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Plasma Exchange for Neurological Disorders
1313
complement, or fibrinolytic cascades and haemorrhage secondary to systemic anticoagulants may also occur. Difficulty with venous access can be overcome by technical skill; femoral or central venous lines
Plasma
Exchange for Neurological Disorders
exchange (PE), first used as an experimental procedure to support nephrectomised dogs,l entered clinical practice as a means for procuring blood products in 19442 and as an experimental treatment for macroglobulinaemia in 1959. Encouraging case-reports and small trials led to the therapeutic use of PE in various putative autoimmune and vasculitic disorders affecting specific organs, including the joints, skin, and kidneys, or multiple systems, such as systemic lupus erythematosus and polyarteritis. Neurological disorders account for approximately half of the 20 000-30 000 therapeutic PE procedures carried out annually in the USA. The effectiveness of this method of treatment in neurological disease has now been discussed at a consensus development conference convened by the National Institute of Neurological PLASMA
and Communicative Disorders and Stroke and the National Institutes of Health Office of Medical Applications of Research.5 Any statement about the usefulness of PE must be prefaced by an acknowledgment of its risks. Informal data collected worldwide between 1978 and 1983 suggest a fatality rate of 3 per 10 000 procedures; some of the deaths may have been due to the use of whole plasma rather than albumin as a replacement fluid.5 Complications include fluid imbalance, hypoproteinaemia, and citrate-induced hypocalcaemia, which should be avoidable. Activation of coagulation, 1. Abel JJ, Rowntree LG, Turner BB. Plasma removal with return of corpuscles. Exptl Ther 1914; 5: 625-41. 2. Co Tui, Bartter FC, Wright AM, Holt RB. Red cell reinfusion and the frequency of plasma 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.
which have their own hazards may be necessary. The risks of transmission of infection and allergic reactions can be minimised by use of albumin as the exchange material. Antibodies to the acetylcholine receptor are present in almost all patients with myasthenia gravis. In individual patients their correlation with severity6 provides a firmer theoretical basis for the therapeutic use of PE in myasthenia than in any other disease. Even those patients in whom antibodies cannot be detected by the usual radioimmunoassay have antibodies which block neuromuscular transmission in mice.7 PE leads to improvement in more than two-thirds of patients, usually within one to three days of the start of the course; the response may be so dramatic that controlled trials have not been conducted. Unfortunately the effects last only a few weeks. Consequently, the consensus conference endorsed the use of PE in myasthenia only in specific situations-the early stage before other treatments have had time to work; in a crisis; or in chronic cases as an adjunct when the response to other forms of immunosuppressive treatment is unsatisfactory. The hope that PE might work synergically to enhance the effect of other immunosuppressive agents has not been realised.8 The Eaton-Lambert myasthenic syndrome is a rare disorder of neuromuscular transmission probably caused by an antibody to calcium channels on the presynaptic membrane.9 PE has been reported to be a useful adjunct to other immunosuppressive treatment. 10 The consensus view was that PE was probably effective in this rare disorder.5 In Guillain-Barre syndrome two small trials did not show definite effects from PE, whereas three other trials, including one involving 250 patients in North America, reported considerable benefits .11-13 The conclusion was that PE is useful for patients whose weakness is so severe that they are unable to walk unaided.5 Treatment should be started early, preferably within the first two weeks of symptoms.5 The benefits anticipated include a shortening of the time to walk unaided by about 30 days from a median of 85 days and, for those patients who are ventilated, 6. Editorial The diagnosis of myasthenia gravis. Lancet 1986; i: 658-60 7. 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 Neurol Neurosurg Psychiatry 1981; 44: 469-75. 9. Lang B, Newsom-Davis J, Wray D, Vincent A, Murray N. Autoimmune aetiology for myasthenic (Eaton-Lambert) syndrome. Lancet 1981; ii: 224-26. 10. Newsom-Davis J, Murray NMF. Plasma exchange and immunosuppressive treatment in the Lambert-Eaton myasthenic syndrome. Neurology (NY) 1984; 34: 480-85. 11. The Guillain-Barré Syndrome Study Group. Plasmapheresis and acute GuillainBarré 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.
1314
halving of the median time spent on the ventilator from 48 days to 24 days." The distress produced by Guillain-Barre syndrome has been eloquently described in Joseph (Catch 22) Heller’s account of his own illness, in which he narrowly avoided ventilation.14 To a shortening of duration of suffering and disability can be added the economic argument that use of PE saves money by considerably reducing intensive 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 are acutely ill, liable to chest infections and cardiac arrhythmias, and, because of autonomic dysfunction, unusually susceptible to hypovolaemia from rapid plasma volume changes. Although a single carefully conducted controlled trial has shown at least temporary benefitfrom PE in the chronic counterpart of Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy,is the conference concluded that benefit 5 was possible or probable rather than proven. Nevertheless, anecdotal reports indicate that in some patients PE can be as dramatically, and briefly, effective as in. myasthenia gravis. Attempts to identify an antibody or toxic factor in the plasma or serum of these individuals have not been successful. In some cases of chronic neuropathy associated with paraproteinaemia antibodies to particular myelin or axonal antigens have been demonstrated. The best characterised disorder is monoclonal gammopathy of undetermined significance associated with an IgMk paraprotein which is an antibody directed against an epitope shared by peripheral nerve myelin glycolipids, myelin associated glycoprotein, and some neuronal surface antigens.16 The evidence is that demyelinating neuropathy is caused by the paraprotein rather than an epiphenomenon. 17 Some patients have improved after cytotoxic treatment combined with PE18 but the place of PE is not yet established in the treatment of this rare disorder.s PE has also been tried in a few patients with motoneurone disease but without benefit 719 a result in keeping with the lack of any notable inflammatory response or demonstrated humoral toxin in this disorder. In severe chronic progressive multiple sclerosis a small double-blind controlled trial of true vs sham PE showed a benefit in favour of the true PE group.20 Both groups also received prednisone and low-dose 14. Heller J, Vogel S. No laughing matter. London: 15. Dyck PJ, Daube J, O’Bnen P, et al. Plasma
Jonathan Cape, 1986. 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. Clin Neuropharmacol 1982; 5: 93-114. 20. Khatri BO, McQuillen 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: 312-19.
(1-5 mg/kg/day) oral cyclophosphamide. The improvements as assessed by the Kurtzke disability status scale were greater in the group receiving true consensus view was that one small trial was insufficient to permit a general recommendation that PE be used in this form of multiple sclerosis.s Until results of ongoing trials of PE and other immunosuppressive treatments are available treatment with PE or other potentially hazardous immunosuppressive regimens must be regarded as experimental. Although about 5 % of patients pursue a malignant course with severe disability in about 5 years, most patients have a more gradual downhill course and survive for 25 years or more. For the great majority of patients, therefore, a treatment as uncomfortable, time consuming, and expensive as PE is unlikely to be appropriate. For those in whom major longstanding neurological deficits have already developed it is unlikely to be effective. Further controlled trials of PE and similar treatments would be appropriate in the minority of patients pursuing a
PE. The
more
malignant course.
The purpose of a consensus development conference is to consider a medical technique or treatment and catalyse its introduction into medical practice. The consensus statement from a panel of experts that the benefits of PE are worth further investigation in Eaton-Lambert syndrome, chronic
inflammatory demyelinating polyradiculoneuropathy, paraproteinaemic neuropathy, and multiple sclerosis should encourage researchers and grantgiving bodies to invest time and resources in this promising area. The clear conclusions that the procedure is of established value in Guillain-Barre syndrome and myasthenia gravis should persuade physicians who look after these patients in general wards and intensive care and neurology units to consider whether they have sufficient resources to provide PE as an emergency or at least urgent procedure; it will almost certainly be necessary to care for these patients in designated regional units. For Guillain-Barre syndrome the case for provision of these facilities can be argued powerfully because the reduction of the time spent on the ventilator and the time taken to walk unaided are considerably shortened. Thus the costs of PE should be more than offset by savings in the costs of accommodation in the intensive care units and hospital ward. On the assumption that reduction of time on the ventilator is equivalent to the same reduction of stay in the intensive care unit, in one UK teaching hospital it was estimated that, on the basis of average costs, use of PE
6500 for each ventilated patient. For nons ventilated patients with severe Guillain-Barre would
save
syndrome,
if reduction of time to walk unaided is with shortened time in hospital, the use of PE equated would save 4000. Joseph Heller calculated that his fairly mild Guillain-Barre syndrome cost him 112 372 dollars and 12 cents.
complement, or fibrinolytic cascades and haemorrhage secondary to systemic anticoagulants may also occur. Difficulty with venous access can be overcome by technical skill; femoral or central venous lines
Plasma
Exchange for Neurological Disorders
exchange (PE), first used as an experimental procedure to support nephrectomised dogs,l entered clinical practice as a means for procuring blood products in 19442 and as an experimental treatment for macroglobulinaemia in 1959. Encouraging case-reports and small trials led to the therapeutic use of PE in various putative autoimmune and vasculitic disorders affecting specific organs, including the joints, skin, and kidneys, or multiple systems, such as systemic lupus erythematosus and polyarteritis. Neurological disorders account for approximately half of the 20 000-30 000 therapeutic PE procedures carried out annually in the USA. The effectiveness of this method of treatment in neurological disease has now been discussed at a consensus development conference convened by the National Institute of Neurological PLASMA
and Communicative Disorders and Stroke and the National Institutes of Health Office of Medical Applications of Research.5 Any statement about the usefulness of PE must be prefaced by an acknowledgment of its risks. Informal data collected worldwide between 1978 and 1983 suggest a fatality rate of 3 per 10 000 procedures; some of the deaths may have been due to the use of whole plasma rather than albumin as a replacement fluid.5 Complications include fluid imbalance, hypoproteinaemia, and citrate-induced hypocalcaemia, which should be avoidable. Activation of coagulation, 1. Abel JJ, Rowntree LG, Turner BB. Plasma removal with return of corpuscles. Exptl Ther 1914; 5: 625-41. 2. Co Tui, Bartter FC, Wright AM, Holt RB. Red cell reinfusion and the frequency of plasma 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.
which have their own hazards may be necessary. The risks of transmission of infection and allergic reactions can be minimised by use of albumin as the exchange material. Antibodies to the acetylcholine receptor are present in almost all patients with myasthenia gravis. In individual patients their correlation with severity6 provides a firmer theoretical basis for the therapeutic use of PE in myasthenia than in any other disease. Even those patients in whom antibodies cannot be detected by the usual radioimmunoassay have antibodies which block neuromuscular transmission in mice.7 PE leads to improvement in more than two-thirds of patients, usually within one to three days of the start of the course; the response may be so dramatic that controlled trials have not been conducted. Unfortunately the effects last only a few weeks. Consequently, the consensus conference endorsed the use of PE in myasthenia only in specific situations-the early stage before other treatments have had time to work; in a crisis; or in chronic cases as an adjunct when the response to other forms of immunosuppressive treatment is unsatisfactory. The hope that PE might work synergically to enhance the effect of other immunosuppressive agents has not been realised.8 The Eaton-Lambert myasthenic syndrome is a rare disorder of neuromuscular transmission probably caused by an antibody to calcium channels on the presynaptic membrane.9 PE has been reported to be a useful adjunct to other immunosuppressive treatment. 10 The consensus view was that PE was probably effective in this rare disorder.5 In Guillain-Barre syndrome two small trials did not show definite effects from PE, whereas three other trials, including one involving 250 patients in North America, reported considerable benefits .11-13 The conclusion was that PE is useful for patients whose weakness is so severe that they are unable to walk unaided.5 Treatment should be started early, preferably within the first two weeks of symptoms.5 The benefits anticipated include a shortening of the time to walk unaided by about 30 days from a median of 85 days and, for those patients who are ventilated, 6. Editorial The diagnosis of myasthenia gravis. Lancet 1986; i: 658-60 7. 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 Neurol Neurosurg Psychiatry 1981; 44: 469-75. 9. Lang B, Newsom-Davis J, Wray D, Vincent A, Murray N. Autoimmune aetiology for myasthenic (Eaton-Lambert) syndrome. Lancet 1981; ii: 224-26. 10. Newsom-Davis J, Murray NMF. Plasma exchange and immunosuppressive treatment in the Lambert-Eaton myasthenic syndrome. Neurology (NY) 1984; 34: 480-85. 11. The Guillain-Barré Syndrome Study Group. Plasmapheresis and acute GuillainBarré 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.
1314
halving of the median time spent on the ventilator from 48 days to 24 days." The distress produced by Guillain-Barre syndrome has been eloquently described in Joseph (Catch 22) Heller’s account of his own illness, in which he narrowly avoided ventilation.14 To a shortening of duration of suffering and disability can be added the economic argument that use of PE saves money by considerably reducing intensive 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 are acutely ill, liable to chest infections and cardiac arrhythmias, and, because of autonomic dysfunction, unusually susceptible to hypovolaemia from rapid plasma volume changes. Although a single carefully conducted controlled trial has shown at least temporary benefitfrom PE in the chronic counterpart of Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy,is the conference concluded that benefit 5 was possible or probable rather than proven. Nevertheless, anecdotal reports indicate that in some patients PE can be as dramatically, and briefly, effective as in. myasthenia gravis. Attempts to identify an antibody or toxic factor in the plasma or serum of these individuals have not been successful. In some cases of chronic neuropathy associated with paraproteinaemia antibodies to particular myelin or axonal antigens have been demonstrated. The best characterised disorder is monoclonal gammopathy of undetermined significance associated with an IgMk paraprotein which is an antibody directed against an epitope shared by peripheral nerve myelin glycolipids, myelin associated glycoprotein, and some neuronal surface antigens.16 The evidence is that demyelinating neuropathy is caused by the paraprotein rather than an epiphenomenon. 17 Some patients have improved after cytotoxic treatment combined with PE18 but the place of PE is not yet established in the treatment of this rare disorder.s PE has also been tried in a few patients with motoneurone disease but without benefit 719 a result in keeping with the lack of any notable inflammatory response or demonstrated humoral toxin in this disorder. In severe chronic progressive multiple sclerosis a small double-blind controlled trial of true vs sham PE showed a benefit in favour of the true PE group.20 Both groups also received prednisone and low-dose 14. Heller J, Vogel S. No laughing matter. London: 15. Dyck PJ, Daube J, O’Bnen P, et al. Plasma
Jonathan Cape, 1986. 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. Clin Neuropharmacol 1982; 5: 93-114. 20. Khatri BO, McQuillen 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: 312-19.
(1-5 mg/kg/day) oral cyclophosphamide. The improvements as assessed by the Kurtzke disability status scale were greater in the group receiving true consensus view was that one small trial was insufficient to permit a general recommendation that PE be used in this form of multiple sclerosis.s Until results of ongoing trials of PE and other immunosuppressive treatments are available treatment with PE or other potentially hazardous immunosuppressive regimens must be regarded as experimental. Although about 5 % of patients pursue a malignant course with severe disability in about 5 years, most patients have a more gradual downhill course and survive for 25 years or more. For the great majority of patients, therefore, a treatment as uncomfortable, time consuming, and expensive as PE is unlikely to be appropriate. For those in whom major longstanding neurological deficits have already developed it is unlikely to be effective. Further controlled trials of PE and similar treatments would be appropriate in the minority of patients pursuing a
PE. The
more
malignant course.
The purpose of a consensus development conference is to consider a medical technique or treatment and catalyse its introduction into medical practice. The consensus statement from a panel of experts that the benefits of PE are worth further investigation in Eaton-Lambert syndrome, chronic
inflammatory demyelinating polyradiculoneuropathy, paraproteinaemic neuropathy, and multiple sclerosis should encourage researchers and grantgiving bodies to invest time and resources in this promising area. The clear conclusions that the procedure is of established value in Guillain-Barre syndrome and myasthenia gravis should persuade physicians who look after these patients in general wards and intensive care and neurology units to consider whether they have sufficient resources to provide PE as an emergency or at least urgent procedure; it will almost certainly be necessary to care for these patients in designated regional units. For Guillain-Barre syndrome the case for provision of these facilities can be argued powerfully because the reduction of the time spent on the ventilator and the time taken to walk unaided are considerably shortened. Thus the costs of PE should be more than offset by savings in the costs of accommodation in the intensive care units and hospital ward. On the assumption that reduction of time on the ventilator is equivalent to the same reduction of stay in the intensive care unit, in one UK teaching hospital it was estimated that, on the basis of average costs, use of PE
6500 for each ventilated patient. For nons ventilated patients with severe Guillain-Barre would
save
syndrome,
if reduction of time to walk unaided is with shortened time in hospital, the use of PE equated would save 4000. Joseph Heller calculated that his fairly mild Guillain-Barre syndrome cost him 112 372 dollars and 12 cents.