Plasma Exchange in Neuroimmunological Disorders Part 2

7/30/2019 Plasma Exchange in Neuroimmunological Disorders Part 2

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NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD

Plasma Exchange in Neuroimmunological Disorders

Part 2. Treatment of Neuromuscular Disorders

Helmar C. Lehmann, MD; Hans-Peter Hartung, MD; Gerd R. Hetzel, MD; Olaf Stuve, MD; Bernd C. Kieseier, MD

Plasma exchange is a well-established therapeutic procedure commonly used in many

neurological disorders of autoimmune etiology. In this second part of our review, we

assess the role of plasma exchange in the treatment of neuromuscular disorders. In Guillain-

Barre syndrome and other immune-mediated neuropathic disorders, randomized con-

trolled trials have demonstrated the therapeutic efficacy of plasma exchange. Myasthenia gravis

and Lambert-Eaton syndrome represent neuromuscular disorders where plasmapheresis might beofpotentialefficacy. ArchNeurol.2006;63:1066-1071

GUILLAIN-BARRE SYNDROME

Guillain-Barre syndrome (GBS) r epre-sents a spectrum of neuropathic disor-ders, including classic acute inflamma-tory demyelinating polyneuropathy,axonalvariants with or without sensory involve-ment (acutemotor andsensory axonal neu-ropathy and acute motor axonal neuropa-thy, respectively), and clinical variants such

as Miller Fisher.1,2

Aberrant humoral andcellular immune response systems are in-volved in the pathogenesis of GBS. Mo-lecular mimicry, in which epitopes inci-dentally shared by microbial antigens andnerve structureselicitan autoreactive T-cellor B-cell response in the wake of an infec-tive illness, may trigger the autoimmuneprocess.3 In about 60% of cases, GBS fol-lows closely an infection, most frequentlycaused by the microbiological agent Cam-pylobacter jejuni.3-5 Activated T cells mi-grate across the blood-nerve barrier andarereactivated in situ when their autoantigen

is appropriately displayed by macro-phages along with major histocompatibil-ity complex II products and co-stimula-torymolecules. Autoantibodies crossing theblood-nerve barrier en passant with T cellsor accessing target structures directlyat the

most proximal or distal parts of the nervecontribute to the inflammatory process byantibody-dependent cytotoxicity and acti-vation of complement (Figure 1).2 A largevariety of antibodies against different gly-colipids,includingGM1, GD1a, andGQ1b,among others, have been described.6

Plasma exchange is well established astreatment in GBS.7 Its therapeutic use overand above supportive care has been dem-

onstrated in 2 large randomized, con-trolled, nonblinded, multicenter trials(class I evidence). In the first study, 245patients were included andreceived plasmaexchange or conventional supportivetherapy8 (Table). Clinical outcomes, thatis, time to improve 1 clinical grade andtime to independent walking, were as-sessed at 4 weeks and 6 months. In thestudy of the French Cooperative Group onPlasma Exchange in Guillain-Barre Syn-drome,9 220 patients were included, 109of whom underwent plasmaexchange andwere compared with 111 patients de-

fined as the control group. Substantial ben-efit was documented for the primary endpoint, that is, time to recover the abilityto ambulate with assistance, and in sec-ondary factors such as thereduction of theproportion of patients who needed as-sisted mechanical ventilation,a morerapidtime of onset of motor recovery, andclini-cal factors such as time to walk with andwithout assistance (Table).9 The samegroup reported also the long-term ben-

Author Affiliations: Departments of Neurology (Drs Lehmann, Hartung, andKieseier) and Nephrology (Dr Hetzel), Heinrich Heine University of Dusseldorf,Dusseldorf, Germany; and Department of Neurology, The University of TexasSouthwestern Medical Center at Dallas (Dr Stuve).

(REPRINTED) ARCH NEUROL/ VOL 63, AUG 2006 WWW.ARCHNEUROL.COM1066

2006 American Medical Association. All rights reserved.

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efit in the plasma exchange population as recovery of fullmuscle strength after 1 year in 71% of patients com-pared with 52% of subjects in thecontrolgroup.10 A 1997study addressed the optimal number of plasma ex-change sessions in the treatment of GBS.11 In this ran-domized, controlled, nonblinded trial, 556 patients wereincluded and randomized to 3 groups according to de-gree of disability. Patients with mild disability under-went either 0 or 2 plasma exchange sessions, those withmoderate disability underwent 2 or 4 sessions, and thosewith severe disability underwent 4 or 6 sessions. It couldbe demonstrated that 2 vs 0 plasma exchange sessionsin patients with mild disability and 4 vs 2 plasma ex-change sessions in patients with moderate disability were

more beneficial. More than 4 treatments did not yield ad-ditional benefit in patients receiving mechanical venti-lation in the group with severe disability. This study pro-vided important guidelines as to the number of plasmaexchange sessions to be performed in patients with dif-ferent degrees of disability (class I evidence) (Table).Also,patients with mild symptoms can benefit from plasma ex-change, whereas more than 4 plasma exchange sessionsare not indicated in patients with severe symptoms.11,12

Based on several studies of class I evidence, plasma ex-change has been established as effective treatment in thetherapy of GBS (type A recommendation), which is re-flected in thelast updated review from theCochrane Col-laboration. Plasma exchange is most beneficial when

started within 7 days of disease onset, but is also effica-cious when started after 30 days.13

PLASMAPHERESIS VS INTRAVENOUSIMMUNOGLOBULIN THERAPY

Compared with the other available therapeutic approachin GBS, that is, intravenous immunoglobulin therapy(IVIG), plasma exchange is considered equally effica-cious (class I evidence).7 This statement is based on theresultsfrom2 trials. Thefirst randomized, controlled, non-

blinded study included 150 patients with GBS assigned toeither undergo plasma exchange or receive IVIG.14 Pri-mary outcome was assessed after 4 weeks as motor recov-ery by at least 1 grade on the predefined 7-point scale ofmotor function (Hughes scale).15 In the IVIG group, 53%of patients demonstrated improvementcomparedwith34%of patients in theplasmaexchange group.Theauthorscon-cluded that IVIG is at least as effective as plasma ex-change in the treatment of GBS and is associated with a

lower rate of complications. A randomized controlled trialof 383 patients with GBS compared the relative efficacyof plasma exchange, IVIG, and IVIG after plasma ex-change.16 Primary outcome measure was also improvedat 4 weeks by at least 1 grade on a 7-point scale of motorfunction. No significant differences in primary and sec-ondary outcome measures were reported. In conclusion,plasma exchange and IVIG are of at least equal efficacy inthetreatmentof GBS (type A recommendation).Thecom-bined treatment of plasma exchange and IVIG does notseem to have an additional benefit.

PLASMAPHERESIS VS CEREBROSPINAL FLUIDFILTRATION (LIQUORPHERESIS)

During cerebrospinal fluid filtration (liquorpheresis),cerebrospinal fluid is automatically withdrawn througha spinal catheter and reinfused. During 1 session, 150 to250 mL of cerebrospinal fluid is cycled, and this isrepeated 5 to 15 times. One randomized controlledstudy17 compared liquorpheresis with plasma exchangein 37 patients with GBS. No differences in the primaryoutcome variable (improvement within 4 weeks) andseveral secondary outcome measures were observed.The authors concluded that the 2 treatments are equallyefficacious. The study raised several concerns. First, thetrial may have been underpowered for the size of thepatient cohort required to show a difference between

the 2 study groups. Another weakness of the unblindedstudy was that important outcome measures used inprevious trials, such as the median time to improve-ment by 1 functional grade, were not assessed.18 Thestudy, therefore, is rated only as a trial of class II evi-dence (type C recommendation).

IMMUNOADSORPTION IN GBS

By use of immunoadsorption, selective removal ofimmunoglobulin fractions can be achieved. In GBS,some small retrospective studies compared efficacy andadverse effects of immunoadsorption with plasma

exchange and found no major differences.19,20

However,the selective elimination of presumed pathogenic anti-bodies by use of specifically designed immune-affinitycolumns might be a future approach to optimize thistherapeutic procedure and minimize adverse effects.Recently, Willison et al21 demonstrated the proof ofprinciple experimentally. AntiGQ1b antibodies couldbe immunodepleted in serum samples from patientswith the Miller Fisher variant of GBS by using a syn-thetic trisaccharide as specific epitope for antiGQ1bantibodies.21

Infection(CMV, C jejuni)

IL-4IL-6

Abs

Blood

BNB

Complement

C jejuni

B

T

NMJ

Complement

T

IL-4IL-6

Myelin

Node ofRanvier

BC5b-9

M

Figure 1. Humoral immune response in inflammatory neuropathic disorders.Autoantibodies crossing the damaged blood-nerve barrier (BNB) or producedby local B cells (B) causing demyelination by complement activation andmacrophage (M)-dependent cytotoxicity. Other pathological effectsinclude interference with nerve conduction at the nodes of Ranvier oralteration of neuromuscular transmission. Abs indicates antibodies;C jejuni, Campylobacter jejuni; IL, interleukin; NMJ, neuromuscularjunction; T, T cells.





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CHRONIC INFLAMMATORYDEMYELINATING POLYNEUROPATHY

Chronic inflammatory demyelinating polyneuropathy(CIDP) is an acquired, immune-mediated, peripheral neu-ropathic disorder. Its response to immunosuppressivetherapy and its clinical resemblance to GBS suggest an

autoimmune origin of the disease.22-24 The presence ofautoantibodies against various proteins and glycolipidsof the peripheral nerve in samples of serum and cere-brospinal fluid from patients with CIDP25-27 may pro-vide a rationale for the therapeutic use of plasma ex-change. Treatment usually consistsof either corticosteroidtherapy or IVIG or plasma exchange, followed by long-

Table. Summary of Selected Trials for Plasma Exchange in Disorders of the Peripheral Nervous System

Trial/Source Study Characteristics and DesignNo. of

Patients Outcome

Guillain-Barre Syndrome

Guilla in-Barre SyndromeStudy Group8

PE vs supportive care; single blinded 245 Improvement at 4 wk, t ime to improve 1 clinical grade,time to independent walking, and outcome at 6 moin the PE group

French CooperativeGroup on PlasmaExchange inGuillain-BarreSyndrome9

PE (4) with albumin (n = 57) vs PE (4)with fresh frozen plasma (n = 52) vs noPE (n = 111); nonblinded

220 Shorter time to recover walking with assistance (30 vs44 d; P.01) in PE group; fewer patients requiringassisted ventilation, shorter time to onset of motorrecovery; no differences between PE groups

French CooperativeGroup on PlasmaExchange inGuillain-BarreSyndrome11

3 Groups: mild disability, 0 vs 2 PEsessions; moderate disability, 2 vs 4 PEsessions; severe disability, 4 vs 6 PEsessions; nonblinded

556 Two PE sessions more effective than 0 sessions fortime to onset of motor recovery (4 vs 8 d; P.001)in group with mild disability; 4 PE sessions superiorto 2 PE sessions for time to walk with assistance(20 vs 24 d; P= .04) in group with moderatedisability; no difference between 4 and 6 PEsessions in group with severe disability

Dutch Guillain-BarreStudy Group14

PE (5) vs IVIG (0.4 g/kg per day, 5 d);nonblinded, bias controlled

150 Improvement1 point on functional score, 34% in PEgroup vs 53% in IVIG group (P= .02); time toimprovement by 1 grade 41 vs 27 d (P= .05); bothtreatments are of equal efficacy, but IVIG may besuperior

Plasma

Exchange/SandoglobulinGuillain-BarreSyndrome TrialGroup16

PE (5) (n = 121) vs IVIG (0.4 g/kg/d, 5 d)

(n = 130) vs PE (5) IVIG (0.4 g/kg/d,5d) (n = 132); single blinded

383 No significant difference in major outcome measure

(improvement on disability scale after 4 wk) orsecondary outcome measures (time to recovery ofunaided walking and time to discontinuation ofmechanical ventilation)

Wollinsky et al17 Liquorpheresis vs PE; nonblinded,crossover to alternative treatment in caseof no improvement

37 Clinical improvement after 28 d similar in both groups;no significant differences in secondary outcomemeasures

Chronic Inflammatory Demyelinating Polyneuropathy

Dyck et al31 PE (6) vs sham treatment; double blinded 29 Significantly better outcome in measurements of nerveconduction (total, motor, proximal, velocity, andamplitude) in PE group

Hahn et al32 PE (10) vs sham treatment; doubleblinded, crossover

18 Significant improvement in PE group in clinicaloutcome measures (NDS) and in mostelectrophysiological measurements

Dyck et al33 PE (7) vs IVIG (0.4 g/kg, 1 per 3 wk, then0.2 g/kg, 1 per 3 wk); single blinded,crossover in case of no improvement orworsening

20 No significant differences between the 2 groups inclinical outcome (NDS) and electrophysiologicalparameters

Paraproteinemic Polyneuropathy

Dyck et al37 PE (6) vs sham treatment; double blinded 39 Marked improvement in NDS (46.3 to 58.3 in PEgroup, 60.5 to 62.5 in sham treatment group;P= .06); no differences in electrophysiologicalparameters (summed motor nerve conductionvelocity, sensory nerve action potentials); morebenefit in the IgG and IgA gammopathy subgroupscompared with the IgM gammopathy population

Myasthenia Gravis

Myasthenia GravisClinical Study Group60

PE 3 (n = 41) vs IVIG (0.4 g/kg) for 3 d(n = 23) vs IVIG (0.4g/kg) for 5 d(n = 23); nonblinded

87 No difference in the primary outcome measure(variation of MMS) between PE and IVIG groups(18 vs15.5; P= .65); similar efficacy betweenthe IVIG groups

Abbreviations: IVIG, intravenous immunoglobulin; MMS, myasthenic muscular score; NDS, neurological disability score; PE, plasma exchange.





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term immunosuppression with azathioprine or cyclo-sporine.7,28-30

Tworandomized,controlled,double-blindstudiespro-vided class I evidence that plasma exchange is superior toshamtreatmentinCIDP.31,32 Thus,plasmaexchangecanberecommendedinthetreatmentofCIDP(typeArecommen-dation).TheefficacyofplasmaexchangecomparedwithIVIGwas investigatedin a small crossover, single-blinded studyin20patientswithCIDP.Aclinicalscoreandsummatedcom-

pound muscle action potential of motor nerves as electro-physical parameter served as primary outcome measures.Animprovementintheprimaryoutcomemeasureswasdocu-mented for both treatments. Statistically significant differ-encesbetween IVIG andplasma exchangewerenotnoted.33

Thepatient cohorts in this study were toosmall to demon-strateasignificantdifferencebetweenthe2treatments;thus,itisratedasatrialofclassIIevidence.Todate,therearenotenoughdataavailableto give preferentialrecommendationto eitherplasmaexchangeor IVIG.There isconsensus thattreatment of CIDP should be tailored to each patient.

PARAPROTEINEMIC NEUROPATHIES

In approximately10%of patientswithidiopathicpolyneu-ropathic disorders, a monoclonal immunoglobulin can bedetected in serum or urine.34 Monoclonal gammopathy ofundetermined significance isthemost frequentform.35 Lym-phoproliferative disorders such as Waldenstrom macro-globulinemia are other monoclonal gammopathies. In ap-proximately 50% of IgM gammopathyassociatedneuropathic disorders, antibodies are directed to myelin-associated glycoprotein.36 In a randomized, controlled,double-blind trial, Dyck et al37 studied the effectiveness ofplasma exchange in the treatment of polyneuropathy as-sociated with monoclonal gammopathy of undeterminedsignificance. Thirty-nine patients were randomly as-signed to receive either plasma exchange twice weekly for

3 weeks or sham treatment. Based on its effects on the2 primary outcome measures, that is, the neuropathy dis-ability score andthesummedcompound muscleactionpo-tentials of motor nerves, a treatment benefit was sug-gested for plasmapheresis,whereasin secondary endpoints,that is, nerve conduction velocity and sensory nerve ac-tion potentials, no statistically significant differences werefound. The study demonstrated, furthermore, that pa-tientswith IgG or IgAgammopathy benefit more than thosewith IgM gammopathy37; hence, plasma exchange can berecommended in at least this subgroup of patients (class Ievidence, type A recommendation).

To date, the role of plasma exchange in the treatmentof neuropathologic disorders associated with lympho-

proliferative disorders (eg, POEMS [polyneuropathy, or-ganomegaly, endocrinopathy, M protein, skin changes]syndrome or Waldenstrom macroglobulinemia)has beenstudied only in small case series38-40 generating class IIIevidence, and, in aggregate, its therapeutic value re-mains unclear (type U recommendation).

MYASTHENIA GRAVIS

Myasthenia gravis is an autoimmune-mediated disorderof the neuromuscular junction, clinically characterized

by fluctuating muscle weakness and fatigability.41,42

Themost common variant of the disease is mediated by cir-culating autoantibodies against the nicotinic acetylcho-line receptor (AChR) (Figure 2)43-46 Mechanisms re-sponsible for loss of functional AChR that compromiseor abort safeneuromuscular transmission include the deg-radation of the AChR,47 complement-mediated lysis ofthe AChR,48 and interference with neurotransmitter bind-ing.49 In subgroups of patients negative for AChR anti-body, other antibodies with different specificities can bedetected, for example, antibodies against the muscle-specific receptor tyrosine kinase (Figure 2).50,51

The treatment of myasthenia gravis includes thymec-tomy and use of acetylcholine esterase inhibitors, corti-

costeroid agents, immunosuppressive agents, plasma ex-change, and IVIG.52 Plasma exchange might be useful inmyasthenic crisis and in the preoperative and postop-erative phases of thymectomy in severe forms of myas-thenia gravis.53 It is presumed that elimination of circu-lating AChR antibodies and other humoral factors ofpathological significance account for the observed ben-eficial effects of plasma exchange.

While current conceptsof thepathogenesisof andclini-cal experience in myasthenia gravis, which have evolvedover more than 2 decades,54-56 have provided a clear ratio-nale forthe useof andcollectively demonstrateda salutaryeffect of plasmaexchange, there is, to date, no convincingrandomizedcontrolled trial to prove short-termbenefit in

myastheniccrisisorlong-termbenefitofplasmaexchange.57,58

Although the level of evidence is lower than in other neu-rological disorders (class IV evidence, type U recommen-dation), the Therapeutics and Technology AssessmentSubcommittee of the American Academy of Neurology59

considered plasma exchange in the preoperative prepara-tion and treatment of myasthenic crisis as established.

A randomized, controlled, 3-armed trial comparedplasmaexchangewith 2 regimensof IVIG in thetreatmentofacute exacerbationsinmyastheniagravis.60 Eighty-sevenpatients were randomizedeither to undergo 3 plasma ex-

ACh

Anti-AChRAnti-MuSK

Muscle

C5b-9

Figure 2. Myasthenia gravis. Autoantibodies against the acetylcholinereceptor (AChR) or against the muscle-specific receptor tyrosine kinase(MuSK) cause muscle weakness by disturbing neuromuscular transmission.ACh indicates acetylcholine.





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change sessions or to receive IVIG (0.4 g/kg per day) for3 or 5 consecutive days. As a primary outcome measure,thechangein myasthenicmuscularscorebetweenrandom-ization and day 15 was chosen. Secondary end points in-cluded, among others, the decreaseofanti-AChRantibodytiters. Clinicalimprovementwasobservedin all patients,butno statisticallysignificant difference intheprimaryendpoint or in theeffect onanti-AChRantibodiesbetween the2 groups (plasmaexchangevs IVIG) wasdocumented.Ad-

verse effects were less frequent in the IVIG group.

LAMBERT-EATON MYASTHENIC SYNDROME

Lambert-Eaton myasthenic syndrome (LEMS) is an im-mune-mediated, presynaptic neuromuscular junctiondis-order mediated by antibodies against neuronal P/Q-typevoltage-gated calcium channels.61-63 In about 60% of pa-tients, LEMS is associated with small cell lung carcinoma,but it can also occur outside the context of neoplasia.

To our knowledge, no randomized controlled trial hasinvestigatedthebenefitofplasmaexchangeinLEMS,althoughcaseserieshaverepeatedlyreportedaneffectonclinicalandelectrophysiological parameters in patients with LEMS,

whether associated with malignancy or not.64-66

Newsom-DavisandMurray65 described9 patientstreatedwith plasmaexchangeandimmunosuppressivedrugs, 8 ofwhomexhib-itedimprovement in clinicaland electrophysiologicalout-come measures (class IV evidence). A description of 2 pa-tientswithLEMStreatedwithplasmaexchangeinvestigatedtiters of antibodies directed by P/Q-type voltage-gatedcal-ciumchannelsduringtheclinicalcourseandthetherapeu-ticprocedure.67 Titersdecreasedaftertreatmentwithplasmaexchange but returned to baseline levels after 1 week. Ac-cordingly, the authors observed only a temporary clinicalimprovementaftertreatment withplasmaexchangealone.Thesefindingssuggestonlytransient benefitforpatientswithLEMS,perhapscaused bythe highrate ofproduction ofan-

tibodiestotheP/Q-typevoltage-gatedcalciumchannels.Therole of plasma exchange in thetreatmentof LEMS remainsto be further explored (type U recommendation).

NEUROLOGICAL DISEASES WITH PROVEDOR ASSUMED INEFFECTIVENESS

OF PLASMA EXCHANGE

One randomized controlled trial investigated the effectof plasma exchange in the treatment of inflammatory my-opathies.68 In this 3-armed, double-blind study, 39 pa-tients with either dermatomyositis or chronic polymyo-sitis refractory to corticosteroid therapy were enrolled toreceive plasma exchange, leukapheresis, or sham treat-

ment in 12 treatment cycles. No statistically significantdifferences were observed for final muscle strength orfunctional capacity. Thus,plasma exchangecannot be rec-ommended in the treatment of inflammatory myopathy(class I evidence, type A recommendation).

Amyotrophiclateral sclerosisischaracterizedbylateon-setand progressiveloss ofmotorneurons,leading to paraly-sisanddeath.69 Severalsmall studiesof plasmaexchangewereconducted70,71 butfailedto detect anysubstantial alterationin the disease course. Therefore, plasma exchange is pos-siblyineffective(classIIIevidence,typeC recommendation).

Multifocal motor neuropathy is an acquired demyelin-atingmotorneuropathy, clinicallycharacterizedby progres-sive, predominantlydistal,andasymmetric limbweaknesswithonlyminorornosensorydeficit.72-74Althoughthepatho-genesis is not known, the frequent occurrence of IgM an-tibodies against GM1 may imply an immune-mediatedorigin. In contrast to other chronic forms of inflammatoryneuropathy,multifocalmotor neuropathy usuallydoes notrespond to corticosteroid therapy,whereas treatment with

IVIGhas shown efficacy.

75

Onlyafewarticlesabouttheuseof plasma exchange in multifocal motor neuropathy havebeen communicated. Most of them did not show any im-provementinclinicalorelectrophysiological parameters,andsome reportedsevereclinicalworsening (classIVevidence,type U recommendation).76,77

CONCLUSIONS

Therapeutic efficacy of plasma exchange in certain neuro-logical conditions, including GBS, CIDP, and paraprotein-emic polyneuropathic disorders,has been demonstrated inlargerandomized controlled studies with a high level of evi-dence.In some of these neurological disorders, plasma ex-

changeis thetherapeutic gold standard to which newtreat-ments are compared, whereas in other neurologicaldisorders, the therapeutic value of plasma exchange re-mains less clear. Despite the long clinical experience andthe frequent use of plasma exchange in neurology, thereremain important unresolved questions. What is the ap-propriate number of plasma exchange sessions in a givenneurological disorder?Does plasma exchangeinterferewithother immunosuppressive or immunomodulatory agents?How can adverse effects be averted to enhance safety andtolerability? What is thelong-term effecton theclinical dis-ease course and the disturbed network of T cells, B cells,and humoral factors? For almost all current indications inneurology, further studies are necessary to developplasma

exchange as an optimized treatment method.

Accepted for Publication: October 26, 2005.Correspondence: Hans-Peter Hartung, MD, Depart-ment of Neurology, Heinrich Heine University of Dus-seldorf, Moorenstrasse 5, 40225 Dusseldorf, Germany([email protected]).Author Contributions: Study concept anddesign: Hartung,Hetzel, and Stuve.Acquisition of data: Stuve.Analysis andinterpretation of data: Lehmann, Hartung, Hetzel, Stuve,and Kieseier. Drafting of the manuscript: Lehmann,Hartung, and Stuve. Critical revision of the manuscript forimportant intellectual content: Hartung, Hetzel, andKieseier. Obtained funding: Kieseier.Administrative, tech-

nical, and material support: Hartung and Stuve. Study su-pervision: Hetzel and Stuve.

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Plasma Exchange in Neuroimmunological Disorders Part 2