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High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis
High-Dose Intravenous Immunoglobulin Therapy in Juvenile Myasthenia Gravis Duygu Selcen, MD, Edward R. Dabrowski, MD, Anne M. Michon, MSN, RN, and Michael A. Nigro, DO Autoimmune neurologic disease management has been significantly modified by the use of high-dose intravenous immunoglobulin (HDIVIG) during the past 15 years. Venous access, readily available IgG (until recently), and the relative lack of serious identifiable complications have prompted its use in myasthenia gravis. In adults, its effectiveness has been inconsistent, with variable acetylcholine receptor (AChR) antibody responses. Ten children were evaluated for clinical responses to, and complications of, HDIVIG. Weekly anti-AChR antibody titers in three patients were obtained. The HDIVIG dosage was 2 gm/kg body weight, infused at variable rates of 2 gm/kg for 1 day, 0.66 gm/kg daily for 3 days, and 0.5 g/kg daily for 4 days; in one patient the total dose was 0.8 gm/kg to correct to the ideal body weight. All children but one tolerated HDIVIG without complications. Eight patients exhibited definite improvement in functional strength after HDIVIG, but a decreasing response to HDIVIG was evident after multiple monthly treatments, warranting the additional use of corticosteroids in two patients. A decrease in anti-AChR antibody levels was observed in the three patients tested, but this decrease was constant in one patient. No correlation was observed between clinical response and antibody titers. HDIVIG is safe and effective in most patients for shortterm management of juvenile myasthenia gravis, in myasthenic crises, and in preparing patients for surgery but appears to be of limited long-term benefit. © 2000 by Elsevier Science Inc. All rights reserved.
Introduction Juvenile myasthenia gravis (JMG) is an acquired autoimmune disorder of childhood, with an onset of difficulties after 12 months of age, in which circulating antibodies against the acetylcholine receptor (AChR) interfere with normal neuromuscular transmission. As a result, transient and even permanent muscle weakness may develop [1]. The mechanism of action of AChR antibodies on the motor end plate may be caused by the binding of AChR antibodies to the postsynaptic receptor, progressive loss of postsynaptic receptors, diminished junctional folds, or more likely a combination of these, which results in the loss of functional AChR [2]. There are four basic strategies for treating myasthenia gravis (MG): (1) increasing the available amount of acetylcholine at the neuromuscular junction with cholinesterase inhibitors; (2) thymectomy; (3) chronic immunosuppression and short-term immunotherapies, including plasmapheresis to remove AChR antibodies; and (4) most recently, high-dose intravenous immunoglobulin (HDIVIG) [3]. The ability to administer HDIVIG without significant side effects and the demonstration that high doses of passively administered immunoglobulin could inhibit antibody synthesis prompted the use of HDIVIG for the treatment of patients with a variety of autoimmune states [4]. Ten patients were prospectively evaluated with JMG for 5 years for clinical responses to, and complications of, HDIVIG. Weekly anti-AChR antibody titers in three patients were obtained. Patients and Methods
Selcen D, Dabrowski ER, Michon AM, Nigro MA. Highdose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol 2000;22:40-43.
From the Department of Neurology, Wayne State University, Children’s Hospital of Michigan, Detroit, Michigan.
40
PEDIATRIC NEUROLOGY
Vol. 22 No. 1
Ten patients were enrolled for HDIVIG therapy. The patients were selected on the basis of refractoriness to cholinesterase inhibitors, complications from or failure of steroids, or incomplete response or inability to effectively use plasmapheresis. Two patients were naive to
Communications should be addressed to: Dr. Nigro; 28595 Orchard Lake Road, Farmington Hills, MI 48334. Received July 9, 1999; accepted September 3, 1999.
© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00112-5 ● 0887-8994/00/$20.00
Table 1.
Demographic data of the patients
Pt. No.
Age (yr)
Sex
1 2 3 4 5 6 7 8 9 10 (NA)
15 16 18 2 8 17 14 16 13 15
M F F M M F M F F F
Ethnicity
MG Duration (mo)
Thymic Pathology
AChR Ab
Pyridostigimine
Prednisone
Plasmaphereisis
Azathioprine
B B B B W B B W H B
36 3 180 2 24 4 72 5 1 7
Hyperplasia NT Hyperplasia NT NT Hyperplasia Hyperplasia NT NT Hyperplasia
⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫺
⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹
⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹
⫹ ⫺ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹
⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
Abbreviations: Ab ⫽ Antibodies AChR ⫽ Acetylcholine receptor B ⫽ Black H ⫽ Hispanic MG ⫽ Myasthenia gravis
NA NT Pt. No. W
⫽ ⫽ ⫽ ⫽
Therapy
Not included in analysis No thymectomy Patient number White
any therapy. The authors were unable to evaluate one of the patients (Patient 10) because she developed severe hypotension during the initial infusion and never received the complete dose. She was only included for the side effect profile. The diagnosis of JMG was established by the clinical findings, including fluctuating generalized or localized muscle weakness; fatigability; weakness of ocular and bulbar muscles, with ptosis, diplopia, dysarthria, and dysphagia; onset of symptoms after 12 months old; a positive response to intravenous edrophonium; a significant decremental response to a neuromuscular transmission study; and the presence of anti-AChR antibodies. The patients fulfilled at least three of four criteria for the diagnosis of JMG. In three patients, HDIVIG was reinitiated before a planned thymectomy. Doses of anticholinesterase medication and prednisone were kept constant during HDIVIG administration and while assessing the response. HDIVIG was administered in various increments to a total of 2 gm/kg as a single infusion, 0.66 g/kg daily for 3 days, or 0.5 gm/kg daily for 4 days. One patient received a dose of 0.2 gm/kg daily for 4 days because of severe obesity. The infusion duration was 12 hours to minimize reactions associated with large-volume infusions and allergic phenomena. Diphenhydramine, 2 mg/kg, was administered intravenously 30 minutes before the infusion. IVIG was obtained from Baxter and later from Sandoz (Central Laboratory Blood Transfusion Service, Swiss Red Cross). It was reconstituted with normal saline to a 3-6% concentration. The HDIVIG infusions were repeated 4-6 weeks after the initial infusion, if necessary, according to the functional status of the patient (grade 2 or higher). Serum levels of anti-AChR antibody were determined by radioimmunoassay method before and at weekly intervals after HDIVIG administration in three patients. The patients’ MG functional status was scored according to the University of Virginia’s modification of Osserman’s classification: grade 1, asymptomatic; grade 2, minor symptoms with repetitive exercise; grade 3, mildly disabled with symptoms readily apparent and restrictions with more demanding activities; grade 4, restricted at daily activities and symptomatic at rest; and grade 5, completely dependent on skilled care for support. A positive response was defined as an improvement of at least one grade in MG functional status.
female (median age ⫽ 13.4 years; range ⫽ 3-18). All patients had generalized JMG. The median duration of the disease was 40 months (range ⫽ 1-180) at the beginning of HDIVIG therapy. Anti-AChR antibodies were detectable in seven of nine patients (Patient 10 not included in analysis). All the patients had grade 4 or 5 functional status with acute relapse at the first infusion of HDIVIG. Three patients required mechanical ventilatory assistance. During the repeated infusions, the functional status of the patients was grade 2 or 3. Four patients had undergone thymectomy. Pathologic examination revealed thymic hyperplasia in all four patients. The results of HDIVIG therapy are listed in Table 2. Eight of nine patients demonstrated positive functional status improvement during acute relapse. The clinical change was evident 1-7 days after the infusion. The
Results
Abbreviations: HDIVIG ⫽ High-dose intravenous immunoglobulin MG ⫽ Myasthenia gravis Pt. No. ⫽ Patient number
The demographic data of the patients are summarized in Table 1. Of the 10 patients, four were male and six were
Table 2.
Pt. No. 1 2 3 4 5 6 7 8 9
Clinical parameters MG Functional Status (First Episode) Before Maximal HDIVIG Improvement 4 3 5 4 3 5 5 4 4
3 2 1 2 2 2 3 2 4
Artificial Ventilation ⫺ ⫺ ⫹ ⫺ ⫺ ⫹ ⫹ ⫺ ⫺
Repeat HDIVIG 0 1 0 5 2 4 2 2 0
Selcen et al: Immunoglobulin Therapy in Myasthenia Gravis 41
duration of improvement varied from 21 to 30 days (median ⫽ 25). One patient did not demonstrate any improvement in functional status; however, ptosis was improved. Twelve days after HDIVIG infusion, prednisone was initiated. Three patients with acute exacerbation of bulbar symptoms demonstrated rapid clinical improvement 24-48 hours after HDIVIG infusion and were withdrawn from the ventilator. In patients in whom a repeated HDIVIG infusion was required, improvement was less evident, warranting the additional use of immunosuppression therapy or an increased dose of cholinesterase inhibitors as tolerated. The markedly obese patient had a moderate response, which was of a shorter duration, probably as a result of the decreased dose of HDIVIG. HDIVIG was effective before and after thymectomy and in one patient who was poorly responsive to plasmapheresis. In two patients in whom HDIVIG was the only treatment the clinical improvement was also remarkable; however, these patients later required additional therapy. Headache was reported in five patients and was relieved by acetaminophen, ibuprofen, or slowing the infusion rate. The patient who had hypotension during the infusion and was excluded from the analysis of the response also experienced transient severe headache. The cause of hypotension was assumed to be related to the infusion rate. Only three patients were available for weekly anti-AChR antibody titer analysis. A decrease in anti-AChR antibody levels was observed in all three patients. The largest reduction was observed between 7 and 15 days after the HDIVIG infusion. Only one of these patients exhibited a persistent decrease; in the other two patients the antibody titers increased to 77-83% of the pre-HDIVIG therapy levels. No correlation was evident between the clinical response and the antibody titers. Discussion The results of the use of HDIVIG in the treatment of patients with generalized JMG during a myasthenic crisis or during chronic maintenance therapy are reported. The study was unblinded and uncontrolled; therefore the authors did not make any changes in the medications patients were already receiving during HDIVIG treatment to exclude other therapies that might alter the patient’s status and response to treatment. All but one of the patients in myasthenic crisis had a significant response to HDIVIG; however, the response was not as prominent with chronic maintenance therapy. Recently reviewed clinical trials testing HDIVIG primarily in adult patients with MG and in three children with JMG [5] revealed positive results in 50-100% of the patients [6-9]. A trial comparing plasma exchange and HDIVIG in MG exacerbation demonstrated a similar efficacy for both treatments and a limited risk for HDIVIG. HDIVIG has been recommended as an alternative for the treatment of myasthenic crisis [10].
42
PEDIATRIC NEUROLOGY
Vol. 22 No. 1
Various mechanisms have been hypothesized for the mode of action of HDIVIG. For example, immunoglobulin might down regulate anti-AChR antibodies by directly binding to them or inhibiting the synthesis or the secretion of these antibodies or by the production of anti-idiotypic antibodies that would inhibit specific B-cell clones; IVIG also might compete with AChR antibody binding to AChR [11,12]. In addition, an increased percentage of CD16⫹ lymphocytes and a decrease in the CD4/CD8 ratio have been reported in patients treated with IVIG [13]. There have been reports demonstrating a decrease or no change in anti-AChR antibody levels after HDIVIG therapy [7,8,14]. In our three patients a decrease in antibody titers was observed. However, in only one patient was this decrease persistent. Although the number is small, this finding suggests that HDIVIG might both decrease the synthesis and interfere with binding of anti-AChR antibodies to the receptors. Two of the antibody-negative patients demonstrated a good response to HDIVIG therapy. The absence of measurable AChR antibodies, itself, is not a contraindication to HDIVIG. However, an alternative diagnosis to acquired autoimmune MG may be considered in patients who are AChR antibody negative and in whom the response to HDIVIG is poor. No consensus has been reached about the dose of IVIG for the morbidly obese patient. To avoid hyperviscosity and large-volume overload, we did not use the usual dose of IVIG in the single obese patient. Her response was moderate and of short duration. Further studies regarding the dosage of IVIG in morbidly obese patients may be warranted. The side effects of HDIVIG were milder than those of corticosteroids and other immunosuppressive agents. However, non-A, non-B hepatitis [15], severe hemolysis [16], renal failure [17], cerebral infarction [18], and recurrent aseptic meningitis [19] have been reported after treatment with HDIVIG. The adverse effects of HDIVIG in the present series were severe transient hypotension in one patient that necessitated stopping the infusion and more frequently headache relieved by analgesics and slowing the rate of the infusion. In an additional 70 patients that were treated with HDIVIG for other neurologic diseases, hypotension was not encountered (unreported data). In the reported series, HDIVIG was effective in eight of nine rapidly deteriorating patients with bulbar symptoms. In conditions in which plasmapheresis is not technically feasible, HDIVIG may be an alternative therapy in myasthenic crises. In the patients who did not respond to chronic HDIVIG therapy the symptoms were controlled with the chronic use of pheresis, steroids, and azathioprine. We administer a program of HDIVIG after pheresis so that the interval between phereses can be lengthened. We also administer HDIVIG before thymectomy to prepare patients for surgery if plasmapheresis is not feasible or effective. We do not anticipate using HDIVIG in the long-term management of JMG and instead rely on thymectomy, cholinesterase inhibitors, or corticosteroids.
Further controlled clinical trials are needed to assess the merits of HDIVIG in JMG in acute exacerbation and for chronic use. References [1] Engel AG. Myasthenia gravis and myasthenic syndromes. Ann Neurol 1984;16:519-34. [2] Drachman DB, Adams RN, Josifek LF, Self SG. Functional activities of autoantibodies to acetylcholine receptors and the clinical severity of myasthenia gravis. N Engl J Med 1982;307:769-75. [3] Drachman DB. Myasthenia Gravis. In: Johnson RT, Griffin JW, eds. Current therapy in neurologic disease, 4th ed. St. Louis: Mosby-Year Book, 1993:379-84. [4] Pahwa RN. New and controversial uses of intravenous gammaglobulin. Pediatr Infect Dis J 1988;7:S34-6. [5] Herrmann DN, Carney PR, Wald JJ. Juvenile myasthenia gravis: Treatment with immune globulin and thymectomy. Pediatr Neurol 1998;18:63-6. [6] Gajdos PH, Outin H, Elkharrat D, et al. High dose intravenous immunoglobulin for myasthenia gravis. Lancet 1984;1:406-7. [7] Fateh-Moghadam A, Wick M, Basinger U, Geursen RG. High dose intravenous gammaglobulin for M.G. Lancet 1984;14:848-9. [8] Evoli A, Palmisani MT, Bartoccioni E, Padua L, Tonali P. High dose intravenous immunoglobulin in myasthenia gravis. Ital J Neurol Sci 1993;14:233-7. [9] Arsura L, Bich A, Brunner NG, Namba J, Grob D. High-dose intravenous immunoglobulin in the management of MG. Arch Intern Med 1986;146:1365-8.
[10] Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann Neurol 1997;41:789-96. [11] Zweiman B. Theoretical mechanisms by which immunoglobulin therapy might benefit myasthenia gravis. Clin Immunol Immunopathol 1989;53:583-91. [12] Durelli L. High-dose intravenous immunoglobulin G treatment of myasthenia gravis. In: Lisak RP, ed. Handbook of myasthenia gravis and myasthenic syndromes. New York: Marcel Dekker, 1994:375-88. [13] Levinson AI. The use of IVIG in neurological disease. Clin Rev Allergy 1992;10:119-34. [14] Osterhuis HJGH, Limburg PC, Hummel-Tappel E. The anti-acetylcholine receptor antibodies in myasthenia gravis: Clinical and serological follow-up of individual patients. J Neurol Sci 1983; 58:371-85. [15] Webster A, Lever A. Non-A non-B hepatitis after intravenous gamma globulin. Lancet 1986;1:322. [16] Copelan EA, Strohn PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26: 410-2. [17] Ahsan N. Intravenous immunoglobulin induced-nephropathy: A complication of IVIG therapy. J Nephrol 1998;11:157-61. [18] Silbert PL, Knezevic WV, Bridge DT. Cerebral infarction complicating intravenous immunoglobulin therapy for polyneuritis cranialis. Neurology 1992;42:257-8. [19] Vera-Ramirez M, Charlet M, Parry GJ. Recurrent aseptic meningitis complicating intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 1992;42:1636-7.
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Selcen et al: Immunoglobulin Therapy in Myasthenia Gravis 43
Introduction Juvenile myasthenia gravis (JMG) is an acquired autoimmune disorder of childhood, with an onset of difficulties after 12 months of age, in which circulating antibodies against the acetylcholine receptor (AChR) interfere with normal neuromuscular transmission. As a result, transient and even permanent muscle weakness may develop [1]. The mechanism of action of AChR antibodies on the motor end plate may be caused by the binding of AChR antibodies to the postsynaptic receptor, progressive loss of postsynaptic receptors, diminished junctional folds, or more likely a combination of these, which results in the loss of functional AChR [2]. There are four basic strategies for treating myasthenia gravis (MG): (1) increasing the available amount of acetylcholine at the neuromuscular junction with cholinesterase inhibitors; (2) thymectomy; (3) chronic immunosuppression and short-term immunotherapies, including plasmapheresis to remove AChR antibodies; and (4) most recently, high-dose intravenous immunoglobulin (HDIVIG) [3]. The ability to administer HDIVIG without significant side effects and the demonstration that high doses of passively administered immunoglobulin could inhibit antibody synthesis prompted the use of HDIVIG for the treatment of patients with a variety of autoimmune states [4]. Ten patients were prospectively evaluated with JMG for 5 years for clinical responses to, and complications of, HDIVIG. Weekly anti-AChR antibody titers in three patients were obtained. Patients and Methods
Selcen D, Dabrowski ER, Michon AM, Nigro MA. Highdose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol 2000;22:40-43.
From the Department of Neurology, Wayne State University, Children’s Hospital of Michigan, Detroit, Michigan.
40
PEDIATRIC NEUROLOGY
Vol. 22 No. 1
Ten patients were enrolled for HDIVIG therapy. The patients were selected on the basis of refractoriness to cholinesterase inhibitors, complications from or failure of steroids, or incomplete response or inability to effectively use plasmapheresis. Two patients were naive to
Communications should be addressed to: Dr. Nigro; 28595 Orchard Lake Road, Farmington Hills, MI 48334. Received July 9, 1999; accepted September 3, 1999.
© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00112-5 ● 0887-8994/00/$20.00
Table 1.
Demographic data of the patients
Pt. No.
Age (yr)
Sex
1 2 3 4 5 6 7 8 9 10 (NA)
15 16 18 2 8 17 14 16 13 15
M F F M M F M F F F
Ethnicity
MG Duration (mo)
Thymic Pathology
AChR Ab
Pyridostigimine
Prednisone
Plasmaphereisis
Azathioprine
B B B B W B B W H B
36 3 180 2 24 4 72 5 1 7
Hyperplasia NT Hyperplasia NT NT Hyperplasia Hyperplasia NT NT Hyperplasia
⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫺
⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹
⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹
⫹ ⫺ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹
⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
Abbreviations: Ab ⫽ Antibodies AChR ⫽ Acetylcholine receptor B ⫽ Black H ⫽ Hispanic MG ⫽ Myasthenia gravis
NA NT Pt. No. W
⫽ ⫽ ⫽ ⫽
Therapy
Not included in analysis No thymectomy Patient number White
any therapy. The authors were unable to evaluate one of the patients (Patient 10) because she developed severe hypotension during the initial infusion and never received the complete dose. She was only included for the side effect profile. The diagnosis of JMG was established by the clinical findings, including fluctuating generalized or localized muscle weakness; fatigability; weakness of ocular and bulbar muscles, with ptosis, diplopia, dysarthria, and dysphagia; onset of symptoms after 12 months old; a positive response to intravenous edrophonium; a significant decremental response to a neuromuscular transmission study; and the presence of anti-AChR antibodies. The patients fulfilled at least three of four criteria for the diagnosis of JMG. In three patients, HDIVIG was reinitiated before a planned thymectomy. Doses of anticholinesterase medication and prednisone were kept constant during HDIVIG administration and while assessing the response. HDIVIG was administered in various increments to a total of 2 gm/kg as a single infusion, 0.66 g/kg daily for 3 days, or 0.5 gm/kg daily for 4 days. One patient received a dose of 0.2 gm/kg daily for 4 days because of severe obesity. The infusion duration was 12 hours to minimize reactions associated with large-volume infusions and allergic phenomena. Diphenhydramine, 2 mg/kg, was administered intravenously 30 minutes before the infusion. IVIG was obtained from Baxter and later from Sandoz (Central Laboratory Blood Transfusion Service, Swiss Red Cross). It was reconstituted with normal saline to a 3-6% concentration. The HDIVIG infusions were repeated 4-6 weeks after the initial infusion, if necessary, according to the functional status of the patient (grade 2 or higher). Serum levels of anti-AChR antibody were determined by radioimmunoassay method before and at weekly intervals after HDIVIG administration in three patients. The patients’ MG functional status was scored according to the University of Virginia’s modification of Osserman’s classification: grade 1, asymptomatic; grade 2, minor symptoms with repetitive exercise; grade 3, mildly disabled with symptoms readily apparent and restrictions with more demanding activities; grade 4, restricted at daily activities and symptomatic at rest; and grade 5, completely dependent on skilled care for support. A positive response was defined as an improvement of at least one grade in MG functional status.
female (median age ⫽ 13.4 years; range ⫽ 3-18). All patients had generalized JMG. The median duration of the disease was 40 months (range ⫽ 1-180) at the beginning of HDIVIG therapy. Anti-AChR antibodies were detectable in seven of nine patients (Patient 10 not included in analysis). All the patients had grade 4 or 5 functional status with acute relapse at the first infusion of HDIVIG. Three patients required mechanical ventilatory assistance. During the repeated infusions, the functional status of the patients was grade 2 or 3. Four patients had undergone thymectomy. Pathologic examination revealed thymic hyperplasia in all four patients. The results of HDIVIG therapy are listed in Table 2. Eight of nine patients demonstrated positive functional status improvement during acute relapse. The clinical change was evident 1-7 days after the infusion. The
Results
Abbreviations: HDIVIG ⫽ High-dose intravenous immunoglobulin MG ⫽ Myasthenia gravis Pt. No. ⫽ Patient number
The demographic data of the patients are summarized in Table 1. Of the 10 patients, four were male and six were
Table 2.
Pt. No. 1 2 3 4 5 6 7 8 9
Clinical parameters MG Functional Status (First Episode) Before Maximal HDIVIG Improvement 4 3 5 4 3 5 5 4 4
3 2 1 2 2 2 3 2 4
Artificial Ventilation ⫺ ⫺ ⫹ ⫺ ⫺ ⫹ ⫹ ⫺ ⫺
Repeat HDIVIG 0 1 0 5 2 4 2 2 0
Selcen et al: Immunoglobulin Therapy in Myasthenia Gravis 41
duration of improvement varied from 21 to 30 days (median ⫽ 25). One patient did not demonstrate any improvement in functional status; however, ptosis was improved. Twelve days after HDIVIG infusion, prednisone was initiated. Three patients with acute exacerbation of bulbar symptoms demonstrated rapid clinical improvement 24-48 hours after HDIVIG infusion and were withdrawn from the ventilator. In patients in whom a repeated HDIVIG infusion was required, improvement was less evident, warranting the additional use of immunosuppression therapy or an increased dose of cholinesterase inhibitors as tolerated. The markedly obese patient had a moderate response, which was of a shorter duration, probably as a result of the decreased dose of HDIVIG. HDIVIG was effective before and after thymectomy and in one patient who was poorly responsive to plasmapheresis. In two patients in whom HDIVIG was the only treatment the clinical improvement was also remarkable; however, these patients later required additional therapy. Headache was reported in five patients and was relieved by acetaminophen, ibuprofen, or slowing the infusion rate. The patient who had hypotension during the infusion and was excluded from the analysis of the response also experienced transient severe headache. The cause of hypotension was assumed to be related to the infusion rate. Only three patients were available for weekly anti-AChR antibody titer analysis. A decrease in anti-AChR antibody levels was observed in all three patients. The largest reduction was observed between 7 and 15 days after the HDIVIG infusion. Only one of these patients exhibited a persistent decrease; in the other two patients the antibody titers increased to 77-83% of the pre-HDIVIG therapy levels. No correlation was evident between the clinical response and the antibody titers. Discussion The results of the use of HDIVIG in the treatment of patients with generalized JMG during a myasthenic crisis or during chronic maintenance therapy are reported. The study was unblinded and uncontrolled; therefore the authors did not make any changes in the medications patients were already receiving during HDIVIG treatment to exclude other therapies that might alter the patient’s status and response to treatment. All but one of the patients in myasthenic crisis had a significant response to HDIVIG; however, the response was not as prominent with chronic maintenance therapy. Recently reviewed clinical trials testing HDIVIG primarily in adult patients with MG and in three children with JMG [5] revealed positive results in 50-100% of the patients [6-9]. A trial comparing plasma exchange and HDIVIG in MG exacerbation demonstrated a similar efficacy for both treatments and a limited risk for HDIVIG. HDIVIG has been recommended as an alternative for the treatment of myasthenic crisis [10].
42
PEDIATRIC NEUROLOGY
Vol. 22 No. 1
Various mechanisms have been hypothesized for the mode of action of HDIVIG. For example, immunoglobulin might down regulate anti-AChR antibodies by directly binding to them or inhibiting the synthesis or the secretion of these antibodies or by the production of anti-idiotypic antibodies that would inhibit specific B-cell clones; IVIG also might compete with AChR antibody binding to AChR [11,12]. In addition, an increased percentage of CD16⫹ lymphocytes and a decrease in the CD4/CD8 ratio have been reported in patients treated with IVIG [13]. There have been reports demonstrating a decrease or no change in anti-AChR antibody levels after HDIVIG therapy [7,8,14]. In our three patients a decrease in antibody titers was observed. However, in only one patient was this decrease persistent. Although the number is small, this finding suggests that HDIVIG might both decrease the synthesis and interfere with binding of anti-AChR antibodies to the receptors. Two of the antibody-negative patients demonstrated a good response to HDIVIG therapy. The absence of measurable AChR antibodies, itself, is not a contraindication to HDIVIG. However, an alternative diagnosis to acquired autoimmune MG may be considered in patients who are AChR antibody negative and in whom the response to HDIVIG is poor. No consensus has been reached about the dose of IVIG for the morbidly obese patient. To avoid hyperviscosity and large-volume overload, we did not use the usual dose of IVIG in the single obese patient. Her response was moderate and of short duration. Further studies regarding the dosage of IVIG in morbidly obese patients may be warranted. The side effects of HDIVIG were milder than those of corticosteroids and other immunosuppressive agents. However, non-A, non-B hepatitis [15], severe hemolysis [16], renal failure [17], cerebral infarction [18], and recurrent aseptic meningitis [19] have been reported after treatment with HDIVIG. The adverse effects of HDIVIG in the present series were severe transient hypotension in one patient that necessitated stopping the infusion and more frequently headache relieved by analgesics and slowing the rate of the infusion. In an additional 70 patients that were treated with HDIVIG for other neurologic diseases, hypotension was not encountered (unreported data). In the reported series, HDIVIG was effective in eight of nine rapidly deteriorating patients with bulbar symptoms. In conditions in which plasmapheresis is not technically feasible, HDIVIG may be an alternative therapy in myasthenic crises. In the patients who did not respond to chronic HDIVIG therapy the symptoms were controlled with the chronic use of pheresis, steroids, and azathioprine. We administer a program of HDIVIG after pheresis so that the interval between phereses can be lengthened. We also administer HDIVIG before thymectomy to prepare patients for surgery if plasmapheresis is not feasible or effective. We do not anticipate using HDIVIG in the long-term management of JMG and instead rely on thymectomy, cholinesterase inhibitors, or corticosteroids.
Further controlled clinical trials are needed to assess the merits of HDIVIG in JMG in acute exacerbation and for chronic use. References [1] Engel AG. Myasthenia gravis and myasthenic syndromes. Ann Neurol 1984;16:519-34. [2] Drachman DB, Adams RN, Josifek LF, Self SG. Functional activities of autoantibodies to acetylcholine receptors and the clinical severity of myasthenia gravis. N Engl J Med 1982;307:769-75. [3] Drachman DB. Myasthenia Gravis. In: Johnson RT, Griffin JW, eds. Current therapy in neurologic disease, 4th ed. St. Louis: Mosby-Year Book, 1993:379-84. [4] Pahwa RN. New and controversial uses of intravenous gammaglobulin. Pediatr Infect Dis J 1988;7:S34-6. [5] Herrmann DN, Carney PR, Wald JJ. Juvenile myasthenia gravis: Treatment with immune globulin and thymectomy. Pediatr Neurol 1998;18:63-6. [6] Gajdos PH, Outin H, Elkharrat D, et al. High dose intravenous immunoglobulin for myasthenia gravis. Lancet 1984;1:406-7. [7] Fateh-Moghadam A, Wick M, Basinger U, Geursen RG. High dose intravenous gammaglobulin for M.G. Lancet 1984;14:848-9. [8] Evoli A, Palmisani MT, Bartoccioni E, Padua L, Tonali P. High dose intravenous immunoglobulin in myasthenia gravis. Ital J Neurol Sci 1993;14:233-7. [9] Arsura L, Bich A, Brunner NG, Namba J, Grob D. High-dose intravenous immunoglobulin in the management of MG. Arch Intern Med 1986;146:1365-8.
[10] Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann Neurol 1997;41:789-96. [11] Zweiman B. Theoretical mechanisms by which immunoglobulin therapy might benefit myasthenia gravis. Clin Immunol Immunopathol 1989;53:583-91. [12] Durelli L. High-dose intravenous immunoglobulin G treatment of myasthenia gravis. In: Lisak RP, ed. Handbook of myasthenia gravis and myasthenic syndromes. New York: Marcel Dekker, 1994:375-88. [13] Levinson AI. The use of IVIG in neurological disease. Clin Rev Allergy 1992;10:119-34. [14] Osterhuis HJGH, Limburg PC, Hummel-Tappel E. The anti-acetylcholine receptor antibodies in myasthenia gravis: Clinical and serological follow-up of individual patients. J Neurol Sci 1983; 58:371-85. [15] Webster A, Lever A. Non-A non-B hepatitis after intravenous gamma globulin. Lancet 1986;1:322. [16] Copelan EA, Strohn PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26: 410-2. [17] Ahsan N. Intravenous immunoglobulin induced-nephropathy: A complication of IVIG therapy. J Nephrol 1998;11:157-61. [18] Silbert PL, Knezevic WV, Bridge DT. Cerebral infarction complicating intravenous immunoglobulin therapy for polyneuritis cranialis. Neurology 1992;42:257-8. [19] Vera-Ramirez M, Charlet M, Parry GJ. Recurrent aseptic meningitis complicating intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 1992;42:1636-7.
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Selcen et al: Immunoglobulin Therapy in Myasthenia Gravis 43