particularly insevere acute myasthenia, in preparing the patient for thymectomy ... In the Eaton-Lambert syndrome muscle weakness, mainly proximal, is present ...
BRITISH MEDICAL JOURNAL
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Plasma exchange in neurological diseases In the past 20 years plasma exchange has become steadily more complex. The procedure consists of removing several litres of plasma and replacing it with normal plasma or a colloid substitute. In plasmapheresis, on the other handalthough the terms are often used interchangeably-less than one litre is taken and it is replaced by a crystalloid solution. Plasma exchange has been used to treat over 100 diseases, and in the United States 20 000-30 000 procedures are carried out annually, roughly a half of them for neurological illnesses.' Most of the published work concerns case reports and shows an efficacy rate of 80%, but the few controlled studies show the figure to be only 40%.2. To resolve the conflicting data in neurological diseases a consensus conference was held last year at the National Institutes of Health in the United States. The major factor hindering evaluation of plasma exchange is that we still do not know how it works. In normal people removing modest amounts of plasma is followed by an increase in protein synthesis, which, together with a decrease in catabolism, maintains the immunoglobulin concentrations at their values before the exchange. If the exchange is continued, however, the homoeostatic mechanisms may be overcome and. the immunoglobulin concentrations remain
low for several weeks after treatment.2 Presumably the concentrations of pathogenic antibodies can be similarly reduced, but the results are not clear cut and the fall in titre may not be as predicted. Other suggested reasons why plasma exchange works include the removal of immune complexes, paraproteins, complement, acute phase reactants, lymphokines, and inhibitors of reticuloendothelial cell function.2 In addition, the replacement solutions may themselves enhance immune competence.3 The National Institutes of Health conference considered six neurological diseases and their variants, all of them immune mediated. In myasthenia gravis the evidence that antiacetylcholine receptor (anti-AChR) antibody has a pathogenic role led to plasma exchange as a means of treatment. Though no controlled trial has been done, on the evidence available the committee recommended plasma exchange in this condition, particularly in severe acute myasthenia, in preparing the patient for thymectomy, and at the start of long term immunosuppressive treatment.' 4 The clinical improvement lasts only about a month. There is controversy over how plasma exchange produces benefit because there is no direct ) BRITISH MEDICAL JOURNAL 1987. All reproduction rights reserved.
relation between the specific antibody titre and the severity of the disease and because the procedure may be effective in patients with no detectable anti-AChR antibody titre.4 Other circulating factors are likely to be concerned. In the Eaton-Lambert syndrome muscle weakness, mainly proximal, is present in association with neoplasia, usually oat cell carcinoma of the lung, or autoimmune disease. Degeneration of terminal motor axons is related to an antibody which blocks the release of neurotransmitter from the terminal presynaptic membranes. In theory, therefore, plasma exchange should help, and in the small uncontrolled trials reported it does appear to work.5 6 Its short term benefit makes it of limited use, but when the mainstays of treatment for this disorder-that is, steroids and immunosuppressive drugs-are contraindicated it can be considered. Plasma exchange has been used to treat the Guillain-Barre syndrome in several multicentre controlled trials.'-9 Some benefit was detectable in severe cases when the procedure was used within two weeks of onset. Since the Guillain-Barre syndrome has a high morbidity and mortality and does not respond to immunosuppressive treatment the early use of plasma exchange was recommended,' a recommendation supported by personal observation (POB) of several such treated patients. It has recently been suggested that after plasma exchange there may be an increased rate of relapse, but, none the less, those who do relapse will improve again, even more rapidly and completely than on the first occasion, with a second course of exchange.'0 Pathogenic immune complexes have been implicated in the Guillain-Barre syndrome," and, theoretically, removing these and other possible injurious factors may be beneficial. Nevertheless, the outcome of the disease also depends on the presence of axonal damage and the nature of the precipitating agent. In chronic inflammatory demyelinating polyradiculoneuropathy'2 a prospective randomised double blind trial of plasma exchange had shown clinical improvement in nine of 15 patients. This proportion had declined within two weeks of stopping the treatment'2; similarly, in limited numbers of patients with associated benign or malignant paraproteinaemias the occasional mild improvement seen with plasma exchange was not maintained. '' Claims that plasma exchange is effective in multiple sclerosis have to be treated with great caution. In the two randomised double blind controlled studies plasma exchange had been given together with steroids and immunoVOLUME 295
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suppressive treatment.5 16 In the first of these some four fifths of patients treated with corticotrophin and high dose cyclophosphamide had shown stabilisation or improvement in their condition at one year, compared with half who had had plasma exchange, corticotrophin, and low dose cyclophosphamide and a fifth who had had corticotrophin alone.5 In the second trial the two groups had been given prednisolone together with oral low dose cyclophosphamide and true or sham plasma exchange. In each group stabilisation and improvement was seen in over four fifths, with a statistically significant benefit in the plasma exchange group. The National Institutes of Health committee concluded that further studies are needed, but these results leave little hope that the technique will help much in routine treatment. Plasma exchange is not effective in patients with motor neurone disease,'718 where it has been used in desperation rather than from any theoretical considerations. The postinfectious encephalomyelitides were not mentioned in the National Institutes of Health report, but, since they may have a similar pathogenesis to that of the Guillain-Barre syndrome,'9 such patients are certainly candidates for the procedure. Finally, an uncontrolled trial of plasma exchange has been done in polymyositis/dermatomyositis.2' Again, other forms of treatment were given, and the exchanges were done over a prolonged period so that the benefit claimed is difficult to accept. Yet again, in this group of disorders as well as in others, anecdotal accounts of excellent responses draw attention to the need for careful trials. One of the points to emerge from the conference was the variable schedules of plasma exchange used-from one to two exchanges in one week only to exchanges carried out for up to a year. A satisfactory protocol, given for example in the Guillain-Barr6 syndrome, consisted of removing roughly one plasma volume per exchange (that is, 40-50 ml/kg) for three to five exchanges over seven to 14 days.' Immunosuppressive treatment is not given for the Guillain-Barre syndrome but is indicated for the other neurological diseases. Standardisation for future trials is recommended for not only the volume processed per exchange but also the frequency and total number of exchanges and the duration of treatment.' Plasma exchange is not innocuous. Indeed, complications have been reported in almost half of patients, with an estimated three deaths per 10 000 procedures.' It must be considered only when experienced staff are available. Nevertheless, when it is successful plasma exchange also offers us new insights into the pathogenesis in these neurological diseases. Clearly it is beneficial in patients with some of these illnesses, and as we learn more of how it works and how the tissues are injured in the immune mediated nervous disorders we may expect it to be used with greater frequency and efficacy. P 0 BEHAN Reader in neurology
WILHELMINA M H BEHAN University of Glasgow, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF
Senior lecturer in pathology
1 National Institutes of Health. 7he utility of therapeutic plasmapheresisfor nerolgical disorders. Vol 6. Washington, DC: US Goverrnment Printing Ogice, 1986:1-7. (NIH consensus development conference statement.) 2 Patten E. Therapeutic plasmapheresis and plasmna exchange. CRC Grit Rev Clin Lab Sci 1986;23: 147-75. 3 Carroll RR, Noges WD, Kitchens CS. High-dose intravenous immunoglobulin in patients with immune thrombocytopenic purpura.J.AMA 1983j249: 1748-50. 4 Harrison R, Behan PO. Myasthenia gravis. In: Bachelard HS, Lunt GG, Marsden CD, eds. Clinical neurochesnisoy. London: Academic Press, 1986:60-265.
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5 Dau PC, Denys EH. Plasmapheresis and immunosuppressive drug therapy in the Eaton-Lambert syndrome. Ann Newrvl 1982;11:570-5. 6 Newsom-Davis J, Murray NMF. Plasma exchange and immunosuppressive drug treatment in the Lambert-Eaton myasthenic syndrome. Neurology 1984;34:480-5. 7 Greenwood RJ, Newsom-Davis J, Hughes RAC, etal. Controlled trial of plasma exchange in acute inflammatory polyradiculoneuropathy. Lancet 1984;i:877-9. 8 Guillain-Barre Syndrome Study Group. Plasmapheresis and acute Guillain-Barre syndrome. Neurology 1985;35:1096-1104. 9 Dyck PJ, Kurtzke JF. Plasmapheresis in Guillain-Barre syndrome. Neurology 1985;35:1105-7. 10 Osterman PO, Fagius J, Safwenberg J, et al. Early relapses after plasma exchange in acute inflammatory polyradiculoneuropathy. Lancet 1986;ii: 1161. 11 Behan PO, Lowenstein LM, Stilmant M, Sax D. Landry-Guillain-Barre-Strohl syndrome and immune-complex nephritis. Lancet 1973;i:850-4. 12 Dyck PJ, Daube J, O'Brien P, et al. Plasma exchange in chronic inflanunatory demyelinating polyradiculoneuropathy. N Engl Med 1986;314:461-5. 13 Sherman WH, Olarte. MR, McKernan G, Sweeney K, Latov N, Hays AP. Plasma exchange treatment- of peripheral neuropathy associated with plasma cell dyscrasia. J Neurol Neurosurg Psychiany 1984;47:813-9. 14 Emerudh J, Brodtkorb E, Olsson T, Vedeler CA, Nyland H, Berlin G. Peripheral neuropathy and monoclonal IgM with antibody activity against peripheral nerve myelin: effect of plasma exchange. J Neuroinmuwol 1986;11:171-8. 15 Hauser SL, Dawson DM, Lehrich JR. Intensive immunosuppression in progressive multiple sclerosis. A randomised, three arm study of high dose intravenous cyclophosphamide, plasma exchange and ACTH. N EnglJ Med 1983;308:173-80. 16 Khatri BO, McQuillan MP, Harrington GJ, Schmoll D, Hoffman RG. Chronic progressive multiple sclerosis: double blind controlled study of plasmapheresis in patients taking immunosuppressive drugs. Neurology 1985;35:312-9. 17 Olarte MR, Schoenfeldt RS, McKieman G, Rowland LP. Plasmapheresis in amyotrophic lateral sclerosis. Ann Neurol 1980;8:644-5. 18 Silani V, Scarlato G, Vai G, Marconi M. Plasma exchange ineffective in amyotrophic lateral sclerosis. Arch Neurol 1980;37:511-3. 19 Behan PO, Feldman RG, Segerra JM, Draper IT. Neurological aspects of mycoplasmal infection. Acta NeuroIScand 1986;74:314-22. 20 Dau PC. Plasmapheresis in idiopathic inflammatory myopathy. Experience with 35 patients. Arch Neurol 1981;38:544-52.
Burnout Concern about psychiatric disorders and substance abuse among doctors has led to elaborate procedures to help sick doctors and their families. Until recently, however, less interest has been shown in the less dramatic but much more common problems related to job dissatisfaction. These appear to be particularly common in obviously stressful settings, such as intensive care, neonatal paediatrics, and terminal care,' 2 and most writers now use the term burnout, introduced in 1974 by Freudenberger to describe a syndrome that he believed was especially common among health workers.3 Recent reports have continued to concentrate on health workers45 and others such as teachers6 and policemen7 who work directly with people, but the problems are common in many other occupations, including business and management.8 The word burnout has become popular, but the syndrome itself has proved elusive and there is no agreed definition. It is usually seen as having three related but independent components: emotional exhaustion (tiredness, somatic symptoms, irritability, accident proneness, depression, and excessive alcohol consumption); depersonalisation (treating patients and other people as if they are objects); and low productivity accompanied by feelings of low achievement.45 Whether these symptoms constitute a distinct burnout syndrome that can be distinguished from other forms of stress and job dissatisfaction is still uncertain. Despite systematic research and the development of standard measures of burnout9 little progress has been made in understanding the causes. The conclusion of a 1982 review still stands: "Thus far burnout has been primarily, if not entirely, a descriptive term yielding little insight into explaining its causes, prevention, and cures."'0 The most important factors are probably personality and characteristics of the job such as responsibility, variety of tasks, hours, support from others, and rewards. Proposals for prevention and treatment have concentrated on modifying these factors. Although the results of research on burnout are disap-
