Wednesday, December 28, 2011

IVIg therapy: neurologic indications, contraindications, precautions, and complications

Intravenous immune globulin (IVIg) is a purified preparation of gamma globulin, comprised of 4 subclasses of antibodies (ie, IgG, IgM, IgA, and IgE), approximating the distribution in human serum. IVIg is derived from large pools of human plasma (ie, greater than 1000 donors per lot) and purified to remove infective agents, vasoactive substances, and aggregated proteins.
IVIg is at least 90% intact IgG, the half-life of which is generally from 18 to 32 days in healthy adults, although it varies depending upon patient factors and which specific product is used. IgG is comprised of 4 subclasses of which IgG1 is the major component in normal serum and in IVIg. IgG1 is involved in tissue protection, complement activation, and virus inactivation. Peak serum levels of IgG are attained immediately after IVIg administration, but drop about half during the first week postinfusion, even though the reported half-life of IgG is somewhat longer. IVIg in immune deficient states simply replaces missing antibodies, whereas immunomodulatory doses of IVIg for autoimmune conditions are considerably larger. Various mechanisms have been proposed for immunomodulatatory actions of IVIg, including promoting blockade of Fc receptors in macrophages (thereby preventing phagocytosis of circulating opsonized platelets or cells tagged with autoantibodies), providing anti-idiotypic antibodies to neutralize pathogenic auto-antibodies, absorbing complement, down regulating immunoglobulin production, neutralizing viruses, enhancing suppression cells, inhibiting lymphocyte proliferation, and reducing interleukin (IL-1) production or activity.
IndicationsIVIg therapy is used either for immunomodulation of autoimmune conditions or for antibody replacement. Neurologic indications are genrally associated with an immunomodulatory role, and include Guillain-Barre syndrome and chronic inflammatory demyelinating neuropathy. Other nonneurologic indications associated with an immunomodulatory role include idiopathic thrombocytopenic purpura, Kawasaki syndrome, and acquired hemophilia. Indications suitable for treatment by IgG replacement include general or specific immunodeficiency states, hepatitis A or rubella prophylaxis, chronic lymphocytic leukemia with hypogammaglobulinemia, multiple myeloma with specific antibody deficiency, low birth weight babies at risk for infection, and infants or children with HIV.



"Off-Label" Neurologic Indications for IVIg (Ratko et al 1995; Dalakas 1999; Bjornson and Grabbenstein 2003).
Evidence supports routine use
(1) Chronic inflammatory demyelinating polyneuropathy: excellent evidence of efficacy. Equivalent to plasma exchange in children and adults.
(2) Guillaine-Barre syndrome: excellent evidence of efficacy. Equivalent to plasma exchange in children and adults.
(3) Multifocal motor neuropathy: good evidence of efficacy in adults, with documented improved strength and reduced conduction block.
Evidence does not support routine use
(1) Dermatomyositis/polymyositis: may be used in severe illness when other therapies have failed or are contraindicated. Fair evidence of possible efficacy in adults.
(2) Diabetic amyotrophy: anecdotal evidence of possible efficacy in an adult.
(3) Epstein-Barr-virus-induced cerebellar ataxia: anecdotal evidence of efficacy in an adult.
(4) Intractable pediatric epilepsy: may be used as a last resort in intractable pediatric epilepsy (eg, West syndrome or Lennox-Gastaut syndrome), especially in patients who may be candidates for surgical resection.
(5) Lambert-Eaton myasthenic syndrome: possible efficacy.
(6) Multiple sclerosis: possible effectiveness in a small number of adult patients.
(7) Myasthenia gravis: may be used in severe cases to treat acute decompensation, when other therapies have failed or are contraindicated. Fair evidence of possible efficacy in adults.
(8) Stiff man syndrome: anecdotal evidence of possible efficacy in adults.
(9) Systemic vasculitic syndromes: may be used in severe illness when other therapies have failed or are contraindicated.

Contraindications
(1) IVIg is contraindicated in patients who have had an anaphylactic or severe systemic reaction following previous administration of gamma globulin, anti-immunoglobulin A antibodies, or thimerosal.
(2) IVIg is relatively contraindicated in patients with isolated IgA deficiency. If IVIg treatment is deemed necessary, such patients should receive products containing the lowest IgA concentration possible and should be monitored closely for anaphylaxis.

Precautions
(1) Pre-existing atherosclerotic disease or vascular risk factors (eg, coronary artery disease, hypertension, cerebrovascular disease, diabetes mellitus).
(2) Sucrose containing products more commonly cause renal dysfunction compared to nonsucrose containing products.
(3) Patients predisposed to acute renal failure, including patients with pre-existing renal insufficiency, diabetes mellitus, older age (greater than 65 years), volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. For such patients administer IVIg at minimum concentration and slowest infusion rate.
(4) Patients with agammaglobulinemia or extreme hypogammaglobulinemia who have never received immunoglobulin substitution therapy, or have not received it within the preceding 8 weeks, may be at risk of developing inflammatory reactions.

Complications
General:
Side effects with IVIg occur in approximately 2% to 6% of patients, usually with the first or second infusion; hence, prophylactic hydrocortisone and antihistamine may be used prior to these infusions (Misbahand Chapel 1993). If an early adverse reaction occurs, it will generally become apparent 30 to 60 minutes after beginning the infusion. Early reactions include muscle pain, malaise, headache, chills, flushing, low back pain, joint pain, fever, tightness of the chest, and nausea. Patients with immediate, infusion-related symptoms should have the infusion slowed or interrupted, and should be pretreated with a nonsteroidal anti-inflammatory agent and antihistamine for subsequent doses. The risk of reactions is significantly higher when active infection is present. Epinephrine should be available for possible anaphylaxis.
To decrease the risk of delayed reactions, reduced doses and rates of infusion should be considered for elderly patients and those with a history of migraine (ie, because of an increase risk of aseptic meningitis), or cardiovascular or cerebrovascular disease (ie, because of an increased risk of stroke or myocardial infarction). Renal complications occur more often in those with pre-existing renal impairment.
Late adverse effects include transmission of infections, including previous transmission of hepatitis C in hundreds of cases. Current IVIg products are considered safe in terms of viral transmission.
Thrombotic events:
High dose or rapid infusion of IVIg is a putative risk factor for thrombotic complications (Frame and Crawford 1986; Sztajzel et al 1999; Elkayam et al 2000; Go and Call 2000; Turner and Wills 2000; Alliot et al 2001; Grillo et al 2001; Emerson et al 2002; Stubleand Dice 2002; Caress et al 2003; Dalakas and Clark 2003; Okuda et al 2003; Zaidan et al 2003). High-dose IVIg may increase blood viscosity and secondarily impair blood flow (Reinhart and Berchtold 1992; Dalakas 1994; Dalakas and Clark 2003). Some preparations also include activated coagulation factor XI as a contaminant in IVIg preparations, which can lead to significant thrombin production and contribute to an increased risk of thrombotic complications after IVIg therapy (Wolberg et al 2000). Other putative mechanisms of increasing thrombotic risk with IVIg are unconfirmed, and include passive infusion of antiphospholipid antibodies with IVIg, activation of platelets, and development of cerebral vasospasm (Frame et al 1986; Sztajzel et al 1999; Sherer et al 2001).
In 1 fatal case of stroke following IVIg therapy, autopsy showed intravascular aggregates of fibrin-IgG, as well as platelets and a necrotizing microangiopathy in the infarcts (Byrne et al 2002).
IVIg should be administered with caution to those at particular risk for thromboembolic events, including elderly patients, patients with pre-existing vascular disease, patients with hyperviscosity states (eg, cryoglobulinemia, monoclonal gammopathies, hypergammaglobulinemia, hyperfibrinogenemia, high lipoproteins, and hypercholesterolemia), and children with HIV infection (Woodruff et al 1986; Hague et al 1990; Reinhart and Berchtold 1992; Misbah and Chapel, 1993; Dalakas 1994; Elkayam et al 2000; Grillo et al 2001; Byrne et al 2002; Caress et al 2003; Dalakas and Clark 2003; Okuda et al 2003).
In patients with atherosclerotic disease or vascular risk factors (eg, cerebrovascular disease, coronary artery disease, hypertension, or diabetes mellitus), the concentration of infused IVIg should be no more than 5%, and infusion rates should be no faster than 0.5 mL/kg per hour increased slowly to a maximum rate of 4 mL/kg per hour if well tolerated (Elkayam et al 2000; Bjornson et al 2003).
There is no consensus on treatment of IVIg-related strokes. Intravascular thrombolysis has been demonstrated with strokes using tPA (Okuda et al 2003), and with inominate vein thrombosis using urokinase (Go and Call 2000). Anticoagulants have been used in some patients (Dalakas and Clark 2003). Patients who develop cerebral vasospasm may benefit from nimodipine (Sztajzel et al 1999).
Rapid infusion of IVIg may also cause flushing and changes in pulse rate or blood pressure, which usually resolve promptly with slowing or temporarily stopping the infusion.
Aseptic meningitis: Aseptic meningitis may occur from 1 hour to 7 days after infusion of IVIg. Symptoms can include fever, headache, nuchal rigidity, nausea, and vomiting. CSF analysis generally shows a neutrophilic pleocytosis with mildly increased protein level and a modestly depressed glucose level, but no bacteria (Kato et al 1988; Casteels-Van Daele et al 1990; Watson et al 1990; Kressebuch et al 1992; Rao et al 1992; Ozsoylu et al 1993; De Vlieghere et al 1994). All reported patients have recovered, although some individuals needed short-term treatment with steroids to alleviate symptoms. In a prospective cohort study of 54 patients treated with high-dose (2 g/kg) IVIg treatment, 6 (11%) developed aseptic meningitis within 24 hours (Sekul et al 1994). Patients with a history of migraine are apparently more likely to develop symptoms of aseptic meningitis.
Encephalopathy:
A small number of cases of transient acute encephalopathy or reversible leukoencephalopathy have been reported (Mathy et al 1998; Lewis et al 2000).
Acquired infections: In 1994, Baxter Healthcare Corporation instituted a worldwide recall of Gammagard® and Polygam® because of reports of 68 cases of possible transmission of hepatitis C occurring between October 1993 and June 1994 related to IVIg administration. Laboratory findings indicate that immunoglobulins screened negative for anti-hepatitis C virus can nevertheless remain infectious, and therefore virus-inactivation procedures during manufacturing are necessary to produce safe IVIg preparations. All IVIg formulations licensed in the United States now include a virucidal step.
There is no evidence that AIDS has been transmitted by IVIg. Since 1985, all blood plasma used for manufacture of IVIg in the United States has been nonreactive in screening for HIV antibody.
Acute renal failure: Acute renal failure has been associated with administration of IVIg. The majority of cases of acute renal failure have been successfully managed, but some deaths have been reported. IVIg products containing sucrose may present a greater risk for acute renal failure. Therapy requiring higher and consecutive doses of IVIg with resulting hyperosmolality may have contributed to renal dysfunction in some cases. Renal histopathologic examination of some of the IVIg-associated acute renal failure cases suggests osmotic injury to the proximal renal tubules, including acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis. Patients at increased risk include those with pre-existing renal dysfunction, diabetes, volume depletion, sepsis, paraproteinemia, older age (greater than 65 years), and those receiving concomitant nephrotoxic drugs. The recommended dose of IVIg should not be exceeded, and the dose or administration rate should be decreased in those at risk for acute renal failure. Renal function tests, including BUN, serum creatinine, and urine output, should be assessed prior to the initial infusion and monitored at periodic intervals thereafter. Patients should report symptoms such as decreased urine output, sudden weight gain, fluid retention or edema, or shortness of breath.
Anaphylaxis:
Anaphylactic reactions are rare with IVIg. They have been reported to occur following intravenous administration of intramuscular preparations. Patients with an absolute absence of IgA and pre-existing anti-IgA antibodies of either IgG or IgE isotypes are at greatest risk of anaphylaxis, and an IgA-depleted IVIg preparation should be used in patients with high titers of IgA antibodies.

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Huang CS, Hsu HS, Kao KP, Huang MH, Huang BS. Intravenous immunoglobulin in the preparation of thymectomy for myasthenia gravis. Acta Neurol Scand 2003;108:136-8.
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Neuropathies, general or otherComi G, Roveri L, Swan A, et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol 2002;249:1370-7.
Creange A, Gregson NA, Hughes RA. Intravenous immunoglobulin modulates lymphocyte CD54 and monocyte FcgammaRII expression in patients with chronic inflammatory neuropathies. J Neuroimmunol 2003;135:91-5.
Crouch ED, Watson LE. Intravenous immunoglobulin-related acute coronary syndrome and coronary angiography in idiopathic thrombocytopenic purpura--a case report and literature review. Angiology 2002;53:113-7.
Dalakas MC. Mechanisms of action of IVIg and therapeutic considerations in the treatment ofacute and chronic demyelinating neuropathies. Neurology 2002;59(12 Suppl 6):S13-21.
Donofrio PD. Immunotherapy of idiopathic inflammatory neuropathies. Muscle Nerve 2003;28:273-92.
Gorson KC, Ropper AH, Weinberg DH, Weinstein R. Efficacy of intravenous immunoglobulin in patients with IgG monoclonal gammopathy and polyneuropathy. Arch Neurol 2002;59:766-72.
Hahn AF. Intravenous immunoglobulin treatment in peripheral nerve disorders--indications, mechanisms of action and side-effects. Curr Opin Neurol 2000;13:575-82.
Ogawa T, Taguchi T, Tanaka Y, Ikeguchi K, Nakano I. Intravenous immunoglobulin therapy for diabetic amyotrophy. Intern Med 2001;40:349-52.
Sharma KR, Cross J, Ayyar DR, Martinez-Arizala A, Bradley WG. Diabetic demyelinating polyneuropathy responsive to intravenous immunoglobulin therapy. Arch Neurol 2002;59:751-7.
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Stiff person syndromeGerschlager W, Brown P. Effect of treatment with intravenous immunoglobulin on quality of life in patients with stiff-person syndrome. Mov Disord 2002;17:590-3.
Khanlou H, Eiger G. Long-term remission of refractory stiff-man syndrome after treatment with intravenous immunoglobulin. Mayo Clin Proc 1999;74:1231-2.
Other neurologic conditionsBen-Nathan D, Lustig S, Tam G, Robinzon S, Segal S, Rager-Zisman B. Prophylactic and therapeutic efficacy of human intravenous immunoglobulin in treating West Nile virus infection in mice. J Infect Dis 2003;188:5-12.
Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.
Cohen HA, Ashkenasi A, Ring H, et al. Poliomyelitis-like syndrome following asthmatic attack (Hopkins' syndrome)--recovery associated with IV gamma globulin treatment. Infection 1998;26:247-9.
Daaboul Y, Vern BA, Blend MJ. Brain SPECT imaging and treatment with IVIg in acute post-infectious cerebellar ataxia: case report. Neurol Res 1998;20:85-8.
Finsterer J, Engelmayer E, Trnka E, Stiskal M. Immunoglobulins are effective in pontine myelinolysis. Clin Neuropharmacol 2000;23:110-3.
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Ishii A, Hayashi A, Ohkoshi N, et al. Clinical evaluation of plasma exchange and high dose intravenous immunoglobulin in a patient with Isaacs' syndrome. J Neurol Neurosurg Psychiatry 1994;57:840-2.
Jayne DR, Chapel H, Adu D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000;93:433-9.
Jayne DR, Davies MJ, Fox CJ, Black CM, Lockwood CM. Treatment of systemic vasculitis with pooled intravenous immunoglobulin. Lancet 1991;337:1137-9.
Karlson EW, Sudarsky L, Ruderman E, et al. Treatment of stiff-man syndrome with intravenous immune globulin. Arthritis Rheum 1994;37:915-8.
Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000;68:479-82.
Latov N, Chaudhry V, Koski CL, et al. Use of intravenous gamma globulins in neuroimmunologic diseases. J Allergy Clin Immunol 2001;108(4 Suppl):S126-32.
Mease PJ, Ochs HD, Wedgewood RJ. Successful treatment of echovirus meningo-encephalitis and myositis-fasciitis with intravenous immune globulin therapy in a patient with x-linked agammaglobulinemia. N Engl J Med 1981;304:1278-81.
Ogawa T, Taguchi T, Tanaka Y, et al. Intravenous immunoglobulin therapy for diabetic amyotrophy. Intern Med 2001;40:349-52.
Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 1999;354:1153-8.
Pranzatelli MR, Tate ED, Kinsbourne M, Caviness VS Jr, Mishra B. Forty-one year follow-up of childhood-onset opsoclonus-myoclonus-ataxia: cerebellar atrophy, multiphasic relapses, and response to IVIG. Mov Disord 2002;17:1387-90.
Ratko TA, Burnett DA, Foulke GE, et al. Recommendations for off-label use of intravenously administered immunoglobulin preparations. JAMA 1995;273:1865-70.
Verma A, Bradley WG. High-dose intravenous immunoglobulin therapy in chronic progressive lumbosacral plexopathy. Neurology 1994;44:248-50.
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Casteels-Van Daele M, Wijndaele L, Hunninck K, et al. Intravenous immune globulin and acute aseptic meningitis (letter). N Engl J Med 1990;323:614-5.
De Vlieghere FC, Peetermans WE, Vermylen J. Aseptic granulocytic meningitis following treatment with intravenous immunoglobulin. Clin Infect Dis 1994;18:1008-10.
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Kressebuch H, Schaad UB, Hirt A, et al. Cerebrospinal fluid inflammation induced by intravenous immunoglobulins (letter). Pediatr Infect Dis J 1992;11:894-5.
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Complications: stroke and other thrombotic eventsAlliot C, Rapin JP, Bessonn M, Bedjaoui F, Messouak D. Pulmonary embolism after intravenous immunoglobulin. J R Soc Med 2001;94:187-8.
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Dalakas MC, Clark WM. Strokes, thromboembolic events, and IVIg: rare incidents blemish an excellent safety record. Neurology 2003;60:1736-7.
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Evangelou N, Littlewood T, Anslow P, Chapel H. Transverse sinus thrombosis and IVIg treatment: a case report and discussion of risk-benefit assessment for immunoglobulin treatment. J Clin Pathol 2003;56:308-9.
Frame WD, Crawford RJ. Thrombotic events after intravenous immunoglobulin. Lancet 1986;ii:468.
Go RS, Call TG. Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: case report and literature review of intravenous immunoglobulin-related thrombotic complications. Mayo Clin Proc 2000;75:83-5.
Okuda D, Flaster M, Frey J, Sivakumar K. Arterial thrombosis induced by IVIg and its treatment with tPA. Neurology 2003;60:1825-6.
Reinhart WH, Berchtold PE: Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 1992;339:662-4.
Sherer Y, Wu R, Krause I, Peter JB, Schoenfeld Y. Antiphospholipid antibody levels in intravenous immunoglobulin (IVIg) preparations. Lupus 2001;10:568-70.
Struble EJ, Dice YG. Intravenous immune globulin (IVIG) precipitating acute myocardial infarction. J Miss State Med Assoc 2002;43:115.
Sztajzel R, Floch-Rohr JL, Eggimann P. High-dose intravenous immunoglobulin treatment and cerebral vasospasm: a possible mechanism of ischemic encephalopathy? Eur Neurol 1999;41:153-8.
Turner B, Wills AJ. Cerebral infarction complicating intravenous immunoglobulin therapy in a patient with Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 2000;68:790-1.
Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-4.
Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenic purpura with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-8.
Zaidan R, Al Moallem M, Wani BA, et al. Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature. Eur J Neurol 2003;10:367-72.
Complications: general or otherBallow M. Intravenous immunoglobulins: clinical experience and viral safety. J Am Pharm Assoc 2002;42:449-58, 824.
Bertorini TE, Nance AM, Horner LH, Greene W, Gelfand MS, Jaster JH. Complications of intravenous gammaglobulin in neuromuscular and other diseases. Muscle Nerve 1996;19:388-91.
Bjorkander J, Wadsworth C, Hanson LA. 1040 prophylactic infusions with an unmodified intravenous immunoglobulin product causing few side effects in patients with antibody deficiency syndrome. Infection 1985;13:102-10.
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Grillo JA, Gorson KC, Ropper AH, Lewis J, Weinstein R. Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology 20021;57:1699-1701.
Ippolito C, Williams LA, Huber S. Toxicity of rapidly infused concentrated intravenous immunoglobulin. Clin Pharm 1992;11:1022-6.
Karussis D, Abramsky O. Is the routine use of intravenous immunoglobulin treatment in neurologic disorders justified?: No. Arch Neurol 1999;56:1028-32.
Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-55.
Levy JB, Pusey CD. Nephrotoxicity of intravenous immunoglobulin. QJM 2000;93:751-5.
Lewis M, Maddison P, Turner B, Wills AJ. Intravenous immunoglobulin causing reversible posterior leukoencephalopathy syndrome? J Neurol Neurosurg Psychiatry 2000;69:704.
Mathy I, Gille M, Van Raemdonck F, et al. Neurological complications of intravenous immunoglobulin (IVIg) therapy: an illustrative case of acute encephalopathy following IVIg therapy and a review of the literature. Acta Neurol Belg 1998;98(4):347-51.
Misbah SA, Chapel HM. Adverse effects of intravenous immunoglobulin. Drug Saf 1993;9:254-62.
Reichl HE, Foster PR, Welch AG, et al. Studies on the removal of a bovine spongiform encephalopathy-derived agent by processes used in the manufacture of human immunoglobulin. Vox Sang 2002;83:137-45.
Stangel M, Hartung HP, Marx P, Gold R. Side effects of high-dose intravenous immunoglobulins. Clin Neuropharmacol 1997;20:385-93.
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