Journal of Clinical Apheresis 7:63-68 (1992)
Ten Years Experience With Therapeutic Apheresis in a Community Hospital Peter Kornfeld, Sondra Fox, Karen Maier, and Mazen Mahjoub Department of Medicine, Mount Sinai Medical Center, New York (P.K.); Apheresis Unit and Department of Medicine, Englewood Hospital, Englewood, New Jersey (P.K., S.F., K. M., M.M.) A retrospective study was carried out on 2,500 therapeutic hemapheresis procedures performed at a community teaching hospital from 1980 to 1990. Seventy-six percent of the procedures consisted of plasmapheresis (PE). The most frequently treated conditions were myasthenia gravis (MG), Guillain-BarrC syndrome (GB), hyperviscosity ( H V ) , and thrombotic thrombocytopenia purpura (TTP). Therapeutic results and clinical implications for these four conditions are discussed. 0 1992 Wiley-Lisr. Inc.
Key words: hemapheresis, plasma exchange, Guillain-Barre syndrome, hyperviscosity syndrome, thrombotic thrombocytopenic purpura, myasthenia gravis
INTRODUCTION
A retrospective study was carried out on 2,500 therapeutic hemapheresis procedures performed at a community teaching hospital from 1980 to 1990. Seventy-six percent of the procedures consisted of plasmapheresis (PE). The most frequently treated conditions were niyasthenia gravis (MG), Guillain-BarrC syndrome (GB), hyperviscosity (HV), and thrombotic thrombocytopenia purpura (TTP). Therapeutic results and clinical implications for these four conditions are discussed. Therapeutic cytapheresis accounted for 24% of all hemaphereses and was performed mainly for leukemias, polycythemias, thrombocytosis, and other myeloproliferative diseases. The treatment of these disorders will be the subject of a separate report. The hemapheresis unit at Englewood Hospital has been in operation since 1980. The unit is staffed by a medical director, two nurse clinicians, and a rotating third year medical resident. Only therapeutic hemaphereses are performed. This review deals only with plasmapheresis (PE). Most referrals come from neurologists, hematologists, oncologists, and general practitioners. In 1990, we performed 440 therapeutic procedures, which represents a 160% increase over the past 3 years. MATERIALS AND METHODS
All applications for apheresis were screened by the unit director to ascertain that the request for treatment was clinically indicated and justified. Both inpatients and outpatients participated in this review. All patients were closely followed by their private physician and the apheresis unit staff. Intermittent venous access was obtained
0 1992 Wiley-Liss,
InC.
via the antecubital vein or the femoral vein. If such access was not feasible, indwelling catheters were placed. While we aimed for a PE of 0.5 to 1 plasma volume, individual adjustments had to be made based on the general conditions of the patient and the particular disease. During the first year of operation, fresh frozen plasma (FFP) was used as replacement fluid, with a resulting 23% allergy reaction rate. Since 1981, however, we have used only 5% albumin and 0.9% sodium chloride solution as replacement fluids, without any side effects. In idiopathic thrombocytopenic purpura (ITP) and in thrombotic thrombocytopenic purpura (TTP), FFP was used as replacement fluid. Sodium citrate was used as the anticoagulant. Clinical evaluation was based on neuromuscular examination, and functional assessment was based on a modified Szobor Disability Scale [ 1 J . A value of 0 was assigned to no PE response, 1 to mild response, 2 + to moderate response, 3 to marked response, and 4 to symptom-free status but still requiring medications. These grading values were then analyzed to study possible correlation with encountered variables. Clinical response was compared between groups with the Wilcox rank sum test. Spearman’s rank correlation was used to determine the relationship between disease duration and clinical response to PE.
+
~
.
+
+
~~~~~
Received for publication March 22, 1991; accepted February 3 . 1992. Dr. Peter Kornfeld is now at the Department of Medicine, Room S102, Stanford University School of Medicine, Stanford, CA Y4305. Address reprint requests to him there.
Parts of this paper were presented at the Third International Congress. World Apheresis Association, Amsterdam, The Netherlands. April, 1990.
64
Kornfeld et al. TABLE I. Disease Incidence, Sex, PE Response Patients
Disease
~
~
n PE Responders
n PE Treatments (mean) ---
~~
16 9 6 4 19
33 15 8 8 34
39 8 15 I1 16
1 0
2
4
3
1
0 0 4
14 15 2
3
1
2
0
17
2 2 2 2
1 0 1
1 2 1
1
1
0 0 3 0
3 3 3 3
1 1
0 1
1 0
1 0
2 2
3 1 1 1
1
0 I
2 0 1 0
2 0 1 1
7 14 10 28
I44
71
73
120
112
Myasthenia gravis GuiIkdin-Barre (acute) Hyperviscosity TTP Myeloprohferdtive disease dnd leukemia Multiple sclerosis Peripherdl neuropathy Rapidly progressive glomerulonephritis Amyotrophic lateral sclerosis (AW Cryoghbuhnemid VdSCUlltlS Anemia (cold agglutinins) Undifferentidted collagen disease Anaphylaxis to allopurinol Disqemindted intravascular coagulation (DIC) Systemic lupus erythematosus Goodpdsture's syndrome ITP Polymyositis Total
Male Female _____
43 17 8 8 34
27 8 2
3 5
5 15
1
RESULTS AND DISCUSSION
Seventy-six percent of our hemapheresis procedures consisted of therapeutic plasmapheresis (PE). One hundred forty-four patients, 71 males and 73 females, ranging in age from 20 to 80 years, were treated. Table I shows the disease incidence, sex distribution, and PE response. Table I also lists diseases encountered too infrequently for us to reach any significant conclusions. Here, we merely report the therapeutic results attained, without further analysis. The plasmapheresis experience in MG, GBS, HV, and TTP is presented in detail. Myasthenia Gravis
The Myasthenia Gravis Clinic at Englewood Hospital has treated 300 patients with MG to date, but only 43
5
(14%) required PE. PE was never used as a routine procedure but was employed only for 1) crisis; 2) severe exacerbations unresponsive to medical therapy; 3) patients with respiratory insufficiency before thymectomy (rarely); 4) patients whose clinical course could not be adequately controlled despite thymectomy , pyridostigmine, steroid, and/or azathioprine administration; and 5) patients who required such large doses of prednisone over long periods that we feared serious steroid side effects and employed PE to try to lower steroid requirements. Table I11 presents a summary profile of the 43 MG patients. They accounted for 30% of the entire PE sample. This was a highly skewed group who had failed on all other forms of therapy. Thirty-six patients (84%) had undergone thymectomy (cervical or transthoracic) . All
TABLE 11. Summarv Profile of Mvasthenia Gravis Patients Therapy Duration of MG (years)
Age range
43 19 24
22-84
12
17
"Osserman et al. 121 classification bGerm~nalcenter5
10
Thymic PE hyperplasia PyridostigThymectomy Thymoma (GC? mine Steroids AI-athioprine response
Clinical classification"
4
I
20
17
5
39 4 (90.7) (9.3)
36 (88.4)
7 (12)
22 (51)
43 (100)
43 (100)
34 (79)
39 (90.6)
Therapeutic Apheresis in a Community Hospital
65
TABLE 111. Myasthenia Gravis Profile
Classification"
n
Age (years)
IIA 1IB
I 20 17 S
75 30-78 22-84 30-76
111
1v
Sex MIF
Duration of MG (years)
1 10/10 7/10 114
1-7 1-16 2-7
1
"Osserman et a]. 121 classification. "Thymic hyperplasia with penninal centers. ' 0 . No response: 1 + , minimal; 2 + , moderate: 3
ACLR AB (n) -
+
I 17 16 5
0
Thymoma
(n)
-
-
3 I -
2 S 1
-
8
9 I
Drug Therapy ( n )
I"PE (')
Pyridostirmine
Steroids
A.mhioarine
1
I 20 17
I 19
20 17 S
5
12 4
Grading of response 0-4
+
0
(mean)'
I 18 IS 5
2 2 0
2 0-4 ( 2 . 7 ) 0-3 (2.2) 2-3 ( 2 4)
+ , marked; 4 + , asymptomatic, bur on medications (gradation W B E baaed o n rimed stimdard tehts and functional stat"$)
43 patients had been on pyridostigmine and prednisone therapy. Thirty-four patients (79%) had received azathioprine as well. The latter drug was generally avoided during the child-bearing years. MG had been present for from 3 months to 16 years prior to PE. Improvement was defined as at least one step up in the Osserman classification [2]. Except for one 74-year-old man in clinical class IIA, only patients in classes IIB, 111, and IV required PE. No purely ocular MG patients (group I) were plasmapheresed. In that we previously observed the occasional appearance of cholinergic symptoms in PE-responsive patients, we have advised cutting pyridostigmine doses over 60 mg by 25% before PE (unpublished data). We interpret this to mean that pyridostigmine requirements in some PE-responsive patients may fall as serum IgG and acetylcholine receptor antibody (AChRAb) levels decrease. We have not observed increased myasthenic weakness during PE. This is in line with previous reports of the very brief serum half-life of pyridostigmine [3]. Aquilonius et al. [4] have called attention to wide serum drug level fluctuations in MG patients. We have not been able in the past to correlate clinical strength with blood pyridostigmine levels [3]. Table I1 also shows that 39 of 43 (90%) MG patients responded to PE. This exceeds the 75% overall improvement rate with PE reported by Szobor [l]. Table 111 lists PE responses as related to clinical classification and severity, age, sex, duration of MG, acetylcholine receptor antibody (AChRAb), and thymic pathology. Five MG patients (lo%), all advanced in age (64-91 years), refused the recommended thymectomy. Patients in class I were never considered for PE, no matter how severe the ocular deficits. Even the patients with MG and thymoma, a more severe and unstable form of illness, responded to PE. This is in agreement with previous reports that MG associated with thymoma also responds well to thymectomy [5]. Age, thymoma, and thymic germinal center hyperplasia had no bearing in PE responsiveness ( P > .05). Female patients had a better PE response than males ( P < ,012). However, all five patients who attained a maximum clini-
-
Clinical response
Thymic Hyperplasia GCsb
cal response of 4 + , had been thymectomized, belonged to classification IIB and 111, and ranged in age from 22 to 51 years, and two patients had a history of thymoma. The duration of MG prior to PE in patients with muximum PE response was significantly shorter ( P < . O l ) than in the other PE response groups. However, the overall correlation between duration of MG and all clinical responses to PE was not significant (correlation cofficient -0.175). This is not surprising in view of previously published data suggesting that short-duration MG is also more responsive to other forms of therapy and tends to carry a better prognosis [5,6]. However, since 84% of the PE sample had been thymectomized and 100% had been immunosuppressed with steroids, azathioprine, or both, it is difficult to know whether PE itself was responsible for the beneficial clinical effects or whether PE merely exerted an additive or synergistic effect [7,8] facilitated by previous thymectomy and immunosuppression. The fact that seven elderly, nonthymectomized, but immunosuppressed patients had a PE response similar to that of the thymectomized group suggests that immunosuppression was the central factor in determining PE response. Indeed, it has been shown previously that PE without immunosuppression is ineffective [7]. MG patients with elevated serum AChRAb responded better to PE than those with absent serum levels, but this was not significant due to the small number of antibodynegative patients involved (9%). However, the PE response rate in the antibody negative group was still 75%. We believe that so-called antibody-negative patients are not truly negative but rather that the assay procedure used does not detect certain classes of antibodies, particularly those of the blocking type [9,10]. While it is known that serum AChRAb levels are generally higher in the more generalized forms of MG and in MG associated with thymoma, this is not universally true [ 10- 121. We have seen the highest antibody titers in two women whose MG has been in remission for several years (unpublished data). While PE invariably produces an immediate drop in serum AChRAb levels, subsequent rebounds in these titers bear little or no relation to the
66
Kornfeld et al.
clinical state [9-111. Our experience with serial AChRAb titer levels in 15 patients has not confirmed Tindall’s [ 121 advocacy of rising titers as a useful predictor of clinical deterioration or improvement [ 131. Hence, we use the serum AChRAb titer as a diagnostic rather than as a prognostic tool [10,12,14]. Since it is known that PE can stimulate T lymphocytes and probably B lymphocytes as well, it would seem that the rebound in serum AChRAb levels results from a change in OKT4/OKT8 cell ratio due to I ) release of previously sensitized lymphocytes into the bloodstream or 2) increased replication of such cells [ 121. It was our clinical impression that the AChRAb rebound phenomenon was delayed and was less marked in patients receiving ongoing interval PE. The average PE was 2.7 liters or 65% of calculated plasma volume but ranged from 1.8 to 4.2 liters. The initial PE course consisted of six treatments over a 10-14 day period, for a total of 18-20 liters of exchange. Treatment frequency was subsequently tapered to 1, 2, 3, or 4 week intervals to wean the patient from PE. Therapy was stopped as soon as the clinical picture had stabilized and clinical classification IIA had been attained. We never stopped PE prior to 20 liters of exchange before labeling the treatment a failure. It was also noted that all responders showed clinical improvement by 8-9 liters of exchange. Those who did not had only minimal or no improvement subsequently. In patients who required more than SO mg prednisone on alternate days for 1 year or more, PE was tried chronically at a 2 week interval. This treatment mode was considered successful if steroid dose could be reduced by at least 50% without concomitant clinical deterioration. We had only four such patients, and in none were we able to achieve this goal for any significant length of time. Normal interval venous access was available in 90% of patients. In five patients who required prolonged indwelling catheters, two developed Stuphylococcus uureus infection of the catheter tip, with subsequent sepsis. Both patients responded to catheter change and antibiotics. All these patients were heavily immunosuppressed. Of interest is the recently reported experience in patients on chronic peritoneal dialysis, in whom a direct relationship was found between positive nasal carriage of S . aureus and subsequent infection by the same organism of the peritoneal catheter [ 1 11. However, another study involving 29 MG patients did not bear this out [ 151. This raises the question of the advisability of such immunosuppressed patients with indwelling catheters receiving antibiotic prophylaxis prior to PE. The overall infection rate in the entire patient sample was < 4%, but this rose to 40% in patients requiring prolonged indwelling catheters. Replacement fluid is not crucial, except in ITP and TTP, in which fresh frozen plasma (FFP) is generally
-
used. No further allergies were encountered after cessation of routine use of FFP in 1980. There is general agreement that the nature of the replacement fluid plays no role in outcome of plasmapheresis in MG [ 121. We added albumin to normal saline solution to maintain oncotic pressure. No deaths or other serious complications occurred. There were three instances of mild hypovolemia, readily reversed by speeding up the rate of fluid replacement. Although four patients complained of mild circumoral tingling, no true hypocalcemia was found. Guillain-Barre Syndrome
Table IV summarizes our plasma exchange experience in 17 patients with acute Guillain-BarrC syndrome. Multinational studies have clearly demonstrated the beneficial effect of this procedure [ 161. The neurologic symptoms were preceded in all instances by viral upper respiratory infections. Ten patients (60%) required ventilatory support. One of the patients had previously been on steroids, but several had been on antibiotics for 3-5 days for upper respiratory infections. Both patients who died were in the seventh decade, one of them dying following surgery for a bowel infarction. Both of these patients had failed to show any neurologic improvement with PE. All others could be weaned from the respirator within 7- 10 days and left the hospital within 3-4 weeks. All patients who improved with PE showed signs of improvement at 7 liters PE. The average PE was 22.5 liters (range 15.9-35.6 liters). The mean number of PE treatments was 8.5 (range 5-16). PE was never stopped in responders before 16 liters or in nonresponders before 20 liters. One patient was treated intermittently for 119 days because of periodic relapses, all of which also responded to PE. The two patients who failed on PE were first treated on days 3 and 7 of illness. Two elderly patients, not treated until days 14 and 15, had an excellent PE response. We have found it beneficial not to stop plasma exchange as soon as any significant neurologic recovery has occurred but to continue PE until the patient is at least ambulatory (unpublished data). This is in accordance with the recent report which questions the concept of early stoppage of PE [17]. Among responders, ventiTABLE IV. PlasrnaDheresis in Guillain-Barre Svndrome n 18 Age (years) 7-79 Male (n) 10 Female (n) 8 Duration of disease before PE 3- 14 days Duration of PE 6-26 days Mean PE 22.5 liters (range 16-36 liters) Length of hospitalization 6-1 19 days (mean 37 days) Positive PE remonse 15 (83%)
Therapeutic Apheresis in a Community Hospital
67
TABLE V. Plasmapheresis (PE) Response in Hyperviscosity Syndrome*
PT
F
I
X
M
2
X
3 4
X
5 6 7 8
X
x X X X
Protein electropheresis spike
Age (years)
Diagnosis
66 59 70 71 59 57 7I 65
Waldenstrom’s Waldenstrom’s Waldcnstrom’s Multiple Myeloma Multiple Myeloma Multiple Myeloma Multiple Myeloma Multiple Myeloma
‘gM IgM IgM IgM
‘gG IgG IgA kG
Duration of PE
Serum viscosity
CNS
2 days 14 days 5 years 3 years 5 days 3 days 150 days 210 days
2.4 1.61 28.2 % 2.4 3.3 ? 1.9 8.4 t 4.0 10.4 ? 1.8 3.5 t 1.2 4.4 ? 4.8 2.6 1.3
*
+
*
0
+ + + + +
Clinical responaea
Total volume exchange (ml)
4+ 4+ 4+ 3+ 3 f 4+ 4 f 3 f
3,150 9,950 148,000 120,000 11,750 8,800 26,950 133,530
* A l l putients on conventional chemotherapy. Patient 3 resistant to chemotherapy; requires weekly Rx to keep viscosity below 4 and to stay symptom-free. “Response meusuremenf: 0, no response; 1 , mild improvement; 2 , moderate improvement; 3 + , marked improvement; 4 , asymptomatic.
+
+
+
latory support could be withdrawn within 7-10 days. PE shortened the average hospital stay by at least 25% when comparing our patients’ hospital stays with the average hospital stay of GB patients in our hospital from 1976 to 1980. Ten patients were able to walk out of the hospital and return home, while four required intensive physiotherapy and rehabilitation in another facility. Several elderly patients, in their late sixties, recovered completely. Our experience suggests that PE should be carried out regardless of the time elapsed since onset of symptoms. The belief that PE has to be started within 7 days of onset of symptoms to be successful, as advocated by the American and French cooperative groups, was not borne out by our uncontrolled study: Some patients treated within 24 hr did not improve, while others did so despite a 14 day delay. The ability to improve regardless of severity of symptoms or age suggests that the nature of the etiologic factor has great influence on the disease’s likelihood of responding to PE. While it is true that rapidly progressing symptoms required longer hospitalization, we could not predict initially which patient was going to respond or to fail on PE. Unfortunately, no neural antibody studies were available. Vriesendorp et al. [17] have reported that serial titers of antiperipheral nerve myelin antibodies may identify patients with antibody rebound associated with clinical recurrence of symptoms, who may then require prolonged PE.
Hyperviscosity
The hyperviscosity data are given in Table V. All patients responded, regardless of the type of serum globulin spike present. We tried to exchange at least one plasma volume per treatment, because rapid results were required. No absolute viscosity reading is necessary to start plasmapheresis in the presence of central nervous system (CNS) or renal signs or symptoms, since they may be followed by permanent organ damage. Such symptoms should be considered emergency indications for PE. Generally, younger patients with viscosity levels under 3 will not complain of CNS symptoms. However, in patients over the age of 50 years, this was not true. The combination of arteriosclerosis and hyperviscosity renders the affected patient more susceptible, even at low viscosity levels. The duration of plasma exchange will depend on the nature and severity of the underlying disease and the efficacy of the associated antitumor therapy. Thrombotic Thrombocytopenic Purpura
Table VI summarizes our experience with TTP (Moschcowitz syndrome). All eight patients entered as acute emergencies, with advanced renal and CNS disease, when seen in the apheresis unit for the first time. One case followed chemotherapy for breast cancer, all others were nontumor related and followed upper respi-
TABLE VI. Plasmapheresis Response in TTP Duration of
Volume of
Number of patients
(years)
M
F
apheresis (days)
PE (ml)
0
8
30-75
4
4
1-180
6,000-177,000
3 (42)
Age
“Response meusuremenr: 0, no response; 1
Response” (%)
I+ 0 (-)
2+
3+
I
4 (54.5)
(12.5)
Deaths 3 (within 24 hr of first Rx)
+ , mild response (Plts); 2 + , moderate response (Plts); 3 + , marked response (Plts, BUN, CNS).
68
Kornfeld et al.
ratory infections. Three patients, all elderly and with advanced CNS disease and renal failure, died within 24 hr. However, five out of eight patients (66%) showed significant response in terms of platelet count and clinical improvement. No laboratory values distinguished the three who succumbed from the five survivors. It must be noted that all patients had also received steriods, platelet aggregation inhibitors (aspirin), intravenous gamma globulin, and FFP. While it was impossible to ascertain the exact quantitative effect exerted by PE, there was marked clinical and laboratory improvement following successive PE in our small series.
SUMMARY
The number of conditions that can benefit from PE continues to grow. Our 10 year treatment experience is presented, but only four disease states, myasthenia gravis, acute Guillain-BarrC syndrome, hyperviscosity , and TTP, occurred frequently enough to allow us to draw the conclusion that PE was highly effective in all four. This review also confirms the safety of the procedure. Finally, the ability of PE to shorten substantially the hospitalization time of inpatients, along with the ease with which PE can be performed on ambulatory patients, implies for plasmapheresis a favorable costibenefit ratio. A hemapheresis unit is an absolute necessity for a medium-sized hospital, even if only therapeutic procedures and no harvesting procedures are performed. During the past 3 years, our hemapheresis volume has increased by 160%. More than 75% of our procedures are done on an outpatient basis. We have not encountered any treatment-related deaths or major complications. We use 0.9% NaCl as plasma expander in all cases except for TTP and ITP where FFP is employed. The question of prophylactic antibiotics in immunosuppressed patients with indwelling catheters requires a controlled, randomized study. ACKNOWLEDGMENTS
We thank Dr. John Mandeli of the Biomathematical Sciences Department, Mount Sinai School of Medicine, New York, for performing the statistical analyses. This work was supported in part by a grant from The Muscular Dystrophy Association.
REFERENCES 1. Szobor A: Myasthenia Gravis. Budapest: Akddemiai Kiado,
1990, p 147. 2. Osserman KE, Kornfeld P, Cohen E, Genkins G , Mendelow H. Goldberg H, Windsley H , Kaplan L1: Studies in myasthenia gravis. A review of 282 cases. Arch Intern Med 102:72-81, 1958. 3 . Kornfeld P, Samuels SM, Wolf RL, Osserman KE: Metabolism of C-14 labelled pyridostigmine in myasthenia gravis. Evidence for multiple metabolites. Neurology 20:634-641, 1970. 4. Aquilonius WWM, Eckemas SA, Hartrig P, Lindstrom B, et al. : Clinical pharmacology of neostigmine and pyridostimine in patients with myasthenia gravis. Neurol Neurosurg Psychiatr 46:929-935, 1983. 5. Osserman KE, Genkins G: Studies with myasthenia gravis. Review of a twenty year experience in 1,200 patients. Mount Sinai J Med 38:497-537, 1971. 6. Genkins G, Kornfeld P. Papatestas AE, Bender AN, Matta KJ: Clinical experience with more than 2,000 patients with myasthenia gravis. Ann N Y Acad Sci 505:595-605, 1987. 7. Hawkey CG, Newsom-Davis J, Vincent A: Plasma exchange and immunosuppressive drug treatment of myasthenia gravis: No evidence for synergy. J Neurol Neurosurg Psychiatr 44:469-47S, 1981. 8. Bogarnini L, Cocito D, Durelli L, Quattrorolo G: Letter to the editor. Opinions about plasma exchange and associated treatment with the therapy of myasthenia gravis. Muscle Nerve 6:456-457, 1983. 9. Mittag T, MassaT, Kornfeld P, Papatestas A, Bender A , Genkins G: Multiple forms of anti-acetylcholine receptor antibody in myasthenia gravis. Muscle Nerve 4(1):16-25, 1981. 10. Vincent A: Immunology of acetylcholine receptors in relation to myasthenia gravis. Physiol Rev 60:757-824, 1980. I I . Lozar MA, Coles GA, Faller R, Slingeneyer A, Dah GD, Briat C, Wone C: Staphylococcus aureus nasal carriage and infection in patients on continuous ambulatory peritoneal dialysis. N Engl J Med 322:505-509. 1990. 12. Tindall RB: Humoral immunity-myasthenia gravis. Biochemical characterization of acquired anti-receptor antibodies and clinical correlation. Ann Neurol 10:437-447, 1981. 13. Mittag T, Kornfeld P, Tormdy A , Woo C: Detection of antiacetylcholine receptor factors in serum and thymus from patients with myasthenia gravis. N Engl J Med 294:691-694, 1976. 14. Komfeld P, Nall J , Smith H, Mittdg TW, et al.: Acetylcholine receptor antibodies in myasthenia gravis. Muscle Nerve 4:413419, 1981. 1s. Johnson RB, Mudev RR, Kominos SD, Nasca TJ: Staphylococcal carriage and infection in myasthenia gravis patients receiving therapeutic apheresis. J Clin Apheresis 4:155-157, 1988. 16. McKhann G, Griffin JW, Cornblak DR, Mellits ED, Feber RS, O’Maskey SA: The Guillain-Barre syndrome study group. Am J Neurol 23:347-353, 1988. 17. Vriesendorp FJ, Mayer RF, Koski CL: Kinetics of antiperipheral nerve myelin antibody in patients with Guillain-Barre syndrome treated and not treated with plasmapheresis. Arch Neurol 48: 858-861, 1991,
Ten Years Experience With Therapeutic Apheresis in a Community Hospital Peter Kornfeld, Sondra Fox, Karen Maier, and Mazen Mahjoub Department of Medicine, Mount Sinai Medical Center, New York (P.K.); Apheresis Unit and Department of Medicine, Englewood Hospital, Englewood, New Jersey (P.K., S.F., K. M., M.M.) A retrospective study was carried out on 2,500 therapeutic hemapheresis procedures performed at a community teaching hospital from 1980 to 1990. Seventy-six percent of the procedures consisted of plasmapheresis (PE). The most frequently treated conditions were myasthenia gravis (MG), Guillain-BarrC syndrome (GB), hyperviscosity ( H V ) , and thrombotic thrombocytopenia purpura (TTP). Therapeutic results and clinical implications for these four conditions are discussed. 0 1992 Wiley-Lisr. Inc.
Key words: hemapheresis, plasma exchange, Guillain-Barre syndrome, hyperviscosity syndrome, thrombotic thrombocytopenic purpura, myasthenia gravis
INTRODUCTION
A retrospective study was carried out on 2,500 therapeutic hemapheresis procedures performed at a community teaching hospital from 1980 to 1990. Seventy-six percent of the procedures consisted of plasmapheresis (PE). The most frequently treated conditions were niyasthenia gravis (MG), Guillain-BarrC syndrome (GB), hyperviscosity (HV), and thrombotic thrombocytopenia purpura (TTP). Therapeutic results and clinical implications for these four conditions are discussed. Therapeutic cytapheresis accounted for 24% of all hemaphereses and was performed mainly for leukemias, polycythemias, thrombocytosis, and other myeloproliferative diseases. The treatment of these disorders will be the subject of a separate report. The hemapheresis unit at Englewood Hospital has been in operation since 1980. The unit is staffed by a medical director, two nurse clinicians, and a rotating third year medical resident. Only therapeutic hemaphereses are performed. This review deals only with plasmapheresis (PE). Most referrals come from neurologists, hematologists, oncologists, and general practitioners. In 1990, we performed 440 therapeutic procedures, which represents a 160% increase over the past 3 years. MATERIALS AND METHODS
All applications for apheresis were screened by the unit director to ascertain that the request for treatment was clinically indicated and justified. Both inpatients and outpatients participated in this review. All patients were closely followed by their private physician and the apheresis unit staff. Intermittent venous access was obtained
0 1992 Wiley-Liss,
InC.
via the antecubital vein or the femoral vein. If such access was not feasible, indwelling catheters were placed. While we aimed for a PE of 0.5 to 1 plasma volume, individual adjustments had to be made based on the general conditions of the patient and the particular disease. During the first year of operation, fresh frozen plasma (FFP) was used as replacement fluid, with a resulting 23% allergy reaction rate. Since 1981, however, we have used only 5% albumin and 0.9% sodium chloride solution as replacement fluids, without any side effects. In idiopathic thrombocytopenic purpura (ITP) and in thrombotic thrombocytopenic purpura (TTP), FFP was used as replacement fluid. Sodium citrate was used as the anticoagulant. Clinical evaluation was based on neuromuscular examination, and functional assessment was based on a modified Szobor Disability Scale [ 1 J . A value of 0 was assigned to no PE response, 1 to mild response, 2 + to moderate response, 3 to marked response, and 4 to symptom-free status but still requiring medications. These grading values were then analyzed to study possible correlation with encountered variables. Clinical response was compared between groups with the Wilcox rank sum test. Spearman’s rank correlation was used to determine the relationship between disease duration and clinical response to PE.
+
~
.
+
+
~~~~~
Received for publication March 22, 1991; accepted February 3 . 1992. Dr. Peter Kornfeld is now at the Department of Medicine, Room S102, Stanford University School of Medicine, Stanford, CA Y4305. Address reprint requests to him there.
Parts of this paper were presented at the Third International Congress. World Apheresis Association, Amsterdam, The Netherlands. April, 1990.
64
Kornfeld et al. TABLE I. Disease Incidence, Sex, PE Response Patients
Disease
~
~
n PE Responders
n PE Treatments (mean) ---
~~
16 9 6 4 19
33 15 8 8 34
39 8 15 I1 16
1 0
2
4
3
1
0 0 4
14 15 2
3
1
2
0
17
2 2 2 2
1 0 1
1 2 1
1
1
0 0 3 0
3 3 3 3
1 1
0 1
1 0
1 0
2 2
3 1 1 1
1
0 I
2 0 1 0
2 0 1 1
7 14 10 28
I44
71
73
120
112
Myasthenia gravis GuiIkdin-Barre (acute) Hyperviscosity TTP Myeloprohferdtive disease dnd leukemia Multiple sclerosis Peripherdl neuropathy Rapidly progressive glomerulonephritis Amyotrophic lateral sclerosis (AW Cryoghbuhnemid VdSCUlltlS Anemia (cold agglutinins) Undifferentidted collagen disease Anaphylaxis to allopurinol Disqemindted intravascular coagulation (DIC) Systemic lupus erythematosus Goodpdsture's syndrome ITP Polymyositis Total
Male Female _____
43 17 8 8 34
27 8 2
3 5
5 15
1
RESULTS AND DISCUSSION
Seventy-six percent of our hemapheresis procedures consisted of therapeutic plasmapheresis (PE). One hundred forty-four patients, 71 males and 73 females, ranging in age from 20 to 80 years, were treated. Table I shows the disease incidence, sex distribution, and PE response. Table I also lists diseases encountered too infrequently for us to reach any significant conclusions. Here, we merely report the therapeutic results attained, without further analysis. The plasmapheresis experience in MG, GBS, HV, and TTP is presented in detail. Myasthenia Gravis
The Myasthenia Gravis Clinic at Englewood Hospital has treated 300 patients with MG to date, but only 43
5
(14%) required PE. PE was never used as a routine procedure but was employed only for 1) crisis; 2) severe exacerbations unresponsive to medical therapy; 3) patients with respiratory insufficiency before thymectomy (rarely); 4) patients whose clinical course could not be adequately controlled despite thymectomy , pyridostigmine, steroid, and/or azathioprine administration; and 5) patients who required such large doses of prednisone over long periods that we feared serious steroid side effects and employed PE to try to lower steroid requirements. Table I11 presents a summary profile of the 43 MG patients. They accounted for 30% of the entire PE sample. This was a highly skewed group who had failed on all other forms of therapy. Thirty-six patients (84%) had undergone thymectomy (cervical or transthoracic) . All
TABLE 11. Summarv Profile of Mvasthenia Gravis Patients Therapy Duration of MG (years)
Age range
43 19 24
22-84
12
17
"Osserman et al. 121 classification bGerm~nalcenter5
10
Thymic PE hyperplasia PyridostigThymectomy Thymoma (GC? mine Steroids AI-athioprine response
Clinical classification"
4
I
20
17
5
39 4 (90.7) (9.3)
36 (88.4)
7 (12)
22 (51)
43 (100)
43 (100)
34 (79)
39 (90.6)
Therapeutic Apheresis in a Community Hospital
65
TABLE 111. Myasthenia Gravis Profile
Classification"
n
Age (years)
IIA 1IB
I 20 17 S
75 30-78 22-84 30-76
111
1v
Sex MIF
Duration of MG (years)
1 10/10 7/10 114
1-7 1-16 2-7
1
"Osserman et a]. 121 classification. "Thymic hyperplasia with penninal centers. ' 0 . No response: 1 + , minimal; 2 + , moderate: 3
ACLR AB (n) -
+
I 17 16 5
0
Thymoma
(n)
-
-
3 I -
2 S 1
-
8
9 I
Drug Therapy ( n )
I"PE (')
Pyridostirmine
Steroids
A.mhioarine
1
I 20 17
I 19
20 17 S
5
12 4
Grading of response 0-4
+
0
(mean)'
I 18 IS 5
2 2 0
2 0-4 ( 2 . 7 ) 0-3 (2.2) 2-3 ( 2 4)
+ , marked; 4 + , asymptomatic, bur on medications (gradation W B E baaed o n rimed stimdard tehts and functional stat"$)
43 patients had been on pyridostigmine and prednisone therapy. Thirty-four patients (79%) had received azathioprine as well. The latter drug was generally avoided during the child-bearing years. MG had been present for from 3 months to 16 years prior to PE. Improvement was defined as at least one step up in the Osserman classification [2]. Except for one 74-year-old man in clinical class IIA, only patients in classes IIB, 111, and IV required PE. No purely ocular MG patients (group I) were plasmapheresed. In that we previously observed the occasional appearance of cholinergic symptoms in PE-responsive patients, we have advised cutting pyridostigmine doses over 60 mg by 25% before PE (unpublished data). We interpret this to mean that pyridostigmine requirements in some PE-responsive patients may fall as serum IgG and acetylcholine receptor antibody (AChRAb) levels decrease. We have not observed increased myasthenic weakness during PE. This is in line with previous reports of the very brief serum half-life of pyridostigmine [3]. Aquilonius et al. [4] have called attention to wide serum drug level fluctuations in MG patients. We have not been able in the past to correlate clinical strength with blood pyridostigmine levels [3]. Table I1 also shows that 39 of 43 (90%) MG patients responded to PE. This exceeds the 75% overall improvement rate with PE reported by Szobor [l]. Table 111 lists PE responses as related to clinical classification and severity, age, sex, duration of MG, acetylcholine receptor antibody (AChRAb), and thymic pathology. Five MG patients (lo%), all advanced in age (64-91 years), refused the recommended thymectomy. Patients in class I were never considered for PE, no matter how severe the ocular deficits. Even the patients with MG and thymoma, a more severe and unstable form of illness, responded to PE. This is in agreement with previous reports that MG associated with thymoma also responds well to thymectomy [5]. Age, thymoma, and thymic germinal center hyperplasia had no bearing in PE responsiveness ( P > .05). Female patients had a better PE response than males ( P < ,012). However, all five patients who attained a maximum clini-
-
Clinical response
Thymic Hyperplasia GCsb
cal response of 4 + , had been thymectomized, belonged to classification IIB and 111, and ranged in age from 22 to 51 years, and two patients had a history of thymoma. The duration of MG prior to PE in patients with muximum PE response was significantly shorter ( P < . O l ) than in the other PE response groups. However, the overall correlation between duration of MG and all clinical responses to PE was not significant (correlation cofficient -0.175). This is not surprising in view of previously published data suggesting that short-duration MG is also more responsive to other forms of therapy and tends to carry a better prognosis [5,6]. However, since 84% of the PE sample had been thymectomized and 100% had been immunosuppressed with steroids, azathioprine, or both, it is difficult to know whether PE itself was responsible for the beneficial clinical effects or whether PE merely exerted an additive or synergistic effect [7,8] facilitated by previous thymectomy and immunosuppression. The fact that seven elderly, nonthymectomized, but immunosuppressed patients had a PE response similar to that of the thymectomized group suggests that immunosuppression was the central factor in determining PE response. Indeed, it has been shown previously that PE without immunosuppression is ineffective [7]. MG patients with elevated serum AChRAb responded better to PE than those with absent serum levels, but this was not significant due to the small number of antibodynegative patients involved (9%). However, the PE response rate in the antibody negative group was still 75%. We believe that so-called antibody-negative patients are not truly negative but rather that the assay procedure used does not detect certain classes of antibodies, particularly those of the blocking type [9,10]. While it is known that serum AChRAb levels are generally higher in the more generalized forms of MG and in MG associated with thymoma, this is not universally true [ 10- 121. We have seen the highest antibody titers in two women whose MG has been in remission for several years (unpublished data). While PE invariably produces an immediate drop in serum AChRAb levels, subsequent rebounds in these titers bear little or no relation to the
66
Kornfeld et al.
clinical state [9-111. Our experience with serial AChRAb titer levels in 15 patients has not confirmed Tindall’s [ 121 advocacy of rising titers as a useful predictor of clinical deterioration or improvement [ 131. Hence, we use the serum AChRAb titer as a diagnostic rather than as a prognostic tool [10,12,14]. Since it is known that PE can stimulate T lymphocytes and probably B lymphocytes as well, it would seem that the rebound in serum AChRAb levels results from a change in OKT4/OKT8 cell ratio due to I ) release of previously sensitized lymphocytes into the bloodstream or 2) increased replication of such cells [ 121. It was our clinical impression that the AChRAb rebound phenomenon was delayed and was less marked in patients receiving ongoing interval PE. The average PE was 2.7 liters or 65% of calculated plasma volume but ranged from 1.8 to 4.2 liters. The initial PE course consisted of six treatments over a 10-14 day period, for a total of 18-20 liters of exchange. Treatment frequency was subsequently tapered to 1, 2, 3, or 4 week intervals to wean the patient from PE. Therapy was stopped as soon as the clinical picture had stabilized and clinical classification IIA had been attained. We never stopped PE prior to 20 liters of exchange before labeling the treatment a failure. It was also noted that all responders showed clinical improvement by 8-9 liters of exchange. Those who did not had only minimal or no improvement subsequently. In patients who required more than SO mg prednisone on alternate days for 1 year or more, PE was tried chronically at a 2 week interval. This treatment mode was considered successful if steroid dose could be reduced by at least 50% without concomitant clinical deterioration. We had only four such patients, and in none were we able to achieve this goal for any significant length of time. Normal interval venous access was available in 90% of patients. In five patients who required prolonged indwelling catheters, two developed Stuphylococcus uureus infection of the catheter tip, with subsequent sepsis. Both patients responded to catheter change and antibiotics. All these patients were heavily immunosuppressed. Of interest is the recently reported experience in patients on chronic peritoneal dialysis, in whom a direct relationship was found between positive nasal carriage of S . aureus and subsequent infection by the same organism of the peritoneal catheter [ 1 11. However, another study involving 29 MG patients did not bear this out [ 151. This raises the question of the advisability of such immunosuppressed patients with indwelling catheters receiving antibiotic prophylaxis prior to PE. The overall infection rate in the entire patient sample was < 4%, but this rose to 40% in patients requiring prolonged indwelling catheters. Replacement fluid is not crucial, except in ITP and TTP, in which fresh frozen plasma (FFP) is generally
-
used. No further allergies were encountered after cessation of routine use of FFP in 1980. There is general agreement that the nature of the replacement fluid plays no role in outcome of plasmapheresis in MG [ 121. We added albumin to normal saline solution to maintain oncotic pressure. No deaths or other serious complications occurred. There were three instances of mild hypovolemia, readily reversed by speeding up the rate of fluid replacement. Although four patients complained of mild circumoral tingling, no true hypocalcemia was found. Guillain-Barre Syndrome
Table IV summarizes our plasma exchange experience in 17 patients with acute Guillain-BarrC syndrome. Multinational studies have clearly demonstrated the beneficial effect of this procedure [ 161. The neurologic symptoms were preceded in all instances by viral upper respiratory infections. Ten patients (60%) required ventilatory support. One of the patients had previously been on steroids, but several had been on antibiotics for 3-5 days for upper respiratory infections. Both patients who died were in the seventh decade, one of them dying following surgery for a bowel infarction. Both of these patients had failed to show any neurologic improvement with PE. All others could be weaned from the respirator within 7- 10 days and left the hospital within 3-4 weeks. All patients who improved with PE showed signs of improvement at 7 liters PE. The average PE was 22.5 liters (range 15.9-35.6 liters). The mean number of PE treatments was 8.5 (range 5-16). PE was never stopped in responders before 16 liters or in nonresponders before 20 liters. One patient was treated intermittently for 119 days because of periodic relapses, all of which also responded to PE. The two patients who failed on PE were first treated on days 3 and 7 of illness. Two elderly patients, not treated until days 14 and 15, had an excellent PE response. We have found it beneficial not to stop plasma exchange as soon as any significant neurologic recovery has occurred but to continue PE until the patient is at least ambulatory (unpublished data). This is in accordance with the recent report which questions the concept of early stoppage of PE [17]. Among responders, ventiTABLE IV. PlasrnaDheresis in Guillain-Barre Svndrome n 18 Age (years) 7-79 Male (n) 10 Female (n) 8 Duration of disease before PE 3- 14 days Duration of PE 6-26 days Mean PE 22.5 liters (range 16-36 liters) Length of hospitalization 6-1 19 days (mean 37 days) Positive PE remonse 15 (83%)
Therapeutic Apheresis in a Community Hospital
67
TABLE V. Plasmapheresis (PE) Response in Hyperviscosity Syndrome*
PT
F
I
X
M
2
X
3 4
X
5 6 7 8
X
x X X X
Protein electropheresis spike
Age (years)
Diagnosis
66 59 70 71 59 57 7I 65
Waldenstrom’s Waldenstrom’s Waldcnstrom’s Multiple Myeloma Multiple Myeloma Multiple Myeloma Multiple Myeloma Multiple Myeloma
‘gM IgM IgM IgM
‘gG IgG IgA kG
Duration of PE
Serum viscosity
CNS
2 days 14 days 5 years 3 years 5 days 3 days 150 days 210 days
2.4 1.61 28.2 % 2.4 3.3 ? 1.9 8.4 t 4.0 10.4 ? 1.8 3.5 t 1.2 4.4 ? 4.8 2.6 1.3
*
+
*
0
+ + + + +
Clinical responaea
Total volume exchange (ml)
4+ 4+ 4+ 3+ 3 f 4+ 4 f 3 f
3,150 9,950 148,000 120,000 11,750 8,800 26,950 133,530
* A l l putients on conventional chemotherapy. Patient 3 resistant to chemotherapy; requires weekly Rx to keep viscosity below 4 and to stay symptom-free. “Response meusuremenf: 0, no response; 1 , mild improvement; 2 , moderate improvement; 3 + , marked improvement; 4 , asymptomatic.
+
+
+
latory support could be withdrawn within 7-10 days. PE shortened the average hospital stay by at least 25% when comparing our patients’ hospital stays with the average hospital stay of GB patients in our hospital from 1976 to 1980. Ten patients were able to walk out of the hospital and return home, while four required intensive physiotherapy and rehabilitation in another facility. Several elderly patients, in their late sixties, recovered completely. Our experience suggests that PE should be carried out regardless of the time elapsed since onset of symptoms. The belief that PE has to be started within 7 days of onset of symptoms to be successful, as advocated by the American and French cooperative groups, was not borne out by our uncontrolled study: Some patients treated within 24 hr did not improve, while others did so despite a 14 day delay. The ability to improve regardless of severity of symptoms or age suggests that the nature of the etiologic factor has great influence on the disease’s likelihood of responding to PE. While it is true that rapidly progressing symptoms required longer hospitalization, we could not predict initially which patient was going to respond or to fail on PE. Unfortunately, no neural antibody studies were available. Vriesendorp et al. [17] have reported that serial titers of antiperipheral nerve myelin antibodies may identify patients with antibody rebound associated with clinical recurrence of symptoms, who may then require prolonged PE.
Hyperviscosity
The hyperviscosity data are given in Table V. All patients responded, regardless of the type of serum globulin spike present. We tried to exchange at least one plasma volume per treatment, because rapid results were required. No absolute viscosity reading is necessary to start plasmapheresis in the presence of central nervous system (CNS) or renal signs or symptoms, since they may be followed by permanent organ damage. Such symptoms should be considered emergency indications for PE. Generally, younger patients with viscosity levels under 3 will not complain of CNS symptoms. However, in patients over the age of 50 years, this was not true. The combination of arteriosclerosis and hyperviscosity renders the affected patient more susceptible, even at low viscosity levels. The duration of plasma exchange will depend on the nature and severity of the underlying disease and the efficacy of the associated antitumor therapy. Thrombotic Thrombocytopenic Purpura
Table VI summarizes our experience with TTP (Moschcowitz syndrome). All eight patients entered as acute emergencies, with advanced renal and CNS disease, when seen in the apheresis unit for the first time. One case followed chemotherapy for breast cancer, all others were nontumor related and followed upper respi-
TABLE VI. Plasmapheresis Response in TTP Duration of
Volume of
Number of patients
(years)
M
F
apheresis (days)
PE (ml)
0
8
30-75
4
4
1-180
6,000-177,000
3 (42)
Age
“Response meusuremenr: 0, no response; 1
Response” (%)
I+ 0 (-)
2+
3+
I
4 (54.5)
(12.5)
Deaths 3 (within 24 hr of first Rx)
+ , mild response (Plts); 2 + , moderate response (Plts); 3 + , marked response (Plts, BUN, CNS).
68
Kornfeld et al.
ratory infections. Three patients, all elderly and with advanced CNS disease and renal failure, died within 24 hr. However, five out of eight patients (66%) showed significant response in terms of platelet count and clinical improvement. No laboratory values distinguished the three who succumbed from the five survivors. It must be noted that all patients had also received steriods, platelet aggregation inhibitors (aspirin), intravenous gamma globulin, and FFP. While it was impossible to ascertain the exact quantitative effect exerted by PE, there was marked clinical and laboratory improvement following successive PE in our small series.
SUMMARY
The number of conditions that can benefit from PE continues to grow. Our 10 year treatment experience is presented, but only four disease states, myasthenia gravis, acute Guillain-BarrC syndrome, hyperviscosity , and TTP, occurred frequently enough to allow us to draw the conclusion that PE was highly effective in all four. This review also confirms the safety of the procedure. Finally, the ability of PE to shorten substantially the hospitalization time of inpatients, along with the ease with which PE can be performed on ambulatory patients, implies for plasmapheresis a favorable costibenefit ratio. A hemapheresis unit is an absolute necessity for a medium-sized hospital, even if only therapeutic procedures and no harvesting procedures are performed. During the past 3 years, our hemapheresis volume has increased by 160%. More than 75% of our procedures are done on an outpatient basis. We have not encountered any treatment-related deaths or major complications. We use 0.9% NaCl as plasma expander in all cases except for TTP and ITP where FFP is employed. The question of prophylactic antibiotics in immunosuppressed patients with indwelling catheters requires a controlled, randomized study. ACKNOWLEDGMENTS
We thank Dr. John Mandeli of the Biomathematical Sciences Department, Mount Sinai School of Medicine, New York, for performing the statistical analyses. This work was supported in part by a grant from The Muscular Dystrophy Association.
REFERENCES 1. Szobor A: Myasthenia Gravis. Budapest: Akddemiai Kiado,
1990, p 147. 2. Osserman KE, Kornfeld P, Cohen E, Genkins G , Mendelow H. Goldberg H, Windsley H , Kaplan L1: Studies in myasthenia gravis. A review of 282 cases. Arch Intern Med 102:72-81, 1958. 3 . Kornfeld P, Samuels SM, Wolf RL, Osserman KE: Metabolism of C-14 labelled pyridostigmine in myasthenia gravis. Evidence for multiple metabolites. Neurology 20:634-641, 1970. 4. Aquilonius WWM, Eckemas SA, Hartrig P, Lindstrom B, et al. : Clinical pharmacology of neostigmine and pyridostimine in patients with myasthenia gravis. Neurol Neurosurg Psychiatr 46:929-935, 1983. 5. Osserman KE, Genkins G: Studies with myasthenia gravis. Review of a twenty year experience in 1,200 patients. Mount Sinai J Med 38:497-537, 1971. 6. Genkins G, Kornfeld P. Papatestas AE, Bender AN, Matta KJ: Clinical experience with more than 2,000 patients with myasthenia gravis. Ann N Y Acad Sci 505:595-605, 1987. 7. Hawkey CG, Newsom-Davis J, Vincent A: Plasma exchange and immunosuppressive drug treatment of myasthenia gravis: No evidence for synergy. J Neurol Neurosurg Psychiatr 44:469-47S, 1981. 8. Bogarnini L, Cocito D, Durelli L, Quattrorolo G: Letter to the editor. Opinions about plasma exchange and associated treatment with the therapy of myasthenia gravis. Muscle Nerve 6:456-457, 1983. 9. Mittag T, MassaT, Kornfeld P, Papatestas A, Bender A , Genkins G: Multiple forms of anti-acetylcholine receptor antibody in myasthenia gravis. Muscle Nerve 4(1):16-25, 1981. 10. Vincent A: Immunology of acetylcholine receptors in relation to myasthenia gravis. Physiol Rev 60:757-824, 1980. I I . Lozar MA, Coles GA, Faller R, Slingeneyer A, Dah GD, Briat C, Wone C: Staphylococcus aureus nasal carriage and infection in patients on continuous ambulatory peritoneal dialysis. N Engl J Med 322:505-509. 1990. 12. Tindall RB: Humoral immunity-myasthenia gravis. Biochemical characterization of acquired anti-receptor antibodies and clinical correlation. Ann Neurol 10:437-447, 1981. 13. Mittag T, Kornfeld P, Tormdy A , Woo C: Detection of antiacetylcholine receptor factors in serum and thymus from patients with myasthenia gravis. N Engl J Med 294:691-694, 1976. 14. Komfeld P, Nall J , Smith H, Mittdg TW, et al.: Acetylcholine receptor antibodies in myasthenia gravis. Muscle Nerve 4:413419, 1981. 1s. Johnson RB, Mudev RR, Kominos SD, Nasca TJ: Staphylococcal carriage and infection in myasthenia gravis patients receiving therapeutic apheresis. J Clin Apheresis 4:155-157, 1988. 16. McKhann G, Griffin JW, Cornblak DR, Mellits ED, Feber RS, O’Maskey SA: The Guillain-Barre syndrome study group. Am J Neurol 23:347-353, 1988. 17. Vriesendorp FJ, Mayer RF, Koski CL: Kinetics of antiperipheral nerve myelin antibody in patients with Guillain-Barre syndrome treated and not treated with plasmapheresis. Arch Neurol 48: 858-861, 1991,
