Plasma exchange in chronic inflammatory demyelinating polyneuropathies

Pergamon

Transfus. Sci. Vol. 17, No. 3,pp. 415-422, 1996 Copyright © 1996 Elsevier Science Ltd. All rights reserved Printed in Great Britain PII: S0955-3886(96~00024-0 0955-3886/96 $15.00 + 0.00

Plasma Exchange in Chronic Inflammatory Demyelinating Polyneuropathies Marion S. Sternbach, MD*t Susan Fawcett, MD*

Marilyn Wolsley, RN* Rose Giammarco, MD* occurred in paraproteinemias. Thus immune modulation with plasma exchange may be useful in CIDPs with paraproteinemias and autoimmune manifestations. Copyright © 1996 Elsevier Science Ltd •

• Chronic Inflammatory Demyelinating Polyneuropathies {CIDP) are characterized by demyelination of peripheral nerves with mononuclear cell infiltrates, electrical conduction slowing or block and elevated cerebrospinal fluid protein with no cells. An immune mediated pathogenesis has been suggested. Immune suppressive therapy, as well as plasmapheresis and intravenous immunoglobulins have been used with variable success. Our objective was to review our results of plasma exchange in this disease in 20 patients with very different underlying diseases, none of them eligible for the Canadian CIDP plasmapheresis study, and define certain guidelines of predictability for the effectiveness of plasma exchange. Five patients had monoclonal gammopathies of unknown significance, two had lung cancer, one breast cancer, one hairy cell leukemia and later carcinoma of the pancreas; two had hepato-splenomegaly and hemolytic anemia; nine were idiopathic {two with autoimmune markers). Plasmapheresis varied from 4 to 31 plasma volumes and procedures with a median of 12, always with 5 % albumin. Two excellent responses, one very good, two moderate transient and 12 had no change in clinical or conduction status. Best response

INTRODUCTION Chronic inflammatory demyelinating neuropathies (CIDP) are the probable chronic counterpart of the GuillainBarr6 syndrome (GBS), the hallmark of these diseases being multifocal and widespread demyelination, mononuclear inflammation and on occasion, axonal degeneration. ~ It is assumed currently that the pathogenesis of both these clinical entities is immune mediated, although one or several antigens eliciting this immune response have not been identified. This has been based upon the facts of mononuclear inflammatory response in the peripheral nerves, or remissions induced by steroids, plasmapheresis and intravenous immunoglobulins (IVIGI 4-6 and on antibodies in sera from patients with CIDP reacting with Ganglioside LM1 and Sulphatide of peripheral nerve myelin by Fredman e t al. 7 Hartung e t al. have also implicated cell-mediated immunity by showing elevated levels of IL-2, the cytokine inducing T-cell proliferation and activation? In experimental allergic neuritis (EAN), induced by Lassman e t al., a major

"Department of Medicine, McMaster University, Hamilton, Ontario, Canada. tAuthor for correspondence at St. Joseph's Hospital, 50 Charlton Avenue East, Room F509, Department of Medicine, Hamilton, Ontario, L8N 4A6, Canada. Received 23/6/95; accepted 19/I/96. 415

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antigen for T-cells was the P2 protein from the peripheral nervous system myelin. The transfer of T lymphocytes sensitized by P2 induced a chronic relapsing neuritis in Lewis rats. 9 CIDPs constitute approximately 20% of all adult neuropathies. ~0 There appears to be a genetical predisposition associated with a linkage disequilibrium of HLA A1 B8 DR3, as shown by Stewart et al. in 1978 and Adams et al. in 1979. H,~2 Diagnostic criteria for CIDP have been established by a subcommittee of the American Academy of Neurology and further very well defined with eligibility criteria by The Canadian Co-operative Study of Plasma Exchange in CIDP. 13,~4 In reviewing our patients we tried to adhere to The Canadian CIDP Study Group criteria since most of our patients were ineligible for the study because of underlying diseases or because their neurological impairment was not advanced enough. Our objective was to review our patients suffering from CIDP, who had undergone therapeutic plasmapheresis most often as a last resort, after they had failed to respond to steroids and immunosuppressant drugs or in whom treatment of the underlying disorder had been unsuccessful. Owing to these circumstances, we were obviously dealing with a rather severe group of CIDP, who also had the disease for several months and sometimes years. Considering neuropathology in general and that of CIDP in particular, one can see that the more longstanding and advanced the demyelination and inflammation of the peripheral nerves would be, the less the chances of success of any therapeutic intervention.

PATIENTS AND METHODS

From October 1989 to February 1994, we treated 20 CIDP patients 116 males and 4 femalesJ with plasma exchange. They ranged in age from 45 to 88 years, with an average of 60.1 years.

To establish the diagnosis of CIDP, we used the criteria and guidelines of the Canadian CIDP Study protocol and all patients had a complete work-up for underlying disorders such as monoclonal gammopathies associated with i m m u n e or lymphoproliferative diseases, autoi m m u n e disorders or malignancy. The accepted clinical criteria for CIDP are as follows: 1. Progressive or recurrent motor or sensory disturbances in legs or arms. 2. Roughly symmetrical distribution of neurological deficit. 3. Mainly large myelinated fibre dysfunction. 4. Reduction or absence of deep tendon reflexes. 5. Duration of at least 6 weeks. The laboratory criteria of CIDP are: 1. Less than 10 cells per/zL in the cerebrospinal fluid. 2. Electrophysiological conduction disturbances: less than 35 m/s in the median nerve and less than 30 m/s in the peroneal nerve. 3. Sural nerve biopsy was not performed in cases with underlying disorders and where the patient did not consent. Classically, histology shows demyelination with little inflammation and no denervation. Investigations performed before and after plasmapheresis therapy were: complete blood count, renal and hepatic functions, prothrombin and partial thromboplastin time, hepatitis B surface antigen and hepatitis C markers when they became available. An i m m u n e profile with ANA, protein eleetrophoresis and quantitative immunoglobulins was always performed before the first, after the sixth and again after the twelfth plasma exchange procedure. Since it became apparent that during repeat plasmapheresis with only 5% albumin some patients dropped their hemoglobin, we started conducting ferritin, vitamin B 12, and serum folate determinations. Plasma exchange was performed on the COBE SPECTRA continuous flow

Plasma Exchange in CIDP

cell separator with only 5% albumin. Non-invasive venous access was established usually with 17 g back eye dialysis needles or angiocaths. Since many patients with CIDP have easily collapsible veins and drawing by pump even at 30 and 35 mL per minute may become difficult, we elected in such cases to start by infusing a bolus of 250-400 mL of 5% albumin before starting to draw, which enhanced the procedure. We exchanged one plasma volume with every procedure, which generally amounted to 3-4 L in men and 2.5-3.0 L in women.

Patients There were nine patients with idiopathic CIDP, five with an underlying paraproteinemia, four with IgG and one with IgM, two with hepato-splenomegaly and hemolytic anemia but no liver cirrhosis, two with small lung cancer, one with breast cancer and one with hairy cell leukemia, and later pancreatic cancer. Plasma exchange was performed twice a week for 3 weeks, following which the patients had subjective and objective clinical evaluation. The next six plasma exchanges were performed once a week. Thereafter electrophysiological studies were repeated in addition to the clinical assessment.

RESULTS The results of plasma exchange are shown in Table 1. Two patients with monoclonal gammopathy had an excellent response with reversal of all the paresthesias, return of their sense of vibration and loss of ataxia. They regained some of their deep tendon jerks and improved by electrophysiological testing. One patient, who also has mild immune thrombocytopenia, had a very good response that lasted for 18 months and is starting to relapse clinically at the time of writing. Two patients, one with small lung cancer and another with IgM monoclonal gammopathy, had

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a moderate transient improvement that lasted only 2-3 weeks. These patients had clearcut responses to plasmapheresis but seemed to relapse within less time than the immunoglobulins' halflife. Three patients, one with lung cancer, one with mixed connective tissue type syndrome, and one with idiopathic CIDP, had only mild transient clinical responses, by improvement of paresthesias, pain and ataxia. The remaining 12 patients did not change clinically or electrophysiologically over an observation period of 6 months. One of our patients with excellent response became chronically dependent on plasmapheresis at 3 week intervals for a period of 2 years and was then switched to IVIG with satisfactory results.

Side Effects of Plasmapheresis There were very few side effects of the procedure itself since the continuous flow system, with a completely computerized control panel, has a very low extracorporeal volume and the blood to ACD-A anticoagulant can be set to a ratio as low as 15-20 to 1. When albumin is used for plasma exchange, the incidence of citrate toxicity with perioral paresthesias and muscle cramping is extremely rare, since the patient receives much less citrate than with plasma containing a substantial amount of CPD Icitrate-phosphate-dextrose). We had, in one female patient, a prolonged episode of nausea, chest pain, and hypotension that was corrected by stopping the procedure and infusing saline and albumin. Subsequent ECG and cardiac enzymes were perfectly normal. All of our patients developed, after six plasma exchanges, hypogammaglobulinemia associated with a sense of marked fatigue and often recurrent upper respiratory tract infections. These patients received WIG 300 mg/kg infusions on these occasions. Some of the patients who started out with a low normal hemoglobin,

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were found to have, after five or six plasma exchanges, mild to moderate anemia, 100 to 80 g/L. This could not be attributed to red blood cell loss during plasmapheresis, since the COBE SPECTRA re-infuses and rinses all red cells from the tubing and software. We did find, in five patients, low levels of serum ferritin and vitamin B12 around 100 pmol/L. We started supplementing these patients with ferrous fumarate and vitamin B12 and their hemoglobins rose to normal.

DISCUSSION

If indeed, the pathogenesis of CIDP is immune, i m m u n e modulation ought to be extremely effective. In our patients, this hypothesis was not borne out since 12 patients had no response whatsoever, and the others had mostly only transient improvement. This, of course, may be also related to their underlying diseases, as well as to the fact that their neuropathies were often longstanding and advanced. The patients who responded best to plasmapheresis were those with either monoclonal gammopathies, hypergammaglobulinemias or other positive auto-immune markers. Plasmapheresis removes, with great efficiency, IgM antibodies (75-90% removal by one plasma volume). IgG antibody removal is much slower (approximately 45% per plasma volume). Most of the IgM is intravascular, while IgG is both intraand extravascular. This may explain our better results in paraproteinemias. In a randomized double blind trial at the Mayo Clinic, plasma exchange compared to sham plasmapheresis has shown a clear advantage of true plasma exchange over the placebo effect in polyneuropathies associated with monoclonal gammopathies of unknown significance. The neuropathy disability score, weakness score, and muscle action potentials improved more with plasmapheresis than with sham procedures) s Interestingly, in the same trial IgG and IgA monoclonal

gammopathies responded better than the IgM paraproteinemias. '5 Plasma exchange probably removes other substances such as breakdown products of myelin and cytokines. If cytokines are the activators of cell-mediated immunity, T cells and macrophages, this means an additional beneficial dampening effect on the i m m u n e destructive process of peripheral nerves. Absence of myelin breakdown products in the perineural sheath decreases chemotaxis for mobilization of scavenger macrophages and hence inflammation. In most immune-mediated diseases in which plasmapheresis has proven useful, it is assumed that either antigens, antibodies, or i m m u n e complexes are removed. ~6-'s McCullough has postulated in a review on hemapheresis, ~9 that removal of excess antibody or antigen may alter the composition of the immune complex and, therefore, change its biological role. Plasma exchange may also unblock the reticulo-endothelial system and render it biologically more efficient. All of these effects, however, are transient. There must be a powerful rebound of both humoral and cellular i m m u n e responses as a result of a feedback recruitment of lymphocytes after plasma exchange. Therefore, plasmapheresis probably ought to be combined with i m m u n e suppression or with intravenous immunoglobulin in CIDP to be administered intermittently following plasma exchange. Intravenous immunoglobulin (WIG) has also proven useful in the treatment of CIDP. 6 Even though this also involves major i m m u n e modulation, its mechanisms of action are different from plasmapheresis. 2°,2' The Fc portion of immunoglobulin binds to the Fc receptor of macrophages, blocking their Fc receptor-dependent phagocytosis. Large doses of immunoglobulins can suppress both B lymphocytes producing antibodies as well as cytotoxic T lymphocytes. Immunoglobulins derived from large multi-individual batches may contain, on occasion, anti-idiotypic antibodies against the offending anti-

Plasma Exchange in CIDP 421

myelin antibody that will bind to it and neutralize it. 2' With regard to paraneoplastic CIDP, our two patients with small cell lung cancer had a remarkable response to plasmapheresis. They walked away from their wheelchair even though the ataxic component of their neuropathy improved m u c h less. Dalmau et al. 22 described the presence of an antineuronal antibody named Hu in the sera of patients with a paraneoplastic, mostly sensory neuropathy, associated with small cell lung cancer. Hu reacts with a protein antigen of 35-40 kDa present in the nucleus and, to a lesser extent, in cytoplasm of small cell lung cancer cells. This Hu antigen may play an important regulatory part in neurogenesis and neuronal maintenance. In conclusion, plasma exchange in longstanding and advanced chronic inflammatory demyelinating neuropathies is unlikely to be successful. CIDP associated with monoclonal or polyclonal gammopathies may benefit from plasmapheresis and may even become chronically dependent on it. Plasmapheresis has been helpful in selected cases of paraneoplastic CIDP associated with small cell lung cancer. Perhaps considering the different paths of i m m u n e modulation, the combination of plasma exchange with subsequent intravenous immunoglobulin would prove most effective in CIDP.

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