Stroke and Deep Venous Thrombosis Complicating ...

CRITICAL SITUATIONS SECTION EDITOR: ANITA G. LICATA, MD

Stroke and Deep Venous Thrombosis Complicating Intravenous Immunoglobulin Infusions Kenneth A. Katz, MD, MSc; Chad M. Hivnor, MD; David E. Geist, BA; Michael Shapiro, MD; Michael E. Ming, MD; Victoria P. Werth, MD; University of Pennsylvania Medical Center, Philadelphia (Drs Katz, Hivnor, Shapiro, Ming, and Werth), and Yale University School of Medicine New Haven, Conn (Mr Geist)

Critical Situations: Dermatology in the Acute Care Setting

REPORT OF CASES

CASE 1 A 67-year-old woman had a 4-year history of dermatomyositis manifesting as a heliotrope rash, shawl sign, Gottron papules, proximal upper and lower extremity muscle weakness, and dysphagia. The creatine kinase level was 424 U/L (reference range, 2-150 U/L) and the erythrocyte sedimentation rate was 40 mm/h (reference range, 0-25 mm/h). Results of the remainder of the laboratory examination, including globulin levels, were within normal limits. Recent screening colonoscopy, mammography, Papanicolaou smear, and cancer antigen 125 levels showed no evidence of malignancy. She was refractory to a treatment regimen of prednisolone, 60 mg/d; mycophenolate mofetil, 750 mg twice daily; and chloroquine, 250 mg/d. She had not tolerated azathioprine or methotrexate, and trials of quinacrine and hydroxychloroquine had failed. She had chronic hypertension, which was controlled with ramipril, 5 mg/d. She was a nonsmoker, with no personal or family history of hypercoagulability. Worsening muscle weakness prompted an admission to the Hospital of the University of Pennsylvania. She was infused intravenously with 1 g/kg per day (60 g/d) of 10% intravenous immunoglobulin (IVIG) in isotonic sodium chloride solution (saline) (Polygam; Baxter Healthcare Corp, Glendale, Calif; distributed by American Red Cross, Washington, DC) for 2 successive days at rates beginning at 3 g/h, doubling each hour to maximum rates of 12.5 g/h. After 4 days in the hospital she was discharged on her prior treatment regimen. Within 2 weeks of the infusion there was marked subjective and objective improvement of her cutaneous symptoms and muscle weakness, including swallowing. The creatine kinase level had fallen to 123 U/L. She was readmitted 4 weeks after the first infusion for another course of IVIG at the same dosage. A total infusion of 60 g of 10% IVIG in saline was started at a rate of 3.5 g/h for the first 2 hours, increased to 7 g/h for the next 2 hours, and increased to 12.5 g/h (REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003 991

for the next 21⁄2 hours. At that point the patient had a witnessed fall. A right facial droop and an expressive aphasia were noted. The IVIG infusion was discontinued after a total infusion of 52.25 g. Computed tomography of the head showed no evidence of hemorrhage or prior infarction. A diagnosis of thromboembolic stroke was made, and tissue plasminogen activator was administered. The facial droop resolved over the next few hours; the expressive aphasia gradually improved over the next several days. Computed tomography of the head performed 1 day after the event showed an evolving left middle cerebral artery infarction. A carotid artery Doppler examination revealed mild to moderate left internal carotid artery stenosis. Transthoracic echocardiogram (without a bubble study) and transcranial Doppler examinations were unremarkable. The patient was discharged home 4 days after the stroke. One month after the event her aphasia had substantially, but not entirely, resolved. Her dermatomyositisrelated cutaneous symptoms and muscle weakness continued to improve. CASE 2 A 65-year-old woman with a 4-year history of pemphigus vulgaris had severely painful oral ulcers that persisted despite treatment with prednisone, 5 mg/d. She had not responded to prednisone dosages as high as 80 mg/d. She had failed or had not tolerated treatment with multiple systemic immunosuppresants, including azathioprine, cyclophosphamide, cyclosporine, dapsone, methotrexate, mycophenolate mofetil, as well as prednisolone swishes and tetracycline, doxycycline, and minocycline. She was a nonsmoker, with no personal or family history of hypercoagulability. She had fractured her right arm as a teenager. Treatment with IVIG was initiated at the outpatient apheresis unit at the Hospital of the University of Pennsylvania, with an intended dosage of 1 g/kg per day for 2 days. Intravenous infusion of 10% IVIG in saline was administered in the right arm at a rate of 2.0 g/h for WWW.ARCHDERMATOL.COM

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1 hour, increasing to 4.0 g/h for the next hour and then to 8.0 g/h. Approximately 4 hours after the infusion began, the patient complained of cramping pain in her right arm. Edema was noted in the distal part of the right arm. A radial pulse was palpable. The infusion was discontinued. The patient was transferred to the emergency department. An ultrasound examination revealed extensive thrombosis of the cubital vein extending into the basilic, axillary, and supraclavicular veins; collateral veins were seen, suggestive of a prior clot. She was admitted to the hospital for heparin and coumadin therapy. There were no further complications, and 18 months later there were no sequelae from the thrombosis. THERAPEUTIC CHALLENGE

Over 50 thrombotic events associated with IVIG administration have been reported in patients treated for various neurologic, 1 rheumatologic, 2 hematologic,3,4 and immunologic diseases,5 as well as, in passing, in patients treated for pemphigus vulgaris6 and toxic epidermal necrolysis.7,8 These IVIG-associated thrombotic events include stroke,3,6 pulmonary embolism,1 myocardial infarction,,2,3,8 deep venous thrombosis,4,7 and central retinal vein occlusion.5 Affected patients have ranged in age from 22 months to 84 years. Thrombotic events in patients treated with IVIG have occurred during infusions and up to 42 days following treatment. Knowledge that thrombotic events might complicate IVIG infusions can lead to appropriate risk-benefit calculations for IVIG therapy, proper monitoring of patients, and prompt recognition and treatment of thrombotic events, should they occur. COMMENT

Intravenous immunoglobulin, composed of pooled, highly purified IgG, has been approved by the Food and Drug Administration (FDA) for the treatment of Kawasaki disease, various primary immunodeficiency diseases, and graft-vs-host disease, as well as for prophylaxis against bacterial infection in a subset of immunocompromised patients.9 Intravenous immunoglobulin is hypothesized to work by stimulating catabolism of all IgG, including those that are pathogenic,10 or by other mechanisms.9,11 Use of IVIG has recently been advocated in a variety of other diseases, including numerous dermatologic diseases such as dermatomyositis, lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, cicatricial pemphigoid, herpes gestationis, linear IgA disease, epidermolysis bullosa acquisita, erythema multiforme, toxic epidermal necrolysis, chronic urticaria, atopic dermatitis, pyoderma gangrenosum, scleromyxedema, and hyperimmunoglobulinemia E syndrome.6-9,11 Two mechanisms linking IVIG to a thrombotic diathesis have been proposed. The first is an IgG dosedependent increase in serum viscosity, which has been shown to peak immediately following IVIG infusion.1,12 Over the following month serum viscosity decreases, although it can remain elevated compared with the baseline level.1 Peaks in serum viscosity are often higher af(REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003 992

ter subsequent monthly IVIG infusions.1 The second potential mechanism is an IVIG-mediated increase in platelet aggregation.3 The FDA has identified high infusion rates and high doses of IVIG as potential risk factors for thrombotic events in at-risk patients.13 Other risk factors for thrombosis may include a history of stroke, myocardial infarction, hypertension, thrombosis, or hypercoagulability; older age; or limited mobility.2,4 No specific characteristic or brand of IVIG has been implicated.13 Intravenous immunoglobulin, particularly sucrosestabilized preparations (according to the FDA), has also been associated with acute renal failure.14 Risk factors for IVIG-associated acute renal failure include preexisting renal insufficiency, diabetes mellitus, age of 65 years or older, volume depletion, sepsis, paraproteinemia, and concomitant treatment with nephrotoxic medications. To reduce risk of acute renal failure in high-risk patients treated with IVIG, the FDA has recommended a lower IVIG dose, concentration, and/or infusion rate, particularly with sucrose-containing preparations. Renal function should be carefully monitored.14 Other serious adverse events associated with IVIG include aseptic meningitis, as well as fluid overload in patients with a compromised cardiovascular system or congestive heart failure.15 The possibility of transmission of blood-borne diseases also exists, evidenced by hepatitis C outbreaks in IVIG recipients in the early 1990s.16 Absolute contraindications to IVIG administration include a history of a severe systemic reaction to IVIG, IgA deficiency, or anti-IgA antibodies.17 Determination of serum IgA levels prior to IVIG therapy has been recommended by some authors.15 Intravenous immunoglobulin has also been associated with vasomotor symptoms (ie, chills, nausea, skin flushing, chest tightness, or wheezing), headache including migraine headache, and abnormalities on posttreatment serologic testing.15 Cutaneous adverse events reported with IVIG use include petechiae, pruritus, urticaria, lichenoid eruptions, alopecia, and leukocytoclastic vasculitis.15 The association between IVIG and thrombotic complications should be taken into account when deciding whether to treat patients with IVIG and in what setting, particularly in patients who are already at risk for thrombosis. To decrease the risk of thrombotic events in patients at high risk for thrombosis, some authors have suggested slower rates of infusion and dosages less than 400 mg/kg per day.4 Concomitant administration of blood products is not recommended, and IVIG should be used only with caution in patients with preexisting gammopathies.4 Careful monitoring of patients for symptoms and signs of thrombotic phenomena should be considered. When determining the appropriate setting for IVIG administration, the convenience and lower cost of infusions at patients’ homes or physicians’ offices should be weighed against a potential need for emergent treatment of thrombotic complications. Finally, adverse events thought to be associated with IVIG infusion, including thrombotic complications, should be reported to the manufacturer and to the FDA at www.fda.gov /medwatch. WWW.ARCHDERMATOL.COM


Accepted for publication March 20, 2003. The authors have no relevant financial interest in this article. Corresponding author and reprints: Kenneth A. Katz, MD, MSc, Department of Dermatology, University of Pennsylvania Medical Center, 2 Rhoads Pavilion, 3600 Spruce St, Philadelphia, PA 19104-4283. REFERENCES 1. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology. 1994;44:223-226. 2. Elkayam O, Paran D, Milo R, et al. Acute myocardial infarction associated with high dose intravenous immunoglobulin infusion for autoimmune diseases: a study of four cases. Ann Rheum Dis. 2000;59:77-80. 3. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet. 1986;2:217-218. 4. Go RS, Call TG. Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: case report and literature review of intravenous immunoglobulinrelated thrombotic complications. Mayo Clin Proc. 2000;75:83-85. 5. Oh KT, Boldt HC, Danis RP. Iatrogenic central retinal vein occlusion and hyperviscosity associated with high-dose intravenous immunoglobulin administration. Am J Ophthalmol. 1997;124:416-418. 6. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol. 2002;47:358-363. 7. Tristani-Firouzi P, Petersen MJ, Saffle JR, Morris SE, Zone JJ. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol. 2002;47:548-552. 8. Prins C, Kerdel FA, Padilla RS, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins. Arch Dermatol. 2003;139:26-32. 9. Dahl MV, Bridges AG. Intravenous immune globulin: fighting antibodies with antibodies. J Am Acad Dermatol. 2001;45:775-783. 10. Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibodymediated autoimmune diseases. N Engl J Med. 1999;340:227-228.

11. Rutter A, Luger TA. High-dose intravenous immunoglobulins: an approach to treat severe immune-mediated and autoimmune diseases of the skin. J Am Acad Dermatol. 2001;44:1010-1024. 12. Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet. 1992;339:662-664. 13. FDA interim statement regarding immune globulin intravenous (IGIV); August 27, 2002. Available at: http://www.fda.gov/cber/infosheets/igiv082702.htm. Accessed November 13, 2002. 14. Important drug warning: actue renal failure with IGIV. Available at: http://www .fda.gov/cber/ltr/igivrenal.htm. Accessed November 25, 2002. 15. Dalakas MC. The use of intravenous immunoglobulin for neurologic diseases. Neurology. 1998;51:S2-S8. 16. Bresee JS, Mast EE, Coleman PJ, et al. Hepatitis C virus infection associated with administration of intravenous immune globulin: a cohort study. JAMA. 1996; 276:1563-1567. 17. Knable AL. Miscellaneous systemic drugs. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. Philadelphia, Pa: WB Saunders Co; 2001:457-60.

Submissions Readers are invited to submit examples of acute or potentially life-threatening disorders that highlight important, new, or difficult diagnostic or therapeutic challenges. Case reports should be submitted using the established “Critical Situations” format, with “Report of Case,” “Challenge,” and “Comment” sections. Please see the “Information for Authors and Readers” for complete instructions. Material should be sent to Anita G. Licata, MD, University of Vermont Division of Dermatology, Fletcher Allen Health Care/University Health Center, 1 S Prospect St, Burlington, VT 05401-3444 (e-mail: [email protected]). Manuscripts without photographs may be submitted electronically via e-mail.

ARCHIVES Web Quiz Winner

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ongratulations to the winner of our May quiz, Chandramani Gurumani, MD, Chennai, India. The correct answer to our May challenge was cryoglobulinemia associated with myeloma. For a complete discussion of this case, see the OffCenter Fold section in the June ARCHIVES (Pol-Rodriguez MM, Crane S, Feinberg DL, Glusac EJ, Bolognia JL. Retiform purpura. Arch Dermatol. 2003;139:803-808). Be sure to visit the Archives of Dermatology World Wide Web site (http://www.archdermatol.com) to try your hand at the Interactive Quiz. We invite visitors to make a diagnosis based on selected information from a case report or other feature scheduled to be published in the following month’s print edition of the ARCHIVES. The first visitor to e-mail our Web editors with the correct answer will be recognized in the print journal and on our Web site and will also receive a free copy of the The Art of JAMA II.

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