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Plasma Exchange for NeurologicalDisorders

PLASMA exchange (PE), first used as an

experimental procedure to support nephrectomiseddogs,l entered clinical practice as a means for

procuring blood products in 19442 and as an

experimental treatment for macroglobulinaemia in1959. Encouraging case-reports and small trials ledto the therapeutic use of PE in various putativeautoimmune and vasculitic disorders affecting specificorgans, including the joints, skin, and kidneys, ormultiple systems, such as systemic lupuserythematosus and polyarteritis. Neurologicaldisorders account for approximately half of the20 000-30 000 therapeutic PE procedures carried outannually in the USA. The effectiveness of this methodof treatment in neurological disease has now beendiscussed at a consensus development conferenceconvened by the National Institute of Neurologicaland Communicative Disorders and Stroke and theNational Institutes of Health Office of Medical

Applications of Research. 5

Any statement about the usefulness of PE must beprefaced by an acknowledgment of its risks. Informaldata collected worldwide between 1978 and 1983

suggest a fatality rate of 3 per 10 000 procedures; someof the deaths may have been due to the use of whole

plasma rather than albumin as a replacement fluid.5Complications include fluid imbalance, hypo-proteinaemia, and citrate-induced hypocalcaemia,which should be avoidable. Activation of coagulation,

1. Abel JJ, Rowntree LG, Turner BB. Plasma removal with return of corpuscles. ExptlTher 1914; 5: 625-41.

2. Co Tui, Bartter FC, Wright AM, Holt RB. Red cell reinfusion and the frequency ofplasma donations. JAMA; 1944; 124: 331-36.

3. Skoog WA, Adams WS. Plasmapheresis in a case of Waldenstrom’s

macroglobulinaemia. Clin Res 1959; 7: 96-97.4 Editorial. Plasmapheresis in macroglobulinaemia. Lancet 1977; li: 807-08.5 Consensus Conference. The utility of therapeutic plasmapheresis for neurological

disorders. Statement. JAMA 1986; 256: 1333-37.

complement, or fibrinolytic cascades and haemor-rhage secondary to systemic anticoagulants may alsooccur. Difficulty with venous access can be overcomeby technical skill; femoral or central venous lineswhich have their own hazards may be necessary. Therisks of transmission of infection and allergic reactionscan be minimised by use of albumin as the exchangematerial.

Antibodies to the acetylcholine receptor are presentin almost all patients with myasthenia gravis. Inindividual patients their correlation with severity6provides a firmer theoretical basis for the therapeuticuse of PE in myasthenia than in any other disease.Even those patients in whom antibodies cannot bedetected by the usual radioimmunoassay haveantibodies which block neuromuscular transmissionin mice.7 PE leads to improvement in more thantwo-thirds of patients, usually within one to three daysof the start of the course; the response may be sodramatic that controlled trials have not beenconducted. Unfortunately the effects last only a fewweeks. Consequently, the consensus conferenceendorsed the use of PE in myasthenia only in specificsituations-the early stage before other treatmentshave had time to work; in a crisis; or in chronic cases asan adjunct when the response to other forms ofimmunosuppressive treatment is unsatisfactory. Thehope that PE might work synergically to enhance theeffect of other immunosuppressive agents has notbeen realised.8 The Eaton-Lambert myasthenicsyndrome is a rare disorder of neuromusculartransmission probably caused by an antibody to

calcium channels on the presynaptic membrane.9 PEhas been reported to be a useful adjunct to otherimmunosuppressive treatment. 10 The consensus viewwas that PE was probably effective in this rare

disorder. 5

In Guillain-Barre syndrome two small trials did notshow definite effects from PE, whereas three othertrials, including one involving 250 patients in NorthAmerica, reported considerable benefits .11-13 Theconclusion was that PE is useful for patients whoseweakness is so severe that they are unable to walkunaided. 5 Treatment should be started early,preferably within the first two weeks of symptoms. 5The benefits anticipated include a shortening of thetime to walk unaided by about 30 days from a medianof 85 days and, for those patients who are ventilated,

6. Editorial The diagnosis of myasthenia gravis. Lancet 1986; i: 658-607. Mossman S, Vincent A, Newsom-Davis J. Myasthenia gravis without acetylcholine-

receptor antibody: a distinct disease entity. Lancet 1986; i: 116-19.8. Hawkey CJ, Newsom-Davis J, Vincent A. Plasma exchanage and immunosuppressive

drug treatment in myasthenia gravis: no evidence for synergy. J NeurolNeurosurg Psychiatry 1981; 44: 469-75.

9. Lang B, Newsom-Davis J, Wray D, Vincent A, Murray N. Autoimmune aetiology formyasthenic (Eaton-Lambert) syndrome. Lancet 1981; ii: 224-26.

10. Newsom-Davis J, Murray NMF. Plasma exchange and immunosuppressivetreatment in the Lambert-Eaton myasthenic syndrome. Neurology (NY) 1984; 34:480-85.

11. The Guillain-Barré Syndrome Study Group. Plasmapheresis and acute Guillain-Barré syndrome. Neurology (NY) 1985; 35: 1096-104.

12. Editorial. Plasma exchange m the Guillain-Barré syndrome. Lancet 1984; ii: 1312-13.13. Hughes RAC. Plasma exchange for Guillain-Barré syndrome. Br Med J 1985; 291:

615-16.

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halving of the median time spent on the ventilatorfrom 48 days to 24 days." The distress produced byGuillain-Barre syndrome has been eloquentlydescribed in Joseph (Catch 22) Heller’s account of hisown illness, in which he narrowly avoidedventilation.14 To a shortening of duration of sufferingand disability can be added the economic argumentthat use of PE saves money by considerably reducingintensive care unit and hospital stay costs and,probably, time off work. However, the caveat

concerning risks of PE applies particularly to

Guillain-Barre syndrome with which patients areacutely ill, liable to chest infections and cardiacarrhythmias, and, because of autonomic dysfunction,unusually susceptible to hypovolaemia from rapidplasma volume changes.

Although a single carefully conducted controlledtrial has shown at least temporary benefit from PE inthe chronic counterpart of Guillain-Barre syndrome,chronic inflammatory demyelinating polyradiculo-neuropathy,is the conference concluded that benefitwas possible or probable rather than proven. 5

Nevertheless, anecdotal reports indicate that in somepatients PE can be as dramatically, and briefly,effective as in. myasthenia gravis. Attempts to identifyan antibody or toxic factor in the plasma or serum ofthese individuals have not been successful.

In some cases of chronic neuropathy associatedwith paraproteinaemia antibodies to particular myelinor axonal antigens have been demonstrated. The bestcharacterised disorder is monoclonal gammopathy ofundetermined significance associated with an IgMkparaprotein which is an antibody directed against anepitope shared by peripheral nerve myelin glycolipids,myelin associated glycoprotein, and some neuronalsurface antigens.16 The evidence is that demyelinatingneuropathy is caused by the paraprotein rather than anepiphenomenon. 17 Some patients have improved aftercytotoxic treatment combined with PE18 but the placeof PE is not yet established in the treatment of this raredisorder.s PE has also been tried in a few patients withmotoneurone disease but without benefit 719 a resultin keeping with the lack of any notable inflammatoryresponse or demonstrated humoral toxin in thisdisorder.

In severe chronic progressive multiple sclerosis asmall double-blind controlled trial of true vs sham PEshowed a benefit in favour of the true PE group.20Both groups also received prednisone and low-dose

14. Heller J, Vogel S. No laughing matter. London: Jonathan Cape, 1986.15. Dyck PJ, Daube J, O’Bnen P, et al. Plasma exchange in chronic inflammatory

demyelinating polyradiculoneuropathy. N Engl J Med 1986; 314: 461-65.16. O’Swannessy DJ, Ilyas AA, Dalakas MC, Mendell JR, Quarles RH. Specificity of

human IgM monoclonal antibodies from patients with peripheral neuropathy.J Neuroimmunol 1986; 11: 131-36.

17. Meier C. Polyneuropathy in paraproteinaemia. J Neurol 1985; 232: 204-14.18. Sherman WH, Olarte MR, McKiernan G, Sweeney K, Latov N, Hays AP. Plasma

exchange treatment of peripheral neuropathy associated with plasma cell dyscrasia.J Neurol Neurosurg Psychiatry 1984; 47: 813-14.

19. Norris FH, Denys EH, Mielke CH. Plasmapheresis in neurologic disorders. ClinNeuropharmacol 1982; 5: 93-114.

20. Khatri BO, McQuillen MP, Harrington GJ, Schmoll D, Hoffman RG. Chronicprogressive multiple sclerosis: double-blind controlled study of plasmapheresis inpatients taking immunosuppressive drugs. Neurology 1985, 35: 312-19.

(1-5 mg/kg/day) oral cyclophosphamide. The

improvements as assessed by the Kurtzke disabilitystatus scale were greater in the group receiving truePE. The consensus view was that one small trial wasinsufficient to permit a general recommendationthat PE be used in this form of multiple sclerosis.sUntil results of ongoing trials of PE and other

immunosuppressive treatments are available treat-ment with PE or other potentially hazardous

immunosuppressive regimens must be regarded asexperimental. Although about 5 % of patients pursue amalignant course with severe disability in about 5years, most patients have a more gradual downhillcourse and survive for 25 years or more. For the greatmajority of patients, therefore, a treatment as

uncomfortable, time consuming, and expensive as PEis unlikely to be appropriate. For those in whom majorlongstanding neurological deficits have alreadydeveloped it is unlikely to be effective. Furthercontrolled trials of PE and similar treatments would be

appropriate in the minority of patients pursuing amore malignant course.

The purpose of a consensus developmentconference is to consider a medical technique ortreatment and catalyse its introduction into medicalpractice. The consensus statement from a panel ofexperts that the benefits of PE are worth further

investigation in Eaton-Lambert syndrome, chronicinflammatory demyelinating polyradiculoneuro-pathy, paraproteinaemic neuropathy, and multiplesclerosis should encourage researchers and grant-giving bodies to invest time and resources in thispromising area. The clear conclusions that the

procedure is of established value in Guillain-Barresyndrome and myasthenia gravis should persuadephysicians who look after these patients in generalwards and intensive care and neurology units to

consider whether they have sufficient resources toprovide PE as an emergency or at least urgentprocedure; it will almost certainly be necessary to carefor these patients in designated regional units. ForGuillain-Barre syndrome the case for provision ofthese facilities can be argued powerfully because thereduction of the time spent on the ventilator and thetime taken to walk unaided are considerablyshortened. Thus the costs of PE should be more thanoffset by savings in the costs of accommodation in theintensive care units and hospital ward. On the

assumption that reduction of time on the ventilator isequivalent to the same reduction of stay in theintensive care unit, in one UK teaching hospital it wasestimated that, on the basis of average costs, use of PEwould save 6500 for each ventilated patient. Fornons ventilated patients with severe Guillain-Barresyndrome, if reduction of time to walk unaided isequated with shortened time in hospital, the use of PEwould save 4000. Joseph Heller calculated that hisfairly mild Guillain-Barre syndrome cost him 112 372dollars and 12 cents.