Plasma exchange in hands of the neurologist

Special article Plasma exchange in hands of the neurologist M.S. van der Knaap* and R . H . W . M . Derksen* *

Introduction

Plasmapheresis is the selective removal of plasma from the circulation. The first application of plasmapheresis in patients in order to influence their disease beneficially dates back to 19521. This first description by Adams et al as well as other early reports clearly showed that in patients with symptoms of the hyperviscosity syndrome secondary to haematological malignancies the removal of plasma is an effective, rapidly acting symptomatic treatment 2. Its efficiency is explained by the direct relationship between levels of circulating paraproteins, serumviscosity and clinical symptoms3. When in the seventies blood-cell separators became available at a large scale, plasma exchange (PE, removal of large volumes of plasma, which are replaced by plasma substitutes) was increasingly used as a therapeutic modality in a variety of disorders. The concept that patients suffering from diseases caused by circulating components might benefit from this procedure, seemed logical and was supported by successes reported in early uncontrolled studies of patients with diseases supposed to be caused by auto-antibodies and/or circulating immune complexes 4-6. At present the application of PE has been reported in more than 90 diseases 7, indicating the epidemic proportions being reached. However, as time went on the original

premise that PE can be expected to be a useful therapeutic modality only in disorders caused by components circulating within the blood plasma, seemed to fall more and more into the background. In many diseases in which PE has been performed, the mere presence of some abnormalities of humoral or cellular immunity of doubtful or of at least unproven pathogenetic relevance seemed a sufficient reason for a trial of therapeutic PE. Apart from a general paucity of clearcut indications the evaluation of the role of PE in successful applications has many pitfalls. PE is a rather crude modality, which removes not only putative pathogenetic components but also mediators of inflammation such as immunoglobulins and complement components. In addition possible beneficial effects of the infusion of components with the plasma substituent and the placebo effect of this time consuming and impressive treatment should not be ignored. Recently critical reviewss,9 noticed that despite a world-wide experience of more than one decade the number of diseases in which efficacy of PE has been proven, is well below ten. Among the large number of diseases in which PE has been applied, are several neurological disorders s,1~ (Table 1). In this article we review current literature on these diseases and we try to delineate the role of PE in the therapeutic arsenal of the neurologist.

* Department of Neurology, * * Department of Internal Medicine, Division oflmmunopathology, University Hospital Utrecht, the Netherlands'. Address for correspondence and reprint requests: M.S. van der Knaap, Department of Neurology, University Hospital Utrecht, Nicolaas Beetsstraat 24, 3511 HG Utrecht, the Netherlands. Accepted 22.10.86 Clin Neurol Neurosurg 1986. Vol. 88-4.

233

Table 1. Neurological disorders in which PE has been applied. Myasthenia gravis Lambert Eaton syndrome Acute inflammatory polyneuropathy Chronic inflammatory polyneuropathy Polymyositis/dermatomyositis Multiple sclerosis Amyotrophic lateral sclerosis Refsum's disease Polyneuropathy associated with paraproteinemias

Myasthenia gravis (MG) MG is a disorder in which there is little doubt that auto-antibodies directed against the acetylcholine receptor of the motor endplate have an important role in causing the disease 12-15. These antibodies are detectable in the serum of almost all patients with generalized MG 16-~9. The clinical symptoms are probably caused by antibody-induced blockade and enhanced breakdown of the receptors ~2,~3,~5. Therefore the application of PE in MG in order to achieve a reduction of serumlevels of the antiacetylcholine receptor antibodies has a clear, theoretical background. Indeed, several uncontrolled studies showed beneficial effects of PE in MG patients 5,2~ The procedure effectively decreased levels of circulating anti-acetylcholine receptor antibodies, and in individual patients a correlation between antibody levels within the circulation and myasthenic weakness was found ~4,18,2~ The interval between PE and clinical improvement varied from less than 24 hours 22 to 2-4 days s,2~ from which it was inferred that improvement may be a consequence of reversion of immunological blockade 22 and resynthesis of acetylcholine receptors free from antibodies 2~ In most cases the MG patients treated with PE were concomitantly treated with immunosuppressive drugs (prednisone and/or cytotoxic drugs such as cyclophosphamide and azathioprine), Because immunosuppressive 234

drugs by themselves may be effective in the treatment of MG, evaluation of an additional beneficial effect of PE when used in combination with such drugs, is difficult. It is still not clear whether with the application of PE any long-term beneficial effects are obtained above those of immunosuppressive therapy alone 21,23,2s.On the other hand, PE without concomitant immunosuppressive medication was observed to have a good but short-lasting effect23. Two randomized controlled trials concerning PE in MG have been performed 24,28,29.Kornfeld et a/24'29 concluded that PE is beneficial in MG. Newsom-Davis et a128 found only short-term effects of PE. However, these studies differ in many aspects. Patients in Kornfeld's trial, who were severely disabled, were treated with PE and prednisone or with prednisone only and had a relatively short period (3-6 weeks) of followup, so only short-term effects were studied. In the study of Newsom-Davis the severity of the disability of the patients was not described, the follow-up period lasted 4-12 months and patients were treated with a combination of PE, prednisone and azathioprine or only with these drugs. In both studies the number of patients was small (12 and 16 respectively) and treatment preceding the trial consisted of prednisone. PE protocols were different. From current literature and personal experience we would advise PE in selected cases of severely disabled MG patients. Firstly PE, having a relatively rapid effect, can be applied as short-term crisis intervention in rapidly deteriorating patients 21,23. Examples of this situation are a myasthenic crisis, worsening induced by the institution of treatment with prednisone or by a dose reduction of prednisone, the initial period after the institution of cytotoxic drugs (a delay in beneficial effects of these drugs of 6 weeks to 6 months can be expected) and worsening of clinical signs before and after thymectomy. Besides PE can be added to conventional treatment consisting of cholineesterase inhibitors, thymectomy, steroids and cytotoxic drugs, if patients appear to be resistent to such treatment or if there are contra-indications for such treatment 21,23. In these, relatively rare, cases frequent PE (three times a week, two liters per session) may induce a remission. In

case of success the frequency of PE can be gradually diminished after some weeks to once per three or four weeks and then stopped, leaving patients with immunosuppressive treatment only. With such a regimen long lasting remissions have been reported 23,26. In summary PE may be a successful mode of therapy for inducing a remission in selected, severely disabled M G patients, while long-term benefits must be expected from other therapeutic actions. In our opinion there is insufficient evidence for PE as long-term therapy.

Lambert Eaton syndrome (LES) LES is a rare myasthenic disorder in which the clinical symptoms are caused by a diminished release of acetylcholine from the presynaptic nerve terminaP ~ Several lines of evidence suggest that auto-antibodies are involved in the pathogenesis of LES 31-33. It is possible to transmit the disorder passively with the IgG fraction of plasma of LES patients 3z'33. It has been suggested that in LES cases associated with a malignant neoplasm antibodies against tumor antigens are cross-reacting with antigenic determinants of the nerve terminal 33. The indications for a pathogenetic role of circulating antibodies formed the rationale for applying PE in LES patients. Several uncontrolled trials suggest that PE as monotherapy can have a favourable effect in LES 32'33. In contrast to the rapid response to PE observed in M G patients a relatively slow onset of improvement is found in LES (onset of improvement after 5 to 15 daily exchanges) 3233. After a short course of PE no beneficial effects were seen 34. There is one controlled cross-over trial on PE in LES 3s. The number of patients included is small (5 patients) and randomization of treatment order has not been performed. The conclusion of the study is that a combination of PE, prednisone and azathioprine is superior to either PE or immunosuppressive drugs alone. A provisional conclusion based on these limited data is that there is an indication for PE in severe LES patients, who are refractory to conventional treatment, which should include treatment of a malignancy if present 3~,37, pyridostigmine 3~, guanidine -~9-4~, 4-amino-

pyridine 4z, 3,4-diaminopyridine 43, nisone 44 and cytotoxic drugs 33,4~.

pred-

Acute inflammatory polyneuropathy (AIP) AIP, also called Guillain-Barr6 syndrome, is a disorder of unknown cause affecting motor, sensory and autonomic nerves. The disease is generally self-limiting, but has considerable morbidity (mechanical ventilation needed in 16-22%), mortality (2-6%), risk of relapse (3-10%) and significant persistent disability (5-22%) 46-5o. There is considerable evidence that immunological abnormalities have pathogenetic significance. Studies have shown both cellmediated immunological reactions against specific rnyelinoproteins 5~.52as well as serological abnormalities in the form of antimyelin antibodies and demyelinating activity in sera of patients 53-58. The presence of immunoglobulin and complement components along the myelin shears of peripheral nerves has also been demonstrated sS. The relatively high morbidity and mortality with symptomatic conservative treatment warranted more aggressive treatment. The effect of steroids was investigated in a controlled trial. Treatment with steroids resulted in detrimental effects in stead of improvement 59. The suggestion for a pathogenetic role of immunological abnormalities provided a rationale for the introduction of PE in AIP in the search of an effective therapy. In many small, uncontrolled trials a favourable effect of PE as monotherapy has been found in a high percentage (60-100%) of treated patients 6~ However, because AIP has an unpredictable natural course, the observed improvement cannot reliably be contributed to the treatment in absence of a control group. At present there are several controlled clinical trials on PE in AIP 67-71. The first, relatively small (25 patients) American study, comparing PE plus prednisone with supportive treatment alone, found no significant differences between the two groups of patients 67,68. However, a beneficial effect of PE might have been masked by a detrimental effect of prednisone. This explanation is supported by the beneficial effects of PE as monotherapy in the other three studies 69-71. In the British trial 69, including 19 235

patients, the course of the disease was slightly but not significantly better in the exchanged group. The results of the Swedish study7~ including 38 patients, are very similar to the most recent large American study 7~, which included 245 patients. Both studies clearly indicate that in case of an early start of PE monotherapy (within one week after the onset) in severely ill AIP patients, not yet requiring ventilatory assistance, recovery starts earlier, is more rapid and more complete, resulting in a shorter period of hospital admission. Cost-benefit analysis is in favour of PE. After one year of follow-up there was less (but not statistically significant) residual disability in patients treated with PE during the acute phase of their disease. No reduction in mortality was observed. Each of the trials cited above may be criticized, either for its small size, alternate rather than truly random allocation of treatment 7~ exclusion of patients randomized to but not receiving P E 71'72 or being not blinded as sham PE was not performed. On balance we conclude that with current data PE should be used as monotherapy in severely affected and worsening AIP patients early in the course of the disease in order to shorten and ameliorate the acute disability. Whether there are long-term benefits from PE, has yet to be established.

Chronic inflammatory polyneuropathy (CIP) CIP is a chronically progressive or relapsing and remitting demyetinating disorder of the peripheral nervous system. The disease is characterized by prolonged periods of disability and may be fatal 73. Comparable to AIP also in CIP abnormalities of both humoral immunity (demyelinating activity of serum of CIP patients TM, antibodies against components of peripheral nerves 75-77) and cellular immunity78,79 have been demonstrated. Treatment with prednisone is an efficacious therapy in CIW ~ However, its positive effect may be unsatisfactory76,s3 or temporary with a relapse following reduction of prednisone dosage 84. Besides, treatment with high doses of prednisone has many side-effects. The same applies to treatment with cytotoxic drugs 76,s5. Because of these problems with conventional 236

treatment, the promising results of PE in AIP and the presence of immunological abnormalities in CIP, PE was also applied in CIP. Uncontrolled trials suggest that PE as monotherapy has a good, but short-lasting effects6,87. However, usually PE is combined with immunosuppressive drugs. In many small, uncontrolled trials it is suggested that with this therapy 60-100% of the patients improve. Often improvement is rapid and dramatic 6~ but may be moderate or absent 75,9~ In case of success the frequency of PE is usually gradually decreased and finally PE is stopped. After cessation of PE long-lasting improvement has been found with continued treatment with prednisone and cytotoxic drugs 76,s9, but also without any further treatment 65,ss. However, some patients relapse after cessation of PE s3. Recently a prospective, controlled, double blind trial 91 compared the effects of PE and sham PE as monotherapy. In 30% of the PE treated patients improvement to a greater degree was detected than for any patient receiving sham PE. Not all patients benefitted to the same extent from PE and some had no benefit at all. After cessation of PE there was a relapse after 10-14 days. In conclusion PE is advisable as supplementary therapy for inducing a remission in severely disabled or seriously worsening patients despite adequate conventional treatment or in case contra-indications for these drugs are present. Presence or absence of success cannot be predicted. In our view it is doubtful, whether there is a place for PE as long-term treatment,

Polymyositis/dermatomyositis (PM/DM) PM/DM is an inflammatory myopathy of unknown cause. Antibodies against muscle components have been found as well as depositions of immunoglobulins and complement in muscle fibres, but the pathogenetic role of these abnormalities is unclear 92-95. On the other hand several lines of evidence suggest an important role of cellular immunity in this disorder, as cellular infiltrations of muscle and a cytotoxic effect of lymphocytes of patients on muscle cells have been s h o w n 96-99. Standard treatment of this disease includes prednisone 1~176 In case of resistance to pred-

nisone cytotoxic drugs are usually added 1~176 However, with such treatment improvement is still unsatisfactory in a proportion of the patients m~,103. Based on the immunological abnormalities mentioned above PE has been applied in PM/DM. In a case report PE as monotherapy was found to have no beneficial effect ~~ In uncontrolled trials PE in combination with steroids and/or cytotoxic drugs produced clinical improvement in up to 100% of the patients, who had been unresponsive to treatment with prednisone or a combination of prednisone and cytotoxic drugs 94'95~1~176 After cessation of PE improvement could be sustained with prednisone and/or cytotoxic drugs for prolonged periods 94-~5, although relapses did occur ~jS. The most substantial improvement was seen in patients with a rapidly progressive disease of relatively short duration 1~ Controlled trials concerning PE in PM/DM have not been performed. Considering the data our advice is to add PE to conventional treatment only in severely disabled PM/DM patients in case of severe sideeffects of or resistance to such treatment.

Multiple sclerosis (MS) MS is a chronic disorder of the central nervous system white matter, associated with inflammation and gliosis. The cause is unknown. Evidence suggesting that immunological factors have a role in the pathogenesis of MS are the presence of auto-antibodies against myelin basic protein in the cerebrospinal fluid l~ serum antibodies against extracts of brains ~~ myelin 1~~ and oligodendroglia 111, circulating immune complexes "2 and an in vitro demyelinating factor in the serum of MS patients "3. However, of none of these factors the pathogenetic significance has been proven ~j4.H5 The theory that MS is an immunological disorder, has led to attempts to influence this disease with help of PE. The first uncontrolled pilot studies found favourable but varying effects z~6-119. Especially in patients with acute exacerbations of MS a rapid improvement was seen with PE 116. Three controlled studies of PE in chronic progressive MS patients have been per-

formed 12~ In the first two studies patients treated with immunosuppressive drugs alone (control group) did equally well 12~ or b e t t e ? 21 than patients treated with PE and immunosuppressive drugs. In the third study 122'123Khatri et al claimed that treatment with PE and immunosuppressive drugs is superior to sham PE and immunosuppressive drugs. However, as Weiner indicated 124, many objections can be made against the design of this study (no untreated control group receiving only sham PE) and against the analysis of the results (the use of disability scores as numerical entities in the statistical analysis; disregard of the course of the disease after cessation of therapy; a small but critical number of patients showing major improvement after PE, who had just had an important deterioration, a category of patients not present in the sham PE group) 124. Especially in the long run treatment with PE and immunosuppressive drugs appeared to have no favourable effects above treatment with sham PE and immunosuppressive drugs 124. A multicenter, double blind study on PE and immunosuppressive drugs in acute exacerbating MS will soon be completed ~25. It is possible that PE is helpful only in this form of MS 116. In conclusion, until now we have found no indication for PE in the individual MS patient. If treatment with PE is carried out, it should be part of carefully controlled trials.

Amyotrophic lateral sclerosis (ALS) ALS is a fatal disease of motor neurons of unknown cause. It is not certain whether or not primary immunological processes are involved in the pathogenesis. A factor toxic to anterior horn cells in the serum of ALS patients has been found in some 126,127,but not in all 128,~29studies. A serum antibody inhibiting sprouting of neurons has been demonstrated j3~ but direct immunohistochemical investigations of motor neurons showed no depositions of immunoglobulines TM. No effective therapy for ALS is known. Both an uncontrolled 132 and a controlled trial 133 showed, that PE had no influence on the course of the disease. There is no indication for PE in ALS. 237

Refsum's disease This rare metabolic disorder is due to a raised blood level of phytanic acid, which is caused by a failure of alpha-oxidation of this fatty acid. The disease is characterized by chronic polyneuropathy, retinitis pigmentosa and ichthyosis. The blood level of phytanic acid correlates directly with the severity of the disease. Treatment with a strict diet, that decreases the blood level of phytanic acid, usually results in improvement. However, it has been shown that large volume PE twice a year combined with a moderately strict diet is an effective and well-tolerated form of long-term therapy TM. Besides PE can be used as acute therapeutic intervention when the patient's condition deteriorates and serum phytanic acid has reached toxic levels during acute mobilization of phytanic acid caused by insufficient caloric intake TM.

Polyneuropathy in paraproteinemias Paraproteinemias comprise a group of disorders in which a clone of abnormal plasma cells produces a monoclonal immunoglobulin. Distinction is made between malignant gammopathy (solitary and multiple myeloma and macroglobulinemia) and benign gammopathy. These disorders can be complicated by neurological sequelae, especially polyneuropathy i35-14~ There is evidence that the polyneuropathy is caused by paraproteins reacting with components of the peripheral nerve136.141-148. In case of solitary osteosclerotic myeloma irradiation of isolated bone lesion is the best treatment. After irradiation improvement of the polyneuropathy has been described ~4~176 Cytotoxic drug therapy is less effective in improving the neuropathy ~4~176 Otherwise cytotoxic drugs have an important place in the treatment of multiple myeloma, macroglobulinemia and benign monoclonal gammopathy135,144. With these drugs both improvement of the polyneuropathy~4~,Is~~53 and absence of improvement have been described 14~176 Also treatment with steroids may have a favourable effect on polyneuropathy in benign monoclonal gammopathy154,t55. 238

In order to remove the pathogenetic paraprotein PE has been introduced as a symptomatic therapy of paraprotein associated neuropathy. In uncontrolled trials successes of treatment with PE alone or in combination with immunosuppressive drugs have been claimed in multiple myeloma156, benign monoclonal gammopathy 142,146a57and probably to a less extent in macroglobulinemia158,159. Therapeutic failures have been reported 143.No controlled studies on PE in paraprotein associated polyneuropathy have been performed. Our advice, based on this scarce information, is that PE as an additional, symptomatic treatment is worth a try in order to ameliorate the disability caused by polyneuropathy in paraproteinemias if the polyneuropathy is severe and does not improve with help of primary treatment of the paraproteinemias.

Conclusion PE has been applied in a number of neurological disorders. In each of these disorders - with the exception of Refsum's disease - the presence of immunological abnormalities formed the basis for the application of PE. However, the pathogenetic significance of these abnormalities is far from clear with the exception of antiacetylcholine receptor antibodies in MG and probably paraproteins in paraprotein-associated polyneuropathy. Because the natural course of most of the neurologic disorders treated by PE is characterized by remissions and exacerbations, the effect of PE cannot be assessed in uncontrolled trials. Besides PE has been almost always combined with prednisone and/or cytotoxic drugs, which have a potential therapeutic effect themselves. Therefore, in absence of control data improvement cannot be claimed to be the effect of PE. However, even controlled trials do not always solve the problem, as the results of different studies not infrequently are contradictory. This can be explained by differences in the selection of patients, PE-protocols, co-medication and small numbers of patients. Notwithstanding all these difficulties some practical conclusions and advices can be formulated:

1. T h e r e is a role for P E in the t r e a t m e n t of M G a n d R e f s u m ' s disease. I n b o t h diseases there is clear e v i d e n c e for a d e m o n s t r a b l e circulating p a t h o g e n e t i c factor, which can be removed by PE parallel with clinical improvement. 2. I n severely disabled patients with L E S , A l P , CIP, P M / D M and p a r a p r o t e i n e m i a associated n e u r o p a t h y P E can be applied w h e n the disease is refractory to c o n v e n t i o n a l treatm e n t , w h e n c o n t r a - i n d i c a t i o n s for such treatm e n t exist, or w h e n no effective c o n v e n t i o n a l t h e r a p y is k n o w n . I n n o n e of these disorders, p r o b a b l y with exception of the p a r a p r o t e i n e m i a s , a circulating factor with p r o v e n

9

10 tl 12 13 14

15

16

17

p a t h o g e n e c i t y is p r e s e n t a n d the application of P E is based on clinical e v i d e n c e of a beneficial effect o n the course of disease. In case of the p a r a p r o t e i n e m i a s t h e r e are clear i n d i c a t i o n s for a p a t h o g e n e t i c role of the p a r a p r o t e i n , but data a b o u t the effect of P E o n the associated n e u r o p a t h y are scarce a n d not conclusive. 3. I n MS P E has to be c o n s i d e r e d an experim e n t a l t h e r a p y with insufficient g r o u n d s for clinical application. 4. T h e r e is no i n d i c a t i o n for P E in ALS.

Acknowledgements

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