6 May 1994. foot. Blood pressure was 100/70 mm Hg lying metric polyneuropathy. Superficial sensation Correspondence to: and 70/60 mm Hg standing. was only disturbed in restricted nerve areas. Dr M Donaghy, Department Investigations included nerve conduction However, the nerve conduction studies gave Clinical Neurology, Radcliffe Infirmary, Woodstock Road, studies. Sensory nerve action potentials were: more proof of neuropathy, but again asymmet- Oxford OX2 6HE, UK. right median 0 pV, left median 10 ftV, left ric and compatible with axonal loss. The Received 5 October ulnar 6 right sural 2,uV. Right posterior amplitudes of sensory action potentials were and in revised form puV, 18 January 1996 tibial nerve motor conduction velocity was 48 low in the right sural nerve and absent in the Accepted 24 January 1996 m/s, distal motor latency 5-8 ms, and F wave right median nerve. Studies of motor nerves Wokke, Morris, Donaghy 685 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.684 on 1 June 1996. Downloaded from Figure 1 Microscopic illustration ofthe bone marrow trephine. There is extensive infiltration of

lymphoid and ."., lymphoplasmacytoid cells !.,. (i and displacement of many :'. .j of the other marrow elements that is most easily appreciated by the absence 6. { of the multinucleate 9 :.# .:: megakaryocytes that wA. , s produce platelets. Haematoxylin and eosin A.s . x 250. t W. s 4 A *f

S 4'9.,;,$

4. t:. * 4 r..

were normal. In addition, the RR interval ratio specific abnormalities neither of these condi- of the ECG had decreased. At this stage a tions can be diagnosed in the present case. biopsy of the affected sural nerve was justified In lepromatous leprosy asymmetric sensory to demonstrate deposits of the M protein on neuropathy is characterised by skin abnormali- myelin sheaths, deposits of amyloid, or alter- ties,4 which were absent in this patient. Painful natively to look for signs of vasculitis. Can we sensory neuropathy may develop in the course see the sural nerve biopsy? of diabetes mellitus, which was excluded by laboratory tests. Dr Morris Finally, both the superficial sensory loss and The sural nerve biopsy showed only moderate the disturbance of autonomic function are in diffuse loss of myelinated fibres of all diame- favour of primary . Amyloid is a ters. No abnormalities were seen in the blood sticky substance, which, once there, cannot be vessels and no amyloid was seen on Congo red removed due to its physicochemical proper- stains either in the walls of blood vessels or ties. It consists of linear, non-branching aggre- within the endoneurium. Electron microscopy gated fibrils with a width of 7-5 to 10 nm and http://jnnp.bmj.com/ was not performed. The teased preparation indefinite length.5 Each fibril consists of two to showed only occasional degenerating axons, a five filaments and is arranged in an antiparallel finding consistent with the diffuse loss of configuration, the so-called cross ,B pleated myelinated axons seen in the wax embedded sheet. The protein resists proteolytic digestion material. and hampers normal tissue function. Amyloid can be demonstrated with the light Dr Wokke microscope as homogeneous and amorphous

The neurological diagnosis is a small fibre sen- pink deposits with haematoxylin and eosin on September 23, 2021 by guest. Protected copyright. sory neuropathy in a patient with B cell lym- staining and it stains metachromatically with phoma with IgM paraproteinaemia and methyl violet. The diagnostic test for demon- secondary immunodeficiency. There are many stration of amyloid is staining with Congo red causes of small fibre sensory loss, the first and viewing with polarised light; it then shows being hereditary sensory and autonomic neu- an apple green birefringence. In addition, spe- ropathy (HSAN). There are five types of this cific antisera make accurate identification of ,' but usually they become manifest in types of amyloid fibrils possible. Using the childhood and lead to acral mutilation in an electron microscope deposition of amyloid fib- early stage. Other accompanying features such rils can be accurately demonstrated in various as deafness and mental retardation may be tissues. Amyloidosis often causes peripheral present. neuropathy and sometimes myopathy.6 There Sensory neuropathy may occur in the are different clinical forms of amyloidosis, course of Tangier disease, which is a very rare which are characterised by distinct types of disorder of plasma lipid transport charac- amyloid. Amyloidosis in gammopathy is called terised by hypocholesterolaemia and absence primary amyloidosis and the amyloid fibril of high density lipoprotein. Painful neuropa- shows homology to the N terminal region of thy is of course a sign of X linked Fabry dis- the variable fragment of an immunoglobulin ease; carriers may have a peripheral light chain.5 The major protein components neuropathy.3 Other features of this disease are a are therefore kappa or lambda light chains. In characteristic maculopapular rash and distur- primary amyloidosis the male:female ratio is bance of renal function. Due to absence of 2:1 and 97% of patients are aged over 40. 686 Lymphoma, paraproteinaemia, and neuropathy

Many have organomegaly and macroglossia tion with Borrelia burgdorferi,'4 which is usually J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.684 on 1 June 1996. Downloaded from may be seen. Many also have orthostatic characterised by intermittent distal limb hypotension and peripheral neuropathy.7 paraesthesiae; however, sometimes these have Patients with primary amyloidosis or lym- a more patchy distribution. Sensory loss, if phoma are among those with the worst prog- present, is only mild and autonomic dysfunc- nosis in IgM gammopathy: 50% die after two tion has not been described. As other manifes- years.8 The neuropathy may manifest as two tations of Lyme disease were absent, infection distinct clinical syndromes: firstly, a carpal with B burgdorferi can be excluded. tunnel syndrome caused by thickening of the A relation between the neuropathy and the transverse carpal ligament after deposition of non-Hodgkin's lymphoma should also be con- amyloid; secondly, a symmetric sensory and sidered. Association of lymphoma and suba- autonomic neuropathy which is characterised cute large fibre sensory neuropathy has been by a loss of feeling, dysaesthesiae, and pain, reported, but it is extremely rare."' This con- and by orthostatic hypotension, bowel dys- dition is a more frequent paraneoplastic function, impotence, and disturbance of manifestation of small cell lung cancer; anti- sweating. Muscle weakness may develop late neuronal, so called anti-Hu antibodies which in the disease.7 Primary amyloidosis may be a are directed against neuronal nuclear antigens, likely explanation in the present case, but the may be demonstrated. 16 The neuropathy is affected sural nerve did not show amyloid characterised by sensory ataxia. Direct infiltra- deposition. tion by lymphocytic cells which may explain Therefore we must first consider other subacute neuropathy could not be demon- causes of the polyneuropathy leading to axonal strated in the sural nerve biopsy. degeneration and characterised by a clinical As all causes seem to have been excluded, and neurophysiological asymmetric distribu- can chronic idiopathic axonal polyneuropathy tion. Of course, many causes of neuropathy (CLAP) be diagnosed? We have recently per- may be detected by a careful clinical work up.9 formed a prospective clinical study in a cohort Asymmetric neuropathy may be a manifesta- of 75 patients with CIAP and have concluded tion of necrotising vasculitis, which may occur that this condition does not take a rapid or systematically or, rarely, isolated in the periph- incapacitating course'7; although the symp- eral nervous system,'0 or associated with can- toms may at onset be asymmetrically distrib- cer.11 Usually the first manifestation is that of uted, the syndrome shows symmetric mononeuritis multiplex followed by asymmetric abnormalities after one to two years. The legs polyneuropathy, evolving to symmetric poly- tend to be more seriously involved and auto- neuropathy. Pain is a frequent symptom as are nomic failure is not seen. motor abnormalities when ischaemic lesions of Therefore I must return to the possibility of nerve segments cause axonal degeneration. an association between the presence of the Neuropathy caused by vasculitis is therefore a gammopathy and neuropathy. Three explana- serious condition and the prognosis is influ- tions should be examined. Firstly that of a enced by involvement of other organs and direct relation between the paraprotein and response to immunosuppressive treatment. the neuropathy. The relation of parapro- The hallmark of the diagnosis is demonstra- teinaemia and neuropathy is well established.818 tion of vasculitic changes in biopsies of The neuropathy usually has a symmetric dis- http://jnnp.bmj.com/ affected tissues, which were absent in the sural tribution and is slowly progressive over years. nerve biopsy of the present case. Patients have both sensory and motor abnor- One of the laboratory abnormalities in the malities leading to unsteadiness, and auto- patient which must be discussed separately is nomic features are not prominent.'9 Of the the presence of anti-S antibodies. These are patients with IgM paraproteinaemia about directed against the MNS system and some- 50% have serum antibodies against the myelin

times occur after maternal-fetal immunisation associated glycoprotein. Neurophysiological on September 23, 2021 by guest. Protected copyright. in pregnancy or after haemotransfusion."2 It is testing shows signs of demyelination and of not clear whether this patient had been preg- axonal degeneration. In sural nerve biopsies nant in the past; neither whether she had deposition of IgM on myelin sheaths can be received blood transfusions for anaemia in regularly shown; there is a predominant reduc- 1984. If so, she might have been infected with tion of large diameter myelinated nerve fibres. HIV. All types of neuromuscular manifesta- In a five year follow up study of 32 patients tions may be associated with HIV type 1 infec- rapid deterioration was seen in five patients; in tion and in as many as 50% of patients,'3 the three of these non-Hodgkin's lymphoma was painful sensory neuropathy which occurs is diagnosed; the other two had features of usually symmetric, and based on distal axonal chronic inflammatory demyelinating polyneu- degeneration from an unknown pathogenetic ropathy.'9 This first explanation does not seem mechanism. Direct viral invasion of the axons to solve the problem of the present case. has been postulated. Mononeuropathy multi- The second explanation may be cryoglobuli- plex also occurs in patients with HIV-1 infec- naemia. Cryoglobulins are serum proteins tion both with and without AIDS."3 the cause which precipitate when cooled and dissolve may be cytomegalovirus infection or again vas- when heated again. There are three types; culitis. The clinical syndrome in the present cryoglobulins type I are composed of isolated case and the sural nerve biopsy findings make monoclonal immunoglobulins (IgG, IgM, HIV-1 infection an unlikely explanation. IgA, or monoclonal light chains), type II are Another cause of sensory disturbances of mixed (two or more immunoglobulins, includ- the peripheral nervous system may be infec- ing one monoclonal immunoglobulin), and Wokke, Morris, Donaghy 687

type III are polyclonal without an M compo- present in longitudinal sections. In another J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.684 on 1 June 1996. Downloaded from nent.20 Cryoglobulinaemia is associated with patient with IgG paraproteinaemia and lymphoma or collagen and is often polyneuropathy the first sural nerve biopsy accompanied by peripheral neuropathy. showed only axonal degeneration. When the Sensory asymmetric neuropathy has been seen situation of this patient deteriorated after one in cryoglobulinaemia type II,20 and neuropathy year despite immunosuppressive treatment, may precede skin manifestations of cryoglobu- and orthostatic hypotension pointed to auto- linaemia. Sural nerve biopsies show features of nomic failure the other sural nerve was biop- axonal degeneration and abnormalities of sied and amyloid depositions were clearly endoneurial microvessels ranging from overt present. Results of biopsies from different tis- vasculitis to thickening of the vessel wall and sues or organs may vary,724 and even affected redundant basal lamina formation.20 21 sites are not always positive.7 Abdominal fat Recently it has been suggested that precipita- and the have been optimally analysed tion of cryoglobulins within the vascular in this respect and biopsies are not very inva- lumen may cause occlusive microangiopathy.22 sive. No evidence in support of cryoglobulinaemia In conclusion, in my opinion all evidence in was found. this patient is in favour of neuropathy associ- Finally, we must return to the first diagnosis ated with primary amyloidosis . The diagnos- of primary amyloidosis, which had to be tic procedure should be a rectal biopsy. rejected after the negative biopsy of the affected sural nerve. Evidence in favour of a diagnosis of primary amyloidosis includes the Pathology discussion clinical syndrome of small fibre neuropathy Dr Morris and autonomic failure, the presence of an IgM As Dr Wokke deduced, the diagnostic investi- monoclonal protein, and the absent reaction gation was indeed a rectal biopsy (fig 2). It on treatment and rapid deterioration leading showed a normal appearing bowel mucosa but to death of the patient six years later. Cranial a large deposit of amorphous and finely fibrillar neuropathy, as occurred in the present patient, faintly eosinophilic material in the lamina pro- does not exclude the diagnosis.23 We must pria. The material stained with Congo red and now consider the possibility of a false negative polarisation showed the focal apple green bire- sural nerve biopsy. It is of course possible that fringence diagnostic of amyloid. Immuno- amyloid depositions may have been present cytochemical staining showed the presence of but beyond the limit of detection. Another epitopes of IgM and lambda light chains explanation may have been the presence of together with the amyloid A protein. These amyloid in a proximal segment of the sural findings demonstrate the systemic deposition nerve, which could not be taken for biopsy. of a paraprotein derived amyloid and support Proximal abnormalities of peripheral nerves the diagnosis of amyloid neuropathy despite leading to distal axonal degeneration have the inability to demonstrate amyloid in the been hypothesised in vasculitic neuropathy. sural nerve biopsy. We have recently diagnosed amyloid deposits As was noted in the protocol the patient in the sural nerve biopsy of a patient with IgM died some two years after the rectal biopsy was paraproteinaemia and small fibre sensory neu- performed. At necropsy, death was shown to http://jnnp.bmj.com/ ropathy and autonomic failure neuropathy; be due to pulmonary oedema without evi- deposits were very small and only sporadically dence of pulmonary infection. Micro-

Figure 2 Part of the rectal biopsy. The rectal glands are normal, but there are masses of amorphous amyloid on September 23, 2021 by guest. Protected copyright. deposited in the hypocellular lamina propria. Haematoxylin and eosin x 125. 688 Lymphoma, paraproteinaemia, and neuropathy

Figure 3 Section from one J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.684 on 1 June 1996. Downloaded from ofthe intradural spinal roots showing a nodule of amyloid on one ofthe small arteries. Haematoxylin and eosin x 50.

scopically, there was amyloid deposition in there was some extension into adjacent both the blood vessels of the lung and in the myocardium with amyloid surrounding some walls of the alveoli which might well have con- of the individual myocytes. As with the rectal tributed to the development of the pulmonary biopsy, immunocytochemistry on the post- oedema. mortem material showed staining for IgM, In the remainder of the systemic examina- lamda light chain, and amyloid A protein. tion, there was para-aortic and thoracic Turning to the nervous system, the brain lymphadenopathy that on microscopic exami- weighed 1430 g and both it and the spinal nation proved to be a result of amyloid deposi- cord had an entirely normal appearance on tion in the lymph nodes rather than external examination, brain slices, and micro- lymphoma. No residual lymphoma was scopic study. As would be expected in a sys- detected either macroscopically or microscopi- temic amyloidosis, no amyloid was seen in any cally. The other systemic organs had a normal of the cerebral or spinal vessels with the excep- macroscopic appearance but microscopic tion of the intradural spinal roots where some examination of the kidney showed amyloid in of the small arteries within the spinal roots had the walls of some of the interlobular arteries amyloid deposited in their walls (fig 3). and in the perinephric fat. Variable amounts of Although, as described, amyloid was clearly http://jnnp.bmj.com/ vascular amyloid were also present in some of present and easy to find in the systemic the other viscera, notably the heart, where organs, there was also extensive amyloid depo-

Figure 4 Section of vagus nerve taken at necropsy. Congo red stain shows very extensive perivascular amyloid on September 23, 2021 by guest. Protected copyright. deposition with extension mtw adjacent endoneurium. Congo red x 50. Wokke, Mor-is, Donaghy 689

sition in muscle and peripheral nerve (fig 3). 5 Pepys MB. Amyloidosis. In Samler M et al, eds. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.6.684 on 1 June 1996. Downloaded from Immunological diseases. 4th ed. Boston: Little, Brown, The muscles sampled were intercostal, ster- 1988:631-74. nomastoid, posterior belly of the digastric, 6 Jennekens FGI, Wokke JHJ. Proximal weakness of the extremities as main feature of amyloid myopathy. Jf , psoas, and quadriceps. With the Neurol Neurosurg Psychiatry 1987;50: 1353-8. exception of the sternomastoid, all these mus- 7 Kyle RA, Dyck PJ. Amyloidosis and neuropathy. In: Dyck PJ et al, eds. Peripheral neuropathy. 3rd ed. Philadelphia: WB cles showed amyloid deposition in the walls of Saunders, 1993:1294-309. blood vessels with, in most cases, some addi- 8 Kyle RA, Garton JP. The spectrum of IgM monoclonal gammopathy in 430 cases. Mayo Clin Proc 1987;62: tional amyloid deposition in the adjacent con- 719-32. nective tissue. 9 Notermans NC, Wokke JHJ, Jennekens FGI. Clinical work-up of the patient with a polyneuropathy. In: De Sections of popliteal and femoral nerve Jong JBMV, ed. Handbook of clinical neurology 16(60). showed focal deposits of amyloid in vessels Amsterdam: Elsevier, 1991:253-69. 10 Hawke SHB, Davies L, Pamphlett R, Guo Y-P, Pollard JD, and the endoneurium, and the vagus nerve McLeod JG. Vasculitic neuropathy. A clinical and patho- showed massive amyloid deposition in blood logical study. Brain 1991;114:2175-90. 11 Oh SJ, Slaughter R, Harrell L. Paraneoplastic vasculitic vessel walls associated with the nerve and in neuropathy: a treatable neuropathy. Muscle Nerve 1991; the endoneurium as well as adjacent epineurial 14:152-6. 12 Silbersten LE, Spitalnik SL. Human blood group antigens tissue (fig 4). Curiously, in view of the consid- and antibodies. In: Hoffmann R et al, eds. Haematology. erable amount of amyloid in the other periph- Basic principles and practice. New York: Churchill Livingstone, 1991:1548-56. eral nerves that were sampled, the sural nerve 13 Lange DJ. AAEM minimonograph No 41: neuromuscular that had not been biopsied was entirely free of diseases associated with HIV-1 infection. Muscle Nerve 1994;17: 16-30. amyloid deposits, although, as with the biop- 14 Halperin J, Luft BJ, Volkman DJ, Dattwyler RJ. Lyme bor- sied sural nerve, there was some axonal degen- reliosis. Peripheral nervous system manifestations. Brain eration that 1990;1207-21. presumably reflected more 15 McLeod JG. Peripheral neuropathy associated with lym- proximal axonal damage from vascular and phomas, leukemias, and polycythemia vera. In: Dyck PJ et al, eds. Penipheral neuropathy. 3rd ed. Philadelphia: WB endoneurial amyloid deposition. As was noted Saunders, 1993;1591-8. by Dr Wokke, the amyloid deposits in the 16 Lennon V. Paraneoplastic autoantibodies: the case for a descriptive generic nomenclature. Neurology 1994;44: sural nerve can be very scattered and incon- 2236-40. spicuous, but it is interesting that, unlike the 17 Notermans NC, Wokke JHJ, van der Graaf Y, Franssen H, he van Dijk GW, Jennekens FGI. Chronic idiopathic axonal patient referred to, in whom the contralat- polyneuropathy: a five year follow up. J Neurol Neurosurg eral sural nerve contained amyloid a year after a Psychiatry 1994;57:1525-7. 18 Kelly JJ. Peripheral neuropathies associated with mono- negative biopsy, in this patient there was still clonal proteins: a clinical review. Muscle Nerve 1985;8: no amyloid in the remaining sural nerve at 138-50. 19 Notermans NC, Wokke JHJ, Lokhorst H, Franssen H, Van necropsy more than two years later. der Graaf Y, Jennekens FGI. A prospective study of polyneuropathy associated with benign gammopathy. Clinical features, laboratory parameters and their prog- nostic value. Brain 1994;117:1385-93. Diagnosis 20 Gemignani F, Pavesi G, Fiocchi A, Manganelli P, Ferraccioli G, Marbini A. Peripheral neuropathy in (1) Non-Hodgkin's lymphoma, with IgM essential mixed cryoglobulinaemia. J Neurol Neurosurg paraproteinaemia Psychiatry 1992;55: 116-20. 21 Cavaletti G, Petrucciolo MG, Crespi V, Pioltelli P, (2) Amyloid neuropathy, IgM-lambda type. Marmiroli P, Tredici G. A clinico-pathological and fol- low up study of 10 cases of essential type II cryoglobuli- 1 Dyck PJ. Neuronal atrophy and degeneration predomi- naemic neuropathy. J Neurol Neurosurg Psychiatry 1990; nantly affecting sensory and autonomic neurons. In: 53:886-9. Dyck PJ et al, eds. Peripheral neuropathy. 3rd ed. 22 Prior R, Schober R, Scharfetter K, Wechsler W. Occlusive

Philadelphia: WB Saunders, 1993:1065-93. microangiopathy by immunoglobulin (IgM-kappa) pre- http://jnnp.bmj.com/ 2 Yao JK, Herbert PN. Lipoprotein deficiency and neuro- cipitation: pathogenetic relevance in paraneoplastic cryo- muscular manifestations. In: Dyck PJ et al, eds. Peripheral globulinemic neuropathy. Acta Neuropathol 1992;83: neuropathy. 3rd ed. Philadelphia: WB Saunders, 1993: 423-6. 1186-93. 23 Traynor AE, Gertz MA, Kyle RA. Cranial neuropathy 3 Brady RO. Fabry disease. In: Dyck PJ et al, eds. Peripheral associated with primary amyloidosis. Ann Neurol neuropathy. 3rd ed. Philadelphia: WB Saunders, 1993: 1991;29:451-4. 1169-78. 24 Kyle RA. Amyloidosis. In: Hoffmann R et al, eds. 4 Sabin TD, Ebner JD. Patterns of sensory loss in leproma- Haematology. Basic principles and practice. New York: tous leprosy. Int I Lepr 1969;37:239-48. Churchill Livingstone, 1991:1038-47. on September 23, 2021 by guest. Protected copyright.