Journal ofNeurology, Neurosurgery, and Psychiatry 1992;55:1 16-120

Peripheral neuropathy in essential mixedcryoglobulinaemia

F Gemignani, G Pavesi, A Fiocchi, P Manganelli, G Ferraccioli, A Marbini

AbstractThe prevalence of various forms of peri-pheral neuropathy has not been previouslyassessed in large series of patients withessential mixed cryoglobulinaemia(EMC). Clinical and electrophysiologicalsigns of peripheral neuropathy were

observed in 21 of37 EMC patients, consist-ing of polyneuropathy in 19, mono-

neuropathy or multiple mononeuropathyin eight, and both in six. The various formsof peripheral neuropathy occurreddifferently in the subgroups of EMC.Isolated polyneuropathy was more com-mon with type II (eight of 10) than typemEMC (two of eight). Multifocalneuropathy, in association with poly-neuropathy, was the most common formin type III EMC (five of eight). Patientswith peripheral neuropathy and type II

EMC were significantly older than type IIEMC patients without neuropathy, regar-

ding present age and age of onset ofEMC.Patients with peripheral neuropathy andtypemEMC tended to have higher valuesof ESR and IgM than type III EMCpatients without neuropathy. Electro-physiological findings and sural nerve

biopsy specimens (nine cases) showedprominent axonal changes. Vascularchanges included vasculitis and altera-tions of the endoneurial microvessels in

type II and type III EMC. Our findingssuggest that distinct pathogenic factorsare implicated in the subgroups ofcryoglobulinaemic neuropathy, possiblyinducing different types of vascularchanges underlying polyneuropathy or,respectively, mononeuropathy andmultiple mononeuropathy.

Institute of Neurology,University ofParma,Parma, ItalyF GemignaniG PavesiA FiocchiA MarbiniRheumatic DiseaseUnit, University ofParma, Parma, ItalyP ManganelliG FerraccioliCorrespondence to:Dr Gemignani, Istituto diNeurologia, Universita diParma, via del Quartiere 4, 1-43100 Parma, ItalyReceived 18 January 1991and in revised form 19 April1991.Accepted 30 April 1991

Cryoglobulinaemia is a condition characterisedby the presence of serum proteins reversiblyprecipitating in the cold, composed of isolatedmonoclonal immunoglobulin (cryoglobulintype I) or with a monoclonal component (typeII) or composed only of polyclonal immuno-globulins (type III).' Cryoglobulinaemia may

be idiopathic (essential mixed cryoglobulin-aemia (EMG)) or secondary to other diseases,such as lymphoproliferative disorders, collagendiseases, and chronic infections.' Peripheralneuropathy associated with cryoglobulinaemiahas long been described,2 most reports, how-ever, deal with single cases3-4 or small groups

of patients.'"20 The data on the prevalence ofperipheral neuropathy in cryoglobulinaemia

are inconsistent, ranging from quite low esti-mates (7%-19%)' 15 16 21 to about half thepatients.202223 We examined a series of EMCpatients to assess the prevalence of variousforms of peripheral neuropathy and to evaluatefactors possibly related to its occurrence. Areport on the pathological findings in some ofthese patients has been published in abstractform.24

Patients and methodsThirty seven consecutive unselected patientswith EMC, followed either as inpatients oroutpatients at the rheumatic disease unit of thishospital between January 1982 and June 1989,were clinically evaluated for symptoms andsigns of peripheral neuropathy and submittedto electrophysiological study when peripheralneuropathy was clinically suspected. Labora-tory studies included routine blood tests,immunological tests (immunoglobulin, Waaler-Rose reaction, latex test for IgM rheumatoidfactor, C3 and C4, organ and non-organspecific antibodies), detection and character-isation of cryoglobulin according to Brouetet al l and special investigations to assessinvolvement of other organs or to excludepossible causes of secondary cryoglobulin-aemia. At the time of the study most patientswere untreated or had had only a short courseof steroid therapy. Peripheral neuropathy wasclinically suspected when symptoms or signs ofsensory or motor involvement, or both, werefound within the territory of single nerves orwith a diffuse distal limb distribution. On thebasis of clinical and electrophysiological find-ings, peripheral neuropathy was classified aspolyneuropathy, mononeuropathy or multiplemononeuropathy,25 Clinical and laboratoryvariables ofneuropathic patients were analysedwith regard to their possible relevance for thepathogenesis of peripheral neuropathy com-pared with the EMC patients withoutneuropathy as "control" group. Subgroups ofpatients with type II or type III EMC weresegregated for further analyses. Student'sunpaired t test and Fischer's exact test wereused for statistical comparison, and p < 005was considered significant.Muscle examination with concentric needle

electrode and nerve conduction studies wereperformed in 23 patients with clinically suspec-ted neuropathy. Motor and sensory nerve con-duction studies were performed with surfaceelectrodes for stimulation and recording.Motor nerve conduction velocities (MNCV)and motor action potentials (MAP) wereevaluated bilaterally in the peroneal nerve of all

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Peripheral neuropathy in essential mixed cryoglobulinaemia

patients. Sensory conduction studies wereperformed antidromically in the sural nerves.Sensory action potentials (SAP) of the suralnerves were obtained by averaging 32-256responses. MNCV of the median, ulnar, andtibial nerves and sensory nerve conductionvelocities (SNCV) of the median, ulnar, andsuperficial peroneal nerves were also examinedin selected patients. Electromyography (EMG)was performed with concentric needle elec-trodes in the distal muscles of the legs. Whenthe neuropathy was focal or multifocal, thecorresponding muscles and nerves wereadditionally examined. Limb temperature wasmaintained at 360 C with an infrared heatinglamp throughout the examination. Biopsyspecimens of the sural nerve 5 cm above theexternal malleolus and of the peroneus brevismuscle were obtained under local anesthesia innine patients. Muscle and nerve biopsyspecimens were processed with standardmethods for histology, histochemistry, andelectron microscopy, and for single fibrepreparation (eight patients).26 Morphometricstudy of the distribution of myelinated fibrepopulation was performed on photomicro-graphs of semithin sections at a magnificationof x 1000, covering at least 0-1 mm2 of endo-neurial area, with an image analyser(MiniMOP, Zeiss Italia). Necrotising vascu-litis was diagnosed according to the criteria ofWees et al27 and Dyck et al,28 when intramuralinfiltration with necrosis of the vessel walls waspresent. Otherwise, pathological changes wereconsidered suggestive but not diagnostic ofvasculitis, or representative of healed vasculitisin the presence of infiltration or necrosis of thevessel wall, or perivascular inflammation, orfibrous scarring and intramural thickening ofthe vessel walls,27 28 Direct immunofluores-

cence on frozen nerve sections was performedwith anti-sera coupled to fluorescein isothio-cyanate.

ResultsClinicalfindingsA total of 37 EMC patients (33 women, fourmen) were examined during the study. Peri-pheral neuropathy was clinically suspected in23 patients, but the diagnosis was confirmed inonly 21 patients (17 women, four men) byelectrophysiological investigation. Other pos-sible causes of peripheral neuropathy wereexcluded. The 16 remaining women who didnot show evidence of peripheral neuropathy,including two patients in whom electro-physiological examination was completely nor-mal in spite of clinical suspicion ofneuropathy,represented the "control" group of non-neuropathic EMC patients. Thus, peripheralneuropathy probably related to EMC wasfound in 21 out of 37 patients (56-8%), with aprevalence similar or slightly lower than othercommon manifestations of EMC in our series,such as purpura (70 3%), arthritis (67-6%),and fever (48-6%). The time elapsed betweenonset of EMC and clinical observation wassimilar in patients with peripheral neuropathy(range 4 months-30 years; median 2 years) andin "controls" (range 3 months-27 years;median 2-5 years).Table 1 summarises the clinical features of

peripheral neuropathy. Polyneuropathy waspresent in 19 patients, seventeen had a pure ormainly sensory type characterised by painfuldysesthesias and sensory loss in a stockingdistribution. Although polyneuropathy wasoften asymmetrical, extensive mononeuritismultiplex was excluded as temporal and spatial

Table 1 Features ofpatients with EMC and peripheral neuropathy

Patient

Age atAge onset Cryoglobulin Mononeuropathy

Number Sex (years) (years) structure Polyneuropathy (multiplex) Main symptoms

1 F 61 - 57EMC type II

IgG-IgMk

2 F 63 62 IgG-IgMk3 F 67 66 IgG-IgMk4 F 57 55 IgG-IgMk5 F 55 54 IgG-IgMk6 F 68 64 IgG-IgMl7 M 64 61 IgG-IgMk8 F 74 72 IgG-IgMk9 F 50 41 IgG-IgMk10 F 44 38 IgG-IgAk

EMC type III11 M 50 43 IgG-IgM12 F 63 41 IgG-IgM

13 F 77 72 IgG-IgM14 F 65 50 IgG-IgM15 F 41 39 IgG-IgM16 F 57 27 IgG-IgM17 F 49 47 IgG-IgM18 F 38 36 IgG-IgM

Sensory, symmetrical

Sensory, symmetricalMainly sensory, symmetricalSensory, symmetricalMainly sensory, asymmetricalSensory, slightly asymmetricalMainly sensory, asymmetricalSensorimotor, symmetricalMainly sensory, symmetrical

Mainly sensory, symmetricalMainly sensory, slightly

asymmetricalSensory, asymmetricalSensory, symmetricalSensory, symmetricalSensory, asymmetricalSubclinical

Peroneal, bilateralSural

MedianMedian, bilateralUlnar, peronealTibialSuperficial, peronealSural, bilateral

Formication, restless legs, mildataxia

Formication, burning feetFormicationFormication, dysesthesiasPricking, restless legsPricking, tightnessNumbness, formication, ataxiaPain, paresthesias, weaknessNumbness, crampsNumbness

Pain, formicationPain, pricking, ataxia

Pain, burningFormication, restless legsBumingFormication, burningBurningPain

19 M 65 6320 F 66 64

21 M 67 66

Not characterised- Sensory, asymmetrical- Mainly sensory, slightly

asymmetrical- Sensorimotor, slightly

asymmetrical

Numbness, cramps, "jabs"Numbness, lightning

Numbness, weakness, ataxia

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Gemignani, Pavesi, Fiocchi, Manganelli, Ferracccioli, Marbini

patterns of symptoms and deficits did notsuggest diffuse nerve involvement from over-

lapping damage of specific nerves.2829 Mono-neuropathy or multiple mononeuropathy was

seen in eight patients, generally with coexistingpolyneuropathy (six patients). Peripheralneuropathy was the first manifestation ofEMCin seven patients, alone in four or associatedwith purpura (two patients), arthritis, fever,and weight loss. In the 14 other patientsperipheral neuropathy was preceded by othermanifestations of EMC-such as, purpura (12patients), arthritis (four patients), fever (threepatients), weight loss (one patient), Raynaud'sphenomenon (one patient)-with an interval of2-60 months (median 15 months).Examining the peripheral neuropathy group

as a whole, we found no significant difference inclinical and laboratory variables with the con-

trols. We thus analysed separately neuropathicpatients with EMC of type II (10 cases) andtype III (eight cases), in comparison with therespective groups of non-neuropathic patients(seven patients in each subgroup). Due to thesmall amount of the cryoprecipitate, cryo-

globulin could not be characterised in threeneuropathic and two non-neuropathic patients,who were not considered in further analyses.The distribution of subtypes of peripheralneuropathy differed in the EMC subgroups.Multiple mononeuropathy (with or withoutpolyneuropathy) was more common in type III(six of eight) than in type II EMC (p = 0 03).Pure polyneuropathy was more common withtype II (eight of 10) than type III EMC(p = 003). An association of (multi) focalneuropathy and polyneuropathy was more

common in type III (five of eight) than type IIEMC (p = 0 3). Patients with peripheralneuropathy and type II EMC were signifi-cantly older than controls with type II EMC,either at onset of EMC (mean (SD) years 57(10-7) v 42 7 (12-5); p < 0O05) or present age

(60 3 (8-9) v 49 7 (7-8); p < 0O05). Comparisonof laboratory findings showed that in neuro-

pathic patients with type III EMC values ofESR and serum Ig M tended to be higher thanin the type III EMC control group: however,the difference was not significant (mean (SD)ESR 31(30) v 16(9) mm/hr and mean (SD) IgM4-6 (2.4) v 2-1 (1.3) g/l). The distribution ofassociated symptoms of EMC was similar inthe various subgroups, as well as the incidenceof abnormal laboratory variables, includingtests for IgM rheumatoid factor, serum com-

plement, organ and non-organ specific anti-bodies, and packed cell volume. A follow up ofat least one year after the initiation of therapywas available for 13 neuropathic patients (sixtreated with steroids, four with interferon a,one with cyclophosphamide, two with associa-tion of steroids and interferon a). From a

clinical viewpoint, polyneuropathy symptoms

did not seem to be influenced by the treatment:however, acute episodes of mononeuropathyseemed to be prevented. Painful or annoyingsensory symptoms were successfully treatedwith amitryptiline in 10 patients.

Electrophysiological findingsTable 2 shows the results ofthe electrodiagnos-tic study. Patients 2 and 11 (not included in thetable) had electrophysiological examinationconfirming polyneuropathy performed atanother laboratory. The most relevant findingconsisted in abnormal SAP ofthe sural nerve inall 18 examined patients, bilaterally in 14 of 17,with completely absent SAP in eight (bilater-ally in four of 17). SNCV was often preserved(10 patients), suggesting that SAP impairmentwas mainly due to axonal degeneration.MNCV of the peroneal nerve was abnormal ineight out of 19 patients, with severe impair-ment in only three cases, whereas decreasedMAP amplitude was more often found (10/19).In some patients (numbers 13, 14, 15, 16),additional nerves which appeared clinicallyaffected were examined, confirming focal or

multifocal involvement, whereas in patient 18the electrophysiological study of the superficial

Table 2 Electrophysiologicalfindings

Peroneal nerve* Sural nerve*EMGt of

MNCV (mls) MAP amplitude (mV) SNCV (mls) SAP amplitude (uV) distal musclesPatientnumber Right Left Right Left Right Left Right Left Right Left

1 450 470 50 50 36-2 33-3 2-0* 3.5* +±++ +++3 42-9 45-6 3.0* 4-1 Absent: 34-2 0* 3.0* + +++ +4 39-1* 31-8* 0.5* 0 5* Absentt Absentt 0* 0* + + + + + +5 38-0* 39.0* 2-5* 2-0* + + ++6 38.5* 38-5* 4-0 1-2* 40-0 Absent$ 0.5* 0* + + + ± +7 45-8 43-0 13-0 12-0 Absent$ 34 0 0* 3-0* + + + + + +8 40.0* 41-2* 2-9* 1 0* 33-1 36-2 1 .0* 1.4* + +++ + + +9 447 44-7 6-5 90 46-8 38-5 4-6* 4-6* + + + + + +10 49-0 52-0 4-8 5-5 38-4 44-0 6-0* 18-0 + +12 30.0* 27-0* 1 0* 0.3* Absentt Absentt 0* 0* + + + + + +13 46-0 42-8 3.0* 1-8* 43-3 0-6* + + + + +14 44-5 45.9 10-0 13-0 37-5 37-8 8-0 6-0* + +15 30.0* Absent* 0.3* 0* Absent$ Absent: 0* 0* + ++ ±+ +16 490 49.4 48 3.9 390 40-8 2-0* 2-5*17 43-8 47-6 3-8 4-3 40-5 39-7 6-0* 4.9* - +18 47-7 48-0 7 0 3-5 Absentt Absent$ 0* 0* + +19 38.0* 36.0* 5-9 2-0* 36-7 35-7 0.5* 1.0* + + + + + +20 470 45-0 5-0 5-5 36-5 397 5.0* 7-0 + + + +21 32.2* 33-1* 3.0* 1-5* Absent$ 27-4* 0* 5.0* + ++ + +

*Normal values of peroneal nerve: MNCV = 43 m/s; MAP amplitude more than 3 0 mV.'3Normal values of sural nerve age-adjusted data from our laboratory, ranging from > 33 m/s (age 40) to 30 m/s (age 70) for SNCV and from 11 uV (age 40) 50 uV(age 70) for SAP amplitude.tGrading of EMG changes: altered MUP parameters +; plus reduced interference + +; plus spontaneous activity + ++.$Abnormal findings.

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Peripheral neuropathy in essential mixed cryoglobulinaemia

peroneal nerves yielded normal results, confir-ming a multiple mononeuropathy limited to thesural nerve bilaterally. Compression at theusual entrapment sites was excluded. In fivepatients with isolated polyneuropathy (num-bers 6, 7, 12, 19, 21), the nerves of the upperlimbs were examined in addition to peronealand sural nerves, showing abnormal motor andsensory examination of the median and ulnarnerve in two of them (patients 12 and 21) asfeatures of subclinical polyneuropathy of theupper limbs. In all 18 patients abnormal EMGfindings, of variable severity, were constantlyobserved in the distal muscles of the lowerlimbs, even in patients with normal electro-neurographic examination of the peronealnerves.

NeuropathologicalfindingsSural nerve biopsy specimens showed myelin-ated fibre loss mainly affecting large fibres(table 3). In four patients there was a severefibre loss of all calibres, with a patchy fasciculardistribution in patient 15. Myelinated fibrecount was globally normal in patients 1, 7, and9 as large fibre loss was compensated for by anincrease of small fibres due to the presence ofclusters of regenerating fibres. Active axonaldegeneration was prominent in three biopsyspecimens (patients 5, 6, and 18), and in theothers previous axonal degeneration was sug-gested by fibre loss or regeneration. Minorfeatures of demyelination or remyelinationwere often associated, and concentric whorls ofsupernumerary Schwann cells were noted inthree specimens (patients 1, 12, 15). Unmyelin-ated fibres were involved only in more severelydamaged nerves (patients 5, 6, 18). Changes ofthe endoneurial microvessels, consisting ofthickening of the vessel walls and obliterationof the lumen, were seen in all specimens butwere especially severe in four (patients 1, 5, 9,12). Scattered erythrocytes around endoneurialcapillaries ("endoneurial purpura"'9 were seenin patient 12). Necrotising vasculitis of theepineurial arterioles was present in twospecimens (patients 5, 15), whereas in fourothers (patients 7, 9, 12, 18) there were signs ofprobable or healed vasculitis. Severe changes ofthe endoneurial vessels were more common intype II EMC (3/5 v 1/3), whereas vasculitistended to be more common in type III EMC(3/3 v 3/5). A sufficient number of teased fibreswere available for examination in five biopsy

specimens, whereas in three others no fibrecould be isolated due to severe myelinated fibreloss (table 3). Axonal degeneration coexistedwith variable degrees of segmental demyelina-tion and remyelination, possibly secondary toaxonal degeneration or atrophy.33"35 Directimmunofluorescence examination showed IgMdeposits in the epineurial vessel walls in patient12 and in the endoneurial vessels in patient 5,whereas it was negative in patients 9 and 15. Inall examined patients peroneus brevis musclebiopsy specimens showed denervation ofvariable entity. Muscle vasculitis was seen infive. Tubulfilamentous structures within thebasement membranes of muscle vessels prob-ably representing cryoglobulin were observedon electron microscopy in patient 6.

DiscussionPrevious works reported clinico-pathologicalfindings in small groups of patients"" orestimated the prevalence of peripheral neuro-pathy in cryoglobulinaemia,l 15 16 2023 however,distinction was not always made between EMCand secondary cryoglobulinaemia.' 151618 Ourstudy demonstrated a high prevalence of peri-pheral neuropathy inEMC (56-8%) and a morecommon occurrence of polyneuropathy(51 4%) than ofmononeuropathy and multiplemononeuropathy (21-6%), with association ofboth in 16-2%. Peripheral neuropathy was thepresenting manifestation ofEMC in 18 9% ofcases, more often than previously reported(12-5% according to Gorevic et a121). Poly-neuropathy was generally of sensory type(45-9%) commonly with features of painfuldysesthesias. Similarly, peripheral neuropathywas found in half the cases of EMC byMigliorini et a122 and by Garcia-Bragadoet a120; however, the data of Garcia-Bragadoet al were obtained from a small group of 16EMC patients, and five out of seven patientswith peripheral neuropathy had a severehepatopathy, which may be a cause of poly-neuropathy.36 In the other prevalencestudies,' 21 23 neurological data were notdetailed, so that the features of peripheralneuropathy and the respective occurrence ofpolyneuropathy or mononeuropathy and mul-tiple mononeuropathy cannot be deduced.Valli et al 23 reported a high incidence (60-9%)of mild peripheral nervous system involve-ment, examining 23 nephropathic patients withEMC. Definite peripheral neuropathy, how-

Table 3 Sural nerve biopsy findings

Density of Myelinated Abnormalities in teasedfibres (% ) *Patient myelinated fibresnumber fibres (>7pm (%)) A+B C+D+F+G E+H

1 6061 0-8 50 31 195 1528 215 - - -

6 2112 8-2 63 16 217 6865 19 5 75 18 79 6821 3-4 Not done12 2765 1-5 735 13-5 1315 3539 1-1 - - -

18 Myelinated fibres virtually absent - -

19 3466 9-4 72 20-5 7-5Controlst 5400-8600/mm2 32-45 89 (SD 9) 9 (SD 9) 0-5 (SD 0-5)

*Classification of teased fibres: A = normal; B = myelin wrinkling; C = demyelination; D = de-remyelination; E = axonaldegeneration; F = remyelination; G = myelin reduplication; H = regeneration. if

tNormal values of myelinated fibre population according to Behse and Buchthal"2; distribution of teased fibre changes in controlsaccording to Ohi et al. 32

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Gemignani, Pavesi, Fiocchi, Manganelli, Ferracccioli, Marbini

ever, was demonstrated in only six patients. Inour opinion, discrepancy within studies show-ing low prevalence (7%-19%) of cryoglobulin-aemic neuropathy,1 15 1621 may be due tooverlooking mild forms and in particularsubjective sensory symptoms.Nerve biopsy specimens showed prominent

axonal degeneration in accord with electro-physiological investigation and with previouspathological studies.90 16-20 23 24 37 Vascularchanges, previously stressed byothers,9 14 16 1820 37 38 consisted of vasculitis of theepineurial vessels or thickening and oblitera-tion of the endoneurial vessels. The formeraspect seems to represent immune complex-mediated vasculitis39 40 whereas the changes ofendoneurial microvessels could be due to adifferent mechanism. Nemni et al 18 ascribed tovascular inflammation the changes of theendoneurial capillaries, which are not,however, in the size range of vessels expected tobe affected by vasculitis (50-300 Ym).2939 Therole of ischaemia in the pathogenesis of cryo-globulinaemic neuropathy is well estab-lished,9 16 1820 37 whereas other possible mechan-isms, such as immunologically mediated nervedamage, remain unsupported.'8 9 37 Our studyshowed that different forms of peripheralneuropathy are associated with the subtypes ofEMC-that is, isolated polyneuropathy in typeIIEMC and (multiple) mononeuropathy, oftencombined with polyneuropathy, in type IIIEMC. In type II EMC patients, old agerepresented a significant risk factor for peri-pheral neuropathy, whereas neuropathicpatients with type III EMC tended to haveincreased ESR and serum IgM levels. Asmultifocal neuropathies are often related tovasculitis of the vasa nervorum,25 and microan-giopathy may cause polyneuropathy4l possiblythe different forms of peripheral neuropathyin EMC are related to different patterns ofvascular involvement. Indeed, type II cryo-globulins are immune complexes containingmonoclonal rheumatoid factor, which fix C3and C4 poorly causing tissue deposition42rather than inflammatory reaction, and thiscould account for endoneurial vessel changes,similar to the putative mechanism involved inthe damage of glomerular capillaries."

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