brain plasma-exchange therapy in chronic inflammatory

Brain (1996), 119, 1055-1066

Plasma-exchange therapy in chronic inflammatorydemyelinating polyneuropathyA double-blind, sham-controlled, cross-over study

A. F. Hahn,1 C. F. Bolton,1 N. Pillay,2 C. Chalk,3 T. Benstead,4 V. Bril,5 K. Shumak,5

M. K. Vandervoort1 and T. E. Feasby6

1 University of Western Ontario, London, 2 University ofManitoba, Winnipeg, 3McGill University, Montreal,4Dalhousie University, Halifax, 5 University of Toronto,Toronto, ̂ University of Calgary, Calgary, Canada

Correspondence to: Dr A. F. Hahn, Department of ClinicalNeurological Sciences, Victoria Hospital, 375 South Street,London, Ontario, Canada N6A 4G5

SummaryEighteen patients with definite, untreated chronic inflam-matory demyelinating polyradiculoneuropathy (CIDP) ofchronic progressive (nine patients) or relapsing course (ninepatients) were randomizedprospectively to receive 10plasma-exchange (PE) or sham plasma-exchange (SPE) treatmentsover 4 weeks in a double-blind trial. After a wash-out periodof 5 weeks or when they returned to baseline scores, patientswere crossed over to the alternate treatments. Neurologicalfunction was assessed serially using a quantitativeneurological disability score (NDS), a functional clinicalgrade (CG) and grip strength (GS) measurements.Electrophysiological studies were done at the beginning andend of each treatment. A primary 'intention to treat' analysisshowed significant improvement with PE in all clinicaloutcome measures: NDS by 38 points, P < 0.001; CG by1.6 points, P < 0.001; GS by +13 kg, P < 0.003 andin selected electrophysiological measurements, Z proximalCMAP, P < 0.01; I motor conduction velocities, P < 0.006;L distal motor latencies, P < 0.01. Fifteen patients completed

the trial and of those, 12 patients (80%) improvedsubstantially with PE; i.e. five out of seven patients withchronic progressive course and seven out of eight patientswith relapsing CIDP improved. There were three drop-outs:one patient lost venous access; one patient suffered a strokeand one patient left the trial to receive open treatmentelsewhere. The improvement in motor functions correlatedwith the electrophysiological data, i.e. with improved motorconduction velocities and reversal of conduction block. Eightof 12 PE responders (66%) relapsed within 7—14 days afterstopping PE. All improved with subsequent open label PE;all but two patients required long-term immunosuppressivedrug therapy for stabilization. The PE non-respondersimproved with prednisone. We conclude that PE is a veryeffective adjuvant therapy for CIDP of both chronicprogressive and relapsing course; concurrent immuno-suppressive drug treatment is required. Exchange treatmentsshould be given two to three times per week until improvementis established; the treatment frequency should then be taperedover several months.

Keywords: chronic demyelinating polyneuropathy; double-blind trial; plasma-exchange; conduction block; prednisone

Abbreviations: CG = clinical grade; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CIDP-MGUS= CIDP with monoclonal gammopathy of undetermined significance; CMAP = compound muscle action potential; GBS =Guillain-Barre syndrome; GS = grip strength; NDS = neurological disability score; PE = plasma-exchange; SPE = shamplasma-exchange

IntroductionChronic inflammatory demyelinating polyradiculoneuropathyis an acquired peripheral nerve disease of presumed auto-immune aetiology (see recent review of Dyck et al., 19936).The diagnostic criteria and the natural history have beencarefully set out (Dyck et al., 1975; Prineas and McLeod,

© Oxford University Press 1996

1976; McCombe et al., 1987; Barohn et al., 1989; Ad HocSubcommittee, 1991; Simmons et al., 1995) separating CIDPfrom the acute inflammatory demyelinating polyneuropathyor the Guillain-Barre syndrome (GBS). Recently a furtherdifferentiation of idiopathic CIDP from a variant form

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1056 A. F. Halm et al.

associated with monoclonal gammopathy of undeterminedsignificance (CIDP-MGUS) has been proposed based onretrospective analyses of large patient series (Gosselin et al.,1991; Bromberg et al., 1992; Simmons et al., 1993, 1995).

Chronic inflammatory demyelinating polyradiculoneuro-pathy usually develops insidiously over weeks to months toyears, causing fairly symmetrical motor and sensory deficitsin the limbs and variable but often significant disability. Thedisease may begin at any age, even in early childhood (Sladkyet al., 1986) and the course may be either chronic progressiveor relapsing with incremental residual deficits (Dyck et al.,1975; McCombe et al., 1987; Barohn et al., 1989). Duringactive phases of their disease patients often require assistedambulation and may become wheelchair- or bed-bound.Despite modern therapy the condition may lead to con-siderable chronic morbidity, prompting a continuous searchfor improved treatments.

The cause of CIDP remains unknown. Clinical andlaboratory evidence support the concept of an immuno-pathogenesis of both the acute and the chronic inflammatorydemyelinating neuropathy [reviewed in Dyck et al. (1993/?)and Hartung et al. (1995)]. Humoral and cell-mediatedresponses against a variety of myelin-derived autoantigenshave been detected in some CIDP patients (Koski et al.,1985; van Doom et al., 1987; Fredman et al., 1991; Ilyaset al., 1992; Khalili-Shirazi, 1992, 1993; Connolly et al.,1993; Simone et al., 1993). However, the findings areinconsistent and, so far, no predominant target epitope hasbeen determined. More direct evidence for the importanceof humoral factors in the pathogenesis of the disease hascome from passive transfer experiments (Saida et al., 1982;Heininger et al., 1984; Pollard, 1987) and from early reportsof repeated favourable responses to therapeutic PE in selectedpatients (Server et al., 1979; Levy el al., 1979; Toyka et al.,1982; van Nunen et al., 1982). The finding that sera of CIDPpatients caused demyelination or functional peripheral nervedeficits with intraneural or systemic transfer provided arationale for the use of PE in CIDP (Heininger et al., 1984;Pollard, 1987). The response to PE was tested in severalsmall groups of patients, yet the observations, often carefullydocumented, were derived from non-blinded assessments andwere therefore subject to bias (Gross and Thomas, 1981;Pollard et al., 1983; Donofrio et al., 1985; Gibbels et al.,1986). Moreover, patients were often treated simultaneouslywith immunosuppressive drugs that could have influencedthe clinical response (Dyck et al., 1982). A more rigorousapproach was taken by Dyck and colleagues at the MayoClinic in a randomized, double-blind, sham apheresis-controlled study of 29 CIDP patients (Dyck et al., 1986). Asignificant beneficial effect with PE was documented in one-third of non-selected patients (in five out of 15 patients inthe controlled trial and in a further four patients of the shamgroup in the subsequent open trial). These important andcritically derived observations underscored the utility of PEfor CIDP (NIH Consensus, 1986). However, the Mayo Clinictrial did not provide information about predictors of response

or the optimal schedule for PE. Subjects were studied foronly 3 weeks. Also, the length of their disease and previoustreatments varied considerably and they receivedimmunosuppressive drugs while being evaluated for PE.

In order to address these issues, we conducted aprospective, double-blind, sham apheresis-controlled, cross-over trial of PE in CIDP patients. The selection criteria forstudy subjects were deliberately very strictly defined (AdHoc Subcommittee, 1991). The disease had to be newlydiagnosed, of short duration, not previously or concomitantlytreated and confirmed by nerve biopsy. Patients with CIDP-MGUS were excluded. The assessment modalities andoutcome measures were similar to the Mayo Clinic studyto allow for comparison of the results. Our specificobjectives were to define (i) the rate and magnitude ofresponse, (ii) the predictors of response, (iii) the applicationof PE, and (iv) the role of corticosteroid therapy.

MethodsPatient selectionPatients were recruited prospectively between 1990 and 1994at the participating centres throughout Canada; they had tofulfill the diagnostic criteria for definite CIDP (Ad HocSubcommittee, 1991) supported by CSF analysis,electrodiagnostic studies and a nerve biopsy. The neuropathy,of either chronic progressive or relapsing course, had to benewly diagnosed, not previously treated and had to beprogressive for >8 weeks and <2 years (to avoid theinclusion of cases with neurological deficits secondary toaxonal degeneration, that could not be expected to changeduring the study period). Muscle weakness had to besignificant, interfering with secure ambulation (NDS ^ 50).The patients had to be aged 18 years or older and gaveinformed consent to take part in the trial which had beenapproved by the institutional ethics review boards for humanexperimentation. Patients were carefully screened for diseasesthat could produce neuropathy and those with associatedmonoclonal gammopathy, HIV or hepatitis were excluded.(Monoclonal paraproteins were determined by high resolutionagarose gel serum and urine electrophoresis, immunoglobulinquantification and immunofixation techniques. Localizedmyeloma was excluded by radiological skeletal survey.)Patients who were judged likely to encounter difficulties withantecubital venous access for serial apheresis were notallowed to participate (the hazards associated with jugular orsubclavian vein access were considered unacceptable, in viewof the SPE treatments). Prior to entry into the study allsubjects had established disease with a stable or slowlyprogressive course.

Study designThe study was designed as a double-blind, placebo-controlled,cross-over trial. The participating patients and evaluating



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Plasma exchange in CIDP 1057

Table 1 Clinical grading scale employed for functionalassessments

Grade Definition

0 Normal1 No disability; minor sensory signs or areflexia2 Mild disability; ambulatory for >200 m; mild weakness

in one or more limbs and sensory impairment3 Moderate disability; ambulatory for >50 m without stick;

moderate weakness MRC Grade 4 and sensoryimpairment

4 Severe disability; able to walk >10 m with support ofstick; motor weakness MRC Grade 4 and sensoryimpairment

5 Requires support to walk 5 m; marked motor and sensorysigns

6 Cannot walk 5 m, able to stand unsupported and able totransfer to wheelchair, able to feed independently

7 Bedridden, severe quadriparesis; maximum strength MRCGrade 3

8 Respirator and/or severe quadriparesis; maximum strengthMRC Grade 2

9 Respirator and quadriplegia10 Dead

neurologist remained blinded throughout the entire trial; onlythe study coordinator and the PE personnel were non-blinded.The code was broken at the time of data analysis. A'monitoring' neurologist served as backup to assure standardmedical care, and was only made aware of the nature of thetreatments in case of complications. The data wereperiodically reviewed by an independent safety oversightcommittee.

Patients were randomly assigned to either a series of PEor SPE. In phase I of the trial, 10 exchanges were given over4 weeks: four in week 1, three in week 2, two in week 3and one in week 4. This schedule was expected to remove>90% of circulating humoral factors such as putative auto-antibodies of either IgG for IgM class in the absence ofresynthesis of autoantibodies (Buffaloe et al., 1983). Thepatients were then monitored closely during a 5-week wash-out, after which they entered phase II of the trial and werecrossed over to receive the alternate treatment (PE or SPE)with a subsequent similar wash-out. No other therapies wereprescribed during the controlled trial. Function was assessedweekly by a quantitative NDS, a CG (Table 1), and GSmeasurements; electrophysiological studies were performedat the beginning and end of each of the two treatment periods.Allowance was made to shorten a treatment or wash-out phasein case of treatment failure or relapse (severe neurologicaldeterioration by 3 CGs, as determined by two independentobservers). Patients who continued to deteriorate to CG 8were to be withdrawn and to be entered into the third andopen phase of the trial. After completion of the two exchangetreatment periods, patients who were still symptomatic wereto enter phase III of the trial. In this phase prednisone wasgiven over a 6-month period. The dose was 60 mg daily for1 month and subsequent tapering of the prednisone daily

dose by 10 mg every month. Patients were also given thechoice of receiving PE treatments twice weekly. Neurologicalfunction was monitored monthly and electrophysiologicalstudies were performed at the beginning and end of phase III.

Neurological assessmentsPatients were assessed by the same blinded observer weeklyduring each of the treatment periods and at the beginning,middle and end of each wash-out period. Tests included themeasurements of NDS (a summed score of strength in 26muscle groups, of sensation and of reflexes, modified fromDyck, 1982; the NDS gives a reliable assessment ofneurological impairment its validity has been demonstratedby Dyck et al., 1994). We also used a dynamometer (JamarTM, TEC, Clifton, NJ, USA) to measure maximal hand grip(GS, best of three; Mathiowetz et al., 1984) and assigned afunctional CG (Table 1).

Electrophysiological studiesA standardized set of electrophysiological measurements wasperformed at the beginning and end of each treatment periodusing conventional techniques with surface stimulating andrecording electrodes and careful monitoring of limbtemperature. Median, ulnar (four-point stimulation: wrist,distal to elbow, proximal to elbow and axilla), tibial andperoneal (three-point stimulation: ankle, fibular head andpopliteal fossa) motor nerve conduction was studied; theparameters evaluated included compound muscle actionpotential (CMAP) amplitudes evoked by proximal and distalstimulation, distal latencies, conduction velocities and F-wave latencies. Sural, median and ulnar antidromic sensoryconduction studies were performed; parameters evaluatedincluded sensory nerve action potential amplitudes, distallatencies and conduction velocities. All recordings wereconsistently performed in the right upper and lower limb toallow for comparison of serial studies. Concentric needleelectromyography of biceps, first dorsal interosseous, vastusmedialis and peroneus brevis was carried out and asemiquantitative assessment of fibrillation potentials andmotor unit recruitment was made.

Nerve biopsyThe left sural nerve was biopsied at the ankle. A portion ofthe specimen was fixed in 2.5% buffered glutaraldehyde,processed in part for teased fibre studies, and in part forembedding in epon according to standard techniques to allowexamination by light and electron microscopy (Dyck et al.,1993a). Teased fibres were analysed according to theclassification of Dyck et al. (1993a). A demyelination indexwas calculated from the sum of percentages of fibres ofcategory C, D and F. A portion of the nerve was mountedin O.C.T. compound, frozen in liquid nitrogen and stored



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1058 A. F. Hahn et al.

Table 2 Clinical and electrophysiological outcome measures in PE versus SPE

Outcome measures

Clinical measure:Neurological disability scoreClinical gradeGrip strength (kg)

Electrophysiological measure:I proximal CMAP (mV)I distal CMAP (mV)£ motor conduction velocity (m s~')1 distal motor latency (ms)

Plasma exchange

Before

73.3±5.34.6±0.4

I5.8±2.3

7.3±l.215.0±2.091.3+11.934.7±5.5

After

35.3±4.5*3.0±0.4*

28.5±2.8

11.0±1.917.3±2.6

IO4.5±11.229.1 ±2.9

Sham exchange

Before

69.4±6.44.3±0.4

15.1+2.7

.7.1 ±1.912.7+2.386.7±9.435.3+4.7

After

71.1 ±7.54.7±0.5

15.2±3.1

6.2+1.412.2+1.783.3±9.937.7±5.1

Significance7

P < 0.001P < 0.001P < 0.003

P < 0.01P < 0.06P < 0.006P < 0.01

Mean±SD. *Decreasing values for NDS and CG signify improvement; *P values were obtained from ANOVAs, repeated measuresoption, and refer to the differences between the effects of PE and SPE treatments.

at -70°C to be used for immunological studies (see Hahnet al., 1996).

Laboratory studiesCerebrospinal fluid, serum protein electrophoresis, serumand urine immuno-electrophoresis, IgA, IgM and IgGquantification, immunofixation, serum glucose, electrolytes,albumin, liver profile, glycosylated haemoglobin andporphyrin screening were performed/measured for eachsubject as were a radiological skeletal survey and serologyfor HIV, hepatitis B and Borrelia burgdorferi.

Apheresis procedurePheresis was performed from an antecubital venous access,using a continuous or intermittent cell separator (Cobe TPE,Cobe Spectra and the V-50 Haemonetics apheresis system).A curtain separated the apheresis equipment from thepatient. The typical schedule prescribed was an exchange of40-50 ml plasma per kg body weight per treatment. Bloodwas drawn and separated into cells and plasma; the cellswere combined with reconstituted 5% human serum albuminand reinfused into the patient with normal saline. Theanticoagulant acid citrate dextrose was used at a ratio of 1:20and the replacement solution was supplemented selectivelywith calcium gluconate 3.75 mEq 1"'. For SPE, blood wasdrawn and separated into cells and plasma, recombined andreinfused into the patient. The PE schedule was expected toremove >90 % of IgG and IgM antibodies in the absenceof synthesis of new autoantibody (Buffaloe et al., 1983). Asample of plasma from the first PE/SPE procedure wasretained for future immunological assessments.

Statistical considerationsThe two-period, double-blind, cross-over design was chosenbecause of its statistical efficiency. Moreover, in this designeach patient acts as his/her own control; this gives a moreprecise estimate of the treatment effect in the individual

patient. Baseline information was then used in a secondaryanalysis aimed at determining predictors of response. Asprimary end-points to assess treatment efficacy, we usedthe NDS, CG, and GS measurements, and selectedelectrophysiological measurements: the summed CMAPs ofmedian, ulnar, tibial and peroneal nerves in response toproximal ( I proximal CMAP) and distal stimulation (Z distalCMAP); the summed motor conduction velocities ( I MCV)and the summed distal motor latencies (Z DML) of median,ulnar, tibial and peroneal nerves.

All analysis was conducted in PC SAS, version 6.08. AllP values reported are directly from PROC GLM, with therepeated measures option specified (SAS Institute Inc. User'sGuide, 1990). A P value <0.05 was considered statisticallysignificant. Unless stated otherwise results are presented asmean±SD.

ResultsEighteen patients, 13 men and five women, were randomizedfor the trial. Their acquired demyelinating neuropathy fulfilledthe criteria of definite CIDP (Ad Hoc Subcommittee, 1991)and was of a mean duration of 4.5 months (range 3-18months) with a chronic progressive (nine patients) or chronicrelapsing (nine patients) course. (Three patients classified aschronic progressive CIDP improved substantially with PE;they then worsened again during wash-out and stabilizedsubsequently with PE plus immunosuppressive drugs; theirrelapse was considered to be treatment related.) Patients hadnot been treated prior to randomization. At entry into thestudy their neuropathy was severe (NDS = 77.0+4.3 points,CG 4.7±0.4) and interfered with ambulation (see Table 4).Evidence for ongoing demyelination was provided by themarked slowing of conduction velocities (mean mediannerve motor conduction velocity 27.2± 12.6 m s~') and thenerve biopsy findings (see Table 3). Three patients did notcomplete the trial: one because of failed access for the secondtreatment arm (PE); one because of a stroke at the end ofthe first treatment arm (PE) and there was one drop-outduring the first treatment series (SPE).



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(A) Before plasmapheresis


- C T — i - - - U i «

(B) Plasmapheresis (10)

Plasmapheresis stopped

J(C) Two weeks

Fig. 1 Representative ulnar motor conduction study from Patient 1(A) prior to entry into the trial, (B) after completion of phase I(10 PE treatments in 4 weeks) and (C) after rebound relapse(recording from abductor digiti minimi and stimulating at the wrist,below elbow, above elbow and axilla). Note the reversal ofconduction block, conduction slowing and dispersion of therecorded action potentials with PE, and the recurrence to an evengreater degree during rebound relapse. Recording conditions wereidentical in the three sessions.

Observations with PEThe observations made with PE versus SPE are summarizedin Table 2. All patients were included in an intention to treatanalysis. The mean values for the NDS, CG, GS andelectrophysiological findings at entry into the respectivetreatment arms were comparable. With PE, significantimprovement was found in all outcome measures: meanchange in NDS, 38 points, P < 0.001; in CG, 1.6 points,P < 0.001; in GS, +13 kg P < 0.003. Analysis ofthe electrophysiological measurements revealed statisticallysignificant improvement with PE in Z proximal CMAP,P < 0.01; in I MCV, P < 0.006; in I DML, P < 0.01; thechange in I distal CMAP almost reached significance(P < 0.06). All measures remained static or worsenedduring SPE.

0 -l•1 --2 -

© - 3 -"° -4 -O) -5 -T5 -s -

| - 7 -

O -8-

-10 -n -

mm ;nilliniumi!iimini in 11111 1^--—

• 14 -12 -10 -8 -6 0 1 2 3 4 5 6 8 10

Weeks12 14 16 18 20 22 24 28 28 30

Fig. 2 Treatment responses in Patient 1 during the controlled trial(CT) and the open trial (OT). The patient had slowly deterioratedin the preceding months (hatched line) to a stable baseline. Hewas allocated to PE in phase one, received 10 PE treatments(arrows) over 4 weeks and improved quickly by 4 CG; hestabilized for only 6 days and deteriorated very rapidly within 3days to his baseline score 6. He crossed over to SPE (hatchedarrow). After one treatment he had reached CG 8. He was putinto the open trial and received 60 mg prednisone daily by mouth(solid bar) plus PE twice weekly with subsequent tapering of PE.Gradual improvement was documented over the next 6 months(phase III).

Twelve of 15 patients (80%) who completed the controlledtrial responded to PE with a substantial improvement in theirneurological function (Table 3). The response was particularlyimpressive in six patients whose neurological dysfunctionimproved by >50 points from baseline in =S4 weeks. Thiscorresponded to an amelioration of up to 5 CGs. First signsof improvement were usually noted 3-6 days after beginningthe PE (i.e. after two to four treatments). Improvementcontinued steadily so that nine of the 12 patients, whoresponded favourably to PE had achieved secure ambulationby the end of 4 weeks. At this time they demonstrated onlyminor motor weakness and the deep tendon reflexes hadoften returned (Table 4). A corresponding improvementwas seen in the electrophysiological testing (Table 3 andFig. 1). One patient aparently improved spontaneously andtwo patients had not changed; one of these had shown aplacebo response with non-sustained improvement duringSPE.

On average, 3546 ml plasma was removed per treatment;a detailed record was kept on each procedure. The PE andSPE were well tolerated with the exception of the followingtwo incidents. An 84-year-old man sustained a stroke afterthe ninth PE treatment. This occurred 1 day after anuncomplicated PE procedure and a clear relationship couldnot be established. His record showed that he had improvedwith PE, but he was not included in the secondary analysis.During phase III of the trial a 44-year-old, healthy manexperienced an adverse reaction (hypotension and abdominalpain) within minutes of having been connected to the cellseparator. He had undergone many previous PE procedureswithout side-effects. His symptoms were interpreted by the



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Table 3 Observations on individual patients at baseline and after PE in the controlled trial

No.

123456789

10II12131415161718

Age(years)/sex

56/M44/M50/M60/M48/F62/M74/M62/M25/M40/M21/F41/F48/M66/M61/F19/F68/M84/M

CIDPlype

ChrRChrRChrPrg'ChrPrgChrRChrPrgChrRChrPrgChrRChrPrgChrRChrRChrPrg*ChrPrg*ChrPrgChrRChrRChrPrg

CIDPdurationmonths

44454363

18353579

18105

MNCV(m s-')

32381347382922174338262923

8134

2446

Biopsy(% fibre)DI/AD

29.9/0.832.5/3.137.6/2.711.0/11.027.3/11.185.8/0.9

0/080.8/12.147.4/025.9/1.320.3/032.4/040.4/1869.3/1.132.0/3.427.0/089.5/8.029.0/19.0

CSFprotein(mg T1)

1194735

25261211314014191596301537504003107039901460820750

100113601810

NDSbefore/after PE(change)

90/25 (-65)76/27 (-49)

120/21 (-99)61/18 (-43)82/DO

105/SI85/63 (-22)54/37 (-17)98/24 (-74)

106/28 (-78)70/17 (-53)66/20 (-46)67/25 (-42)61/12 (-49)72/FA50/52 (+2)

106/21 (-85)67/DO

CGbefore/after PE(change)

6/2 (-4)3/1 (-2)7/2 (-5)4/2 (-2)5/DO7/S17/4 (-3)3/3 (0)(-4)7/2 (-5)3/2 (-1)6/3 (-3)4/2 (-2)3/1 (-2)3/FA3/3 (0)5/3 (-2)6/DO

Increasein gripafter PE(kg)

+ 29+26+ 28+9DOSI-A+6.5+ 25+ 21+ 23+6+ 17+ 15FA+6+ 21-

Physiologyafter PE

ImprovedImprovedImprovedUnchanged—ImprovedUnchangedImprovedImprovedImprovedImprovedImprovedImprovedImproved-WorseImproved-

ChrR = chronic relapsing; ChrPrg = chronic progressive; Dl = deniyelination index of teased fibres C + D + F; AD = axonal degeneration; DO = drop-out; SI = spontaneousimprovement; FA = failed access. Single relapse with D/C PE.

oo



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Plasma exchange in C1DP 1061

Table 4 Functional state of each patient at baseline, their response to PE and other therapies and functional state at lastfollow-up

Patient

12

345678

91011

12131415161718

Baselinewalking

Bed boundWalker

Bed boundWalkerWheelchairBed boundWheelchairTwo canes

WheelchairBed boundSingle cane

WheelchairSingle caneDifficultyDifficultyDifficultyWheelchairWheelchair

First signof responsetoPE

2-3 days3—^ days

2 days4-5 davsDOSI3—4 weeksNone

3—4 days5-6 days5-6 days

5-6 days3-4 days3—4 daysFANone3-4 days2 weeks

Weeks toimproveby 1 CG

<11

<1<1_

656

<262

<2<1<11424

<1DO

Weeks tosecurewalking

32

43

_1120

6

382

15<1<114245

Stroke

Reboundrelapse afterPE (days)

713

14No_—NoNo

NoNo9

1013-1540-No10-15-

Responseto prednisone(±PE)

YesYes

YesYesYes_YesYes

Yes_Yes

YesNo

tYesYesYesYes

Other drugsneeded tostabilize

AZAAZA, Ivlg,CycloNoNoAZA.lvlgNoNo-

NoNoAZA, Cyclo,IvlgAZA, CycloCycloCycloNoAZA, IvlgAZA, Cyclo-

Walkingat end ofstudy*

NormalNormal

NormalNormalOne caneNormalNormalSingle

caneNormalNormalNormal

NormalNormalNormalNormalNormalOne caneWalker

DO = drop-out; SI = spontaneous improvement; FA = failed access; AZA = azathioprine; Cyclo = cyclophosphamide; Ivlg = i.v.immunoglobulin G. 'Observation time 1-4 years, declined drugs; on maintenance PE for 3 weeks, later cyclophosphamide.

attending personnel as an anaphylactic reaction and he wasgiven an injection of diphenhydramine 50 mg i.v. andadrenaline 1:1000, 1 ml subcutaneously. Shortly thereafterhe became diaphoretic and developed chest pain. Anelectrocardiogram showed changes of anterior inferiormyocardial ischaemia. An emergency coronary angiogramshowed an isolated thrombotic occlusion of the left anteriordescending coronary artery associated with a mild localizedstenosis but with no other evidence of coronary artery disease.The coronary circulation was restored by an angioplasty andhe made a full recovery. While being observed in the coronarycare unit, his neurological function deteriorated rapidly andhe became quadriplegic, despite the prior and ongoingprescription of prednisone 60 mg daily for 8 weeks. He thenresponded favourably to treatment with i.v. immuno-globulin G.

Treatment related relapsesEight of the 12 patients (66%) who had improvedsubsequently relapsed after stopping PE; in seven thedeterioration occurred 7-14 days after the last PE treatment.Six patients with apparently stable, chronically smoulderingdisease at randomization deteriorated rapidly over a few daysand became more severely paralysed than they had been atentry into the study (Fig. 2). Deterioration occurred duringthe first wash-out in six patients. According to the predefinedcriteria, they were prematurely crossed over to receive thesecond treatment: one completed 10 sham treatments while

deteriorating slowly; one terminated the sham period afterseven treatments because of a rapid deterioration to CG 6and the other four patients received only 4, 3, 1 and 1sham treatments, respectively. Their neurological functiondeteriorated so rapidly that within days they had reached CG7-8. The deterioration was documented by two independentobservers and confirmed by electrophysiological studies(Fig. 1); in accordance with the study protocol these patientswere withdrawn from the controlled trial so that they couldenter the third and open phase of the trial. Two patients whohad received PE during the second controlled treatment armrelapsed during wash-out; one deteriorated rapidly within 14days of the last PE and was entered into phase III, the otherworsened much more gradually within 40 days of the lastPE treatment. This patient declined corticosteroids and wasmaintained on PE every 3 weeks; cyclophosphamide 150 mgas a daily oral dose was added after 4 months and thefrequency of PE was tapered. His condition stabilized so thathe could return to his employment as an orderly. The conditionof one patient with known relapsing CIDP deteriorated 100days after the last PE; this was considered a spontaneousrelapse.

Observations during the open phase (HI)Fourteen patients were monitored monthly for 6 monthswhile being treated with either prednisone alone (sevenpatients) or in combination with PE (seven patients). Allpatients improved, including the two patients who had not



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responded to PE alone during the controlled trial. Those whohad relapsed after the improvement with controlled PEtreatments responded again promptly. After 6 months, 10patients had almost completely recovered; only minimalneurological signs remained and they did not interfere witha normal life. One patient was left with a bilateral fixedpartial foot drop requiring a single cane.

Four patients had a fluctuating course. They improvedinitially with prednisone and PE to almost normal function.However, upon reducing the frequency of PE, they promptlyrelapsed, in spite of having been medicated with high doseprednisone for >8 weeks. Azathioprine was added to themanagement without noticeable effect; they were laterchanged to cyclophosphamide (prescribed as a daily oraldose of 75-150 mg or as monthly i.v. pulse therapy at a doseof 12 mg per kg body weight) and their disease becamestabilized. One patient with a very unstable course wastreated with i.v. immunoglobulin G infusion pulse therapyafter sustaining a complication with PE that precluded furthertreatments (see details above).

Observation during long-term follow-upLong-term follow-up of duration of 33.9±3.5 months (range15-56 months) was possible in 16 patients. All except threepatients maintained secure ambulation and they still haveeither a normal neurological examination or minor residualsigns. Three patients remain with moderate distal weakness(MRC Grade 4 of 5) and walk with a single cane. Severalrelapses occurred in seven patients; in four patients theseoccurred when prednisone was tapered to a low dose. Theyimproved each time the steroid was increased. Various othertherapies were added (azathioprine, cyclophosphamide andhuman immunoglobulin G infusions) and all patients havebeen stabilized.

DiscussionIn this double-blind, controlled trial we were able to docu-ment significant benefit from therapeutic PE in 80% ofprospectively enrolled, previously untreated patients withstrictly defined CIDP of either static or progressive course.We demonstrated statistically significant improvement (by amean of 38 points, P < 0.001) in a quantitative NDS adaptedfrom Dyck et al. (1982) that expresses the neurological statusof the patient and correlates well with electrophysiologicalmeasurements that are not subject to observer or patient bias(Dyck et al., 1994). The NDS has been used as a primaryend-point to assess treatment efficacy in earlier neuropathytrials from the Mayo Clinic (Dyck et al., 1986, 1991, 1992,1994). This allows us to compare our results with thosereported by Dyck et al. (1986). In our trial the magnitude ofchange in NDS and the response rate to PE was much higher(80% versus 33%) than that reported in the only previouscontrolled trial with unselected patient enrollment (Dycket al., 1986). The improvement with PE began within days

of commencing the treatments and progressed steadily sothat nine out of 12 patients who responded favourably to PEhad only minor residual dysfunction at the end of 4 weeksafter receiving 10 PE treatments. The observed changesrepresented a very large biological effect, since the majorityof patients were severely disabled at entry into the trial(Table 4). The striking differences in the outcome of the twotrials may be explained in part by the much more vigorousPE scheduling in our study (10 versus six treatments) andthe longer observation time. Also, and more likely, theycould relate to our more strict selection of cases, in whichthe pathology was characterized by prominent but morereadily reversible demyelination. The latter assumption issupported by our electrophysiological observations beforeand after PE, which demonstrated significant increases in theevoked compound motor amplitudes in response to proximalstimulation (I proximal CMAP, P < 0.01), indicating reversalof conduction block (Fig. 1); significant reductions in distalmotor latencies (Z DML, P < 0.01) and improvements inthe motor conduction velocities ( I MCV, P < 0.006) werealso seen. The changes indicate an improvement in theconduction in motor fibres as would be seen withremyelination, which can proceed with remarkable speed(Hahn et al., 1987). The clinical and electrophysiologicaldeficits seen in CIDP probably reflect a balance betweencontinuously ongoing demyelination and remyelination(Feasby et al., 1985). The observed rapid and impressiveimprovements with PE probably represent a shift in thisbalance towards remyelination with reversal of conductionblock as illustrated in Fig. 1.

In a more recent study by Dyck et al. (1994) in which theauthors compared the response to PE versus immunoglobulininfusions in CIDP patients, the rate and magnitude of responseto PE was very similar to those in our study. However, inthis Mayo Clinic trial only six out of 19 patients enrolledhad not received prior immunotherapy. Several study patientshad been treated earlier with PE and were known to respond.Therefore the assessment of PE in this cohort is not free ofselection bias. Yet the remarkable agreement between thetwo studies of the measured treatment effect demonstratesthe value of standardized evaluations and confirms theusefulness of PE in CIDP.

Our trial had been initiated and planned in collaborationwith the Canadian Apheresis Group, a group that monitorsand collects data on all apheresis procedures in Canada andkeeps a specimen bank of samples taken from patients witha variety of disorders treated by PE. The objective of ourstudy was to evaluate critically the use of PE in CIDP andto determine the optimal application of this expensive therapy.Patient selection criteria were therefore deliberately restrictiveand no concurrent immunosuppressive medication wasprescribed during the controlled portion of the trial; thiswas admittedly a somewhat artificial situation. Patients withassociated diseases such as HIV infection, hepatitis andglomerulonephritis, and those associated with monoclonalparaproteins were excluded. Recent reports propose a



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distinction between CIDP and CIDP-MGUS, which is basedon differences in the natural history and response to therapy(Gosselin etal., 1991; Bromberg era/., 1992; Simmons etal.,1993, 1995). However, circulating monoclonal paraproteinscan be found in otherwise typical cases of idiopathic CIDPand such a strict separation may not be justified (Pollardet al., 1983; Julien et al., 1984; Cornblath et al., 1991;Vallderiola et al., 1993).

By chance, we enrolled an equal number of patients withchronic progressive and with chronic relapsing disease course.In the final analysis eight patients with relapsing disease andseven patients with chronic progressive disease could beevaluated. All but two (one in each group) showed substantialimprovement with PE in all clinical outcome measures; 10also had electrophysiological improvement. One patient withsevere neurological deficits was found to have improved by2 CGs prior to receiving PE in the second study phase. Thefurther improvement during the active treatment may havebeen spontaneous. Spontaneous improvements have beenobserved in cases with subacute CIDP and monophasic course(Hughes et al, 1992; Vermeulen, 1993). Whether such casesshould be regarded as variant forms of GBS remains to bedetermined. Our patient had developed paralysis and severesensory deficits with gradual continuous progression over 8weeks to quadriplegia, but sparing the facial nerves andpulmonary function. The electrophysiological assessmentsindicated a severe demyelinating motor and sensoryneuropathy. The nerve biopsy taken at 9 weeks, whenexamined by light and electronmicroscopy and by teasedfibre analysis, showed severe and ongoing macrophage-associated demyelination and remyelination and only veryrare endoneurial mononuclear inflammatory cells. Thepathological changes reflected the chronic smouldering courseof the disease.

In only one previous report was an attempt made to definethe predictors of response to PE by careful analysis andcorrelation of clinical and pathological observations in fivetreated CIDP patients (Pollard et al., 1983). The authorsconcluded that patients with chronic relapsing disease andelectrophysiological and pathological findings of predominantdemyelination are likely to respond to PE. By contrast, thosewith chronic progressive disease, with demyelination andassociated axonal degeneration would probably not respond(Pollard, 1987). Our analysis of the 15 patients who hadcompleted the blinded trial allowed us to define the predictorsof response to PE more accurately. Among the eight patientswith relapsing disease, seven showed substantialimprovement in the original trial and with subsequentrepeated treatments. The electrophysiological findings inall patients were consistent with a severe demyelinatingneuropathy without evidence of axonal loss or ongoingaxonal degeneration. The impression was confirmed in thepathological examination of the nerve biopsies. Examinationof plastic-embedded cross-sections of the nerves by light andelectron microscopy showed a near normal complement ofmyelinated nerve fibres (except for one case with severe

ongoing demyelination) and a variable number of randomlyscattered axons that were ensheathed by disproportionatelythin myelin, indicating prior de/remyelination. The acuity ofthe disease was much more accurately shown by the teasedfibre analysis, which gave evidence for active primarydemyelination and little or no axonal degeneration. In theone chronic relapsing case that did not improve, teased fibresgave a similar result. However, the examination of nervesections showed evidence of much more chronicdemyelination, with prominent onion bulb formation. Thispatient improved with prednisolone.

Among the seven patients with chronic progressive disease,five responded unequivocally to PE. One patient had shownspontaneous improvement prior to starting active treatmentand was therefore discounted; the remaining patient (no. 7in Table 3) showed a non-significant improvement. Theelectrophysiological and pathological measurements in thisgroup were more variable. The degree of slowing of nerveconduction varied among cases and needle electromyographygave evidence of ongoing axonal degeneration. The pathologyin nerve sections and in teased nerve fibres indicated aprocess of primary demyelination with associated axonaldegeneration that varied in degree. In two cases the observedchanges in the nerve biopsy correlated poorly with the degreeof clinical symptoms, suggesting that the disease process wasproximal and more prominent in nerve roots (Dyck et al.,1975). The one case that did not respond to PE showed aremarkable degree of onion bulb formation and evidence ofaxonal loss. The pathological changes appeared very chronicand were inconsistent with the patient's claim that the diseasehad begun only 3 months before. The observed pathologicalfeatures and the prominent peroneal motor deficit in thispatient raised the possibility of hereditary motor and sensoryneuropathy type I. However, there was no family history ofneuropathy, and genomic DNA analysis did not reveal thecommon mutations. Both patients that failed to respond to PEimproved subsequently with a prescription of corticosteroids,thus supporting the clinical impression that their disease wasacquired and likely to have been immune mediated.

Given the foregoing observations, we conclude that abeneficial effect with PE may be expected in patients witheither chronic relapsing or chronic progressive CIDP if theclinical, electrophysiological and histological features supportprimary demyelination and if chronic secondary axonal lossis not yet established, that is early in their disease course.

On planning the PE schedules for our trial we postulatedthat humoral factors, possibly auto-antibodies, might beimportant in the pathogenesis of CIDP (Pollard, 1987). Thedevised schedule for the apheresis procedures was aimed atremoving -90% of the putative pathogenetic factors fromthe circulation for at least 4 weeks (Buffaloe et al., 1983).Since it was our objective to make a critical evaluation ofthe effect of PE on CIDP, no concurrent immunosuppressivemedication was prescribed during the controlled trial. Weanticipated that benefit from PE might only be temporary(Server et al., 1979; Gross et al., 1981; Toyka et al., 1982)



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and that only a portion of patients would respond to PE(Pollard et al., 1983, Dyck et al., 1986). Therefore, in asubsequent third and open phase of the trial we planned toassess in the same patient group the response to prednisone,a proven effective immunosuppressant in CIDP (Dyck et al.,1982). In this part of the trial PE was optional. The intentwas to determine (i) whether the combined treatments wouldprovide added benefit and could stabilize patients and (ii)whether patients that received no benefit from PE wouldrespond to prednisone.

We were aware of the so-called rebound phenomenon, astill unexplained worsening after PE, that is possibly causedby an overshooting synthesis of antibodies or otherpathogenetic factors or by alterations in immunoregulatorymechanisms (Branda et al., 1975; Heininger et al., 1990;Dwyer et al., 1992; Rudnicki et al., 1992; Thornton andGriggs, 1994). However, we were surprised by the very rapidand profound deterioration in five patients, which occurredwithin a few days of stopping PE (illustrated in Fig. 2); anotherthree patients deteriorated more slowly. Electrophysiologicalstudies demonstrated profound conduction block, slowingof conduction velocities and dispersion of the recordedpotentials (Fig. 1) indicating very active demyelination. Atrandomization all patients appeared to have slowlyprogressive or static disease. During the rebound relapse, fivepatients deteriorated so rapidly that their disease mimicked thetime course and profile of GBS. All patients improvedsubsequently with maintenance PE and immunosuppressivedrug therapy. However, on long-term follow-up, the fivepatients with rapid rebound continued to have a very activerelapsing disease, suggesting the possibility that PE had alonger lasting effect on immunoregulation. This assumptionremains speculative, since the overt disease prior to entryinto the study had been of only short duration (3-5 months).The observations suggest that it may be important to prescribeconcurrent immunosuppression while performing PE; theyalso stress the importance of a tapering schedule of PE. Onlyone patient in our series, who had become bedbound andcompletely helpless while deteriorating further with shampheresis, improved and stabilized with PE alone. Theremainder, even those who originally had not responded toPE, improved with corticosteroids. Four patients required theadded prescription of cyclophosphamide (oral dailyprescription or 1 monthly i.v. pulse therapy; detailed earlier).In long-term follow-up (33.9±3.5 months) all patientsappeared stable and they remain well or have only mildneurological deficits.

Our observations lead us to conclude that a favourable,often marked response to PE can be expected in most patientswith CIDP, but that immunosuppressive drug treatment isoften needed in the long-term. We have shown that the rapidand impressive improvement in neurological function is dueto reversal of conduction block. Studies regarding the natureof humoral factors involved make use of plasma samples takenat various points during this trial (H.-P.Hartung, unpublishedresults). As guidelines for the PE schedule we recommend

(i) two to three apheresis procedures per week until improve-ment has occurred with (ii) subsequent tapering of the PEfrequency. Immunosuppressive drug treatments have to beindividualized according to the patient's response; prednisoneappears to be an appropriate and effective drug in mostpatients, but occasionally cyclophosphamide may benecessary.

AcknowledgementsThe authors would like to thank the following: Dr Gail Rock,chairperson of the Canadian Apheresis Group for initiatingand supporting the study and members of the group, Drs T.Shore, W. Clark, M. Katz and M. Gorelick, for theirparticipation in the trial and their supervision of the PEand SPE procedures; Drs P. Bourque, D. Zochodne, F.Grand'Maison and the late Dr Humphrey for theirparticipation in planning the trial; Drs K. Shumak, G. Ebersand A.P. Donner for acting as a safety oversight committee;and Dr Gordon Doig from the biostatistical support unit,Department of Epidemiology and Biostatistics, TheUniversity of Western Ontario for his expert assistance inthe statistical analysis of the data. The authors are gratefulto Mrs J. Miklovic and Miss B. Toth for the preparation andtyping of the manuscript and to Mr H. Remtulla and Ms L.Wilkie for preparing the illustrations. This study wassupported by a grant from the Muscular DystrophyAssociation of Canada.

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Received November 10, 1995. Revised January 26, 1996Accepted February 26, 1996



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