-Special Article Neurology 199Q4Z840-843 Assessment of plasmapheresis Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology In this article, we have assessed the value of plasma- fused with the reconstituted solution; that is, either blood pheresis as a tool for treatment of patients with neu- goes out or the reconstitute goes in, but both do not occur rologic disorders. We chose to use the more common simultaneously. The newer and more efficient continuous- term “plasmapheresis,” which technically means re- flow machines remove whole blood from one intravenous moval of plasma only, for the proper term, “plasma site while simultaneously and continuously returning the exchange,” which technically refers to both removal reconstituted elements through another intravenous site. of plasma and its replacement. In the literature, Continuous-flow machines shorten the time of PP. If ve- these terms are used interchangeably. nous access is limited, most continuous-flow machines can Using the Medline search, including the “back 90” be operated in a discontinuous manner with one venous and “back 85” backfiles, we batched the terms “plas- access. mapheresis” and “neurologic disease (exploded)” Replacement solutions. Usually 1 to 1%plasma vol- from 1985 to 1995, which yielded a total of 544 arti- umes are removed at each procedure. This requires re- cles. The titles of these articles were scanned and placement with albumin or plasma protein fractions in those thought relevant to the assessment were re- combination with sterile saline. There is no risk of disease viewed in their entirety. In addition, a Medline transmission if blood products other than albumin and search was made that cross-referenced the terms plasma protein fractions are avoided. “plasmapheresis” and “neurologic diseases (explod- Anticoagulants. Regional anticoagulation with citrate ed)” with “randomized controlled trial” (publication is usually used. While this may result in transient hy- type). We excluded articles about plasmapheresis pocalcemia, it is less risky than using systemic anticoagu- used to treat stroke. This led to only six citations. We lation with heparin. also relied upon the NIH Consensus Conference of Presumed mechanisms. A variety of possible mecha- 1986 on Plasmapheresis and Neurologic Disease.* nisms for the actions of therapeutic PP has been pro- We spoke with experts in the field, and several indi- posed, including removal of antibody, removal of allo- viduals wrote directly to the AAN to express their antibody, removal of immune complexes, removal of a opinions. monoclonal protein, removal of toxin or cytokine(s), re- plenishment of a specific plasma factor, and, lastly, the placebo effect. For most neurologic diseases, PP presum- Plasmapheresis. Mechanics. Plasmapheresis (PP) is ably removes pathogenic antibodies from the immuno- the removal of whole blood from the patient,RETIRED its separation globulin fraction of serum. Only in myasthenia gravis by machine into component parts, and then the return of (MG), however, has this presumption been shown,2J in certain of those components to the patient. The PP de- that patient improvement is associated with a drop in scribed in this assessment is the separation of the formed antibody titers as a result of PP. In most of the other elements from the liquid elements in blood, the reconstitu- tion of the formed elements with another plasma source diseases discussed below, the pathogenic antibodies are (either natural or artificial), and the reinfusion of that not identified or, if identified, have not been measured plasma source along with the patient’s own formed ele- in a rigorous fashion. It should be noted, however, that ments. On occasion, although rarely used in neurologic other mechanisms may exist. Indeed, PP can be looked disorders, this procedure can be adjusted to remove white upon as a “blunderbuss” that removes all the nonformed cells, platelets, or immunoglobulins alone. elements in plasma, including immunoglobulins, cyto- The literature refers to both discontinuous- and contin- kines, and other serum factors, in a nonspecific fashion. uous-flow machines. In discontinuous-flow machines-the The specific factor whose removal is crucial in therapeu- older and now less common type-whole blood is removed tically successful PP is thus not specifically known. Sur- from the patient, separated and reconstituted, and then prisingly, systematic data on the effects of PP in controls the removal of whole blood stopped and the patient rein- are scarce; that is, little is known about the effects of PP See page 842 for Panel and Subcommittee members. Approved by Therapeutics and Technology Assessment Subcommittee November 5, 1995. Approved by the AAN Practice Committee December 9, 1995. Approved by the AAN Executive Board January 13, 1996. Received February 7, 1996. Accepted in final form February 12, 1996. Address correspondence and reprint requests to the Therapeutics and Technology Assessment Subcommittee, American Academy of Neurology, 2221 University Avenue SE, Suite 335, Minneapolis, MN 55414. c 840 Copyright 0 1996 by the American Academy of Neurology Table Summary of the American Academy of Neurology mendation. Whether PP should be used in patients with assessment of plasmupheresis GBS who are less severely affected is unknown at this ~~ ~~~~ time. Disease Definitions Quality Strength ~ ~ ~~ ~~ Chronic inflammatory demyelinating polyrat-liculoneu- Guillain-Barre Established Class I Type A ropathy. A randomized controlled trial performed by syndrome-severe Dyck et al." showed that a significant proportion of pa- Chronic inflammatory Established Class I Type A tients with chronic inflammatory demyelinating polyneu- demyelinating ropathy improved following PP. Thus, PP is a useful mo- polyneuropathy dality of therapy in this group of patients, who may also Polyneuropathy with benefit from oral prednisone and intravenous human im- monoclonal mune globulin, as shown in randomized controlled tri- gammopathies of als.9-11 Which of these therapies is best will depend on a undetermined number of factors, as has been reviewed recently.1oPP is significance: considered established for this disorder, with minimal IgGAgA Established Class I Type A Class Z evidence and a Type A recommendation. Polyneuropathy associated with monoclonal gammopa- IgM Investigational Class I thies of undetermined significance, A randomized con- Myasthenia gravis- Established Class 111 Type C trolled trial'" has shown that patients with polyneuropathy Pre-op preparation associated with IgA and IgG monoclonal gammopathies of and crisis undetermined significance (MGUS) improve following Lambert-Eaton Possibly useful Class IIDII therapy with PP. Those with IgM MGUS and polyneurop- my asthenic athy did not improve. The patients entering this study syndrome were heterogeneous and included those with both demyeli- Refsum's disease Investigational Class I11 nating and axonal polyneuropathies. Patients in the IgM Acquired Investigational Class I11 MGUS group may have included those with anti-myelin- neuromyotonia associated glycoprotein antibodies. Because of continuing StifT-man syndrome Investigational Class I11 controversy concerning the exact relationship of the mono- Cryoglobulinemic Investigational Class 111 clonal protein to the neuropathy, treatment decisions in pol yneuropathy these patients remain individualized. PP may be consid- ered possibly useful for these disorders. For those with IgA Central nervous system Investigational Class I11 systemic lupus and IgG, Class Z evidence would indicate that PP is estab- lished. Acute disseminated Investigational Class 111 Myasthenia gravis. Although no controlled clinical tri- encephalomyelitis als have been performed of PP in MG, a sufficient number Multiple sclerosis Possibly useful Class I/II of case series, as well as the experiences of experts, have ~~~ ~ ~~~ ______ been reported1;'J2J" to establish clearly the value of PP in MG. The two most common indications for PP in myasthe- on serum levels of the variety of factors now known to be nia are preoperative preparation and treatment of myas- important in immune reactions. thenic crisis. PP would be considered established for MG Cost. The cost of PP varies considerably, typically for these indications, based on Class ZII evidence, Type C. $1,000 to $2,000 per procedure. Thus, a five-session course PP may occasionally be used in the chronic long-term ther- of PP can cost between $5,000 and $10,000.RETIRED apy of patients with myasthenia,14although most authori- Safety profile. In experienced hands, PP is extremely ties prefer immunosuppressant drugs.15 safe. Although hypotension, dizziness, and perioral tin- Lambert-Eaton myasthenic syndrome. While no con- gling (hypocalcemia) may occur either during or following trolled trials exist on the use of PP in the Lambert-Eaton PP, most of these reactions are rapidly recognized and myasthenic syndrome (LEMS), a case series'" has sug- reversed, and are rarely seri~us.~There is a risk of infec- gested a benefit. The rationale is similar to that in myas- tion from the intravenous manipulations, but this has thenia; that is, patient strength should be improved by the proven to be minimal. Probably the greatest risk to pa- removal of the pathogenic antibody to the voltage-gated tients are the procedures necessary to ensure adequate calcium channel. In most cases, patients are treated long- venous access, in particular the placement of the central