Complications of intravenous immune globulin treatment in neurologic disease

Intravenous immune globulin (IVIg) has been advocated as a safe treatment for immune-mediated diseases and has gained wide use in neurologic practice. ^[1-3] Controlled studies have demonstrated benefit in dermatomyositis, ^[4] Guillian-Barre syndrome, ^[5] and chronic inflammatory demyelinating polyneuropathy (CIDP). ^[6] Benefit is reported for inclusion body myositis, ^[7] myasthenia gravis, ^[8] multiple sclerosis, ^[9] multifocal motor neuropathy with conduction block, ^[10] paraproteinemic neuropathy associated with antibodies to myelin-associated glycoprotein, ^[11] refractory polymyositis, ^[12] Lambert-Eaton syndrome, ^[13] stiff-man syndrome, ^[14] and Rasmussen's encephalitis. ^[15]

Reported complications include renal failure, ^[16-22] transmission of hepatitis C virus, ^[23,24] thromboembolism, ^[25,26] aseptic meningitis, ^[27-29] neutropenia, ^[30-32] coagulopathy, ^[33] rash, ^[34-37] anaphylaxis, ^[36] immune-complex arthritis, ^[38] and hemolysis. ^[39,40] Postulated risk factors include increased age, preexisting renal failure, diabetes, high infusion rate, ^[17] and high concentrations of sucrose as a stabilizing agent ^[3,20] for renal failure. Vascular disease, paraproteinemia, and other causes of increased serum viscosity are risks for thromboembolism. ^[25] Migraine increased the risk of aseptic meningitis ^[27] and IgA deficiency increased the risk of anaphylaxis. ^[36] Adverse effects are encountered in 1 to 15% of patients. ^[1,36,41,42] Because patients with neurologic diseases include many with possible risk factors, we reviewed the complications of IVIg therapy among patients with neurologic disease.

Methods.

We reviewed the medical records of all patients who received IVIg for a neurologic illness as inpatients or as outpatients in the hemotherapy laboratory from June 1992 to September 1994 at the Columbia-Presbyterian Medical Center. Cases were identified from pharmacy, outpatient hemotherapy laboratory, and neurology admission records. We excluded 12 patients who received only the first infusion under observation in the outpatient unit and the remainder with home therapy.

Results.

Eighty-eight patients received one to 18 courses of IVIg for a total of 650 infusions. Ages ranged from 16 to 81 years. A total of 413 infusions were given on an inpatient basis and 237 as outpatient. The total dose was generally 2 g/kg given in 2 to 5 days, but the daily dose ranged from 20 to 100 g given for 1 to 9 days.

Diagnostic indications included CIDP 25, myasthenia gravis 14, Guillain-Barre syndrome 10, inclusion body myositis 6, inflammatory diabetic neuropathy 6, ALS 5, neuropathy associated with monoclonal gammopathy 4, other neuropathy 4, polymyositis 4, brachial plexitis 2, multifocal motor neuropathy with conduction block 2, dermatomyositis 1, HTLV-1 myelopathy 1, cytomegalovirus polyradiculitis 1, multiple sclerosis 1, CNS vasculitis 1, and presumed paraneoplastic encephalomyelitis 1.

Seventeen patients (19%) had diabetes mellitus and were treated for inflammatory diabetic neuropathy, inclusion body myositis, brachial neuritis, polymyositis, Guillain-Barre syndrome, CIDP, or myasthenia gravis.

Major complications included the following: congestive heart failure, deep venous thrombosis, acute hypotension, and acute oliguric renal failure.

Congestive heart failure occurred in a patient with polymyositis with secondary cardiomyopathy and paroxysmal atrial fibrillation. She was to receive 50 g of IVIg in 10.5 hours for each of 2 days, a dose she had tolerated in three earlier courses. However, midway through the second day she developed dyspnea and orthopnea. The infusion was discontinued and furosemide was given intravenously, with prompt improvement.

Deep venous thrombosis was diagnosed in a patient with CIDP who was bed-bound; the left leg became edematous while she was receiving IVIg.

A severe hypotensive episode occurred during the first infusion of IVIg in a patient with a recent myocardial infarction. Intravenous vasopressor therapy was given to support blood pressure for 1 day. The patient tolerated further courses of IVIg without problem.

Acute oliguric renal failure developed in a 62-year-old woman with diabetic inflammatory neuropathy and mild diabetic nephropathy (blood urea nitrogen [BUN] 39 mg/dl, creatinine (Cr) 1.9 mg/dl before IVIg, proteinuria 761 mg/24 hr 18 months previously). After two consecutive days of IVIg (60 g at 5 g/hour), the BUN rose to 62 mg/dl and Cr to 6.5 mg/dl. Quantitative urinary protein was 21 g in 24 hours. One hemodialysis treatment was given and renal function rapidly improved, with a new baseline Cr of 2 to 3 mg/dl within 1 week.

Other adverse effects included vasomotor symptoms (defined below): 26 (30%), headache: 23 (26%), leukopenia: 4 (WBC < 4), rash: 5 (6%), fever: 3 (3%), neutropenia: 1, proteinuria: 1, pruritus: 1, dyspnea: 1, viral syndrome (sore throat, myalgias, adenopathy, fever, and elevated transaminases): 1.

Vasomotor symptoms were broadly defined as any combination of chills, nausea, skin flushing, chest tightness, or wheezing. ^[43] All of these symptoms were seen 10 minutes into the first dose of IVIg in one woman with multifocal motor neuropathy with conduction block; the syndrome was attributed to anaphylaxis and resolved within minutes after the infusion was stopped and diphenhydramine was given intravenously. Her vital signs were stable throughout the episode. Of the 26 patients with vasomotor symptoms, chills occurred in 14 patients, nausea in 12, arthralgias in 5, chest tightness in 5, vomiting in 5, facial flushing in 4, myalgias in 4, fatigue in 3, and dizziness in 2.

Neutropenia was seen in one patient. After two days of IVIg, the WBC dropped from 4.2 to 1.9 (10³/mm³). After four doses the WBC was 1.7 and the absolute neutrophil count was 306/mm³. The neutrophil count began to recover the day after the last IVIg infusion and then returned to normal.

Leukopenia developed in four patients. Rash occurred in five (6%) patients. Proteinuria occurred in an 18-year-old woman with Guillain-Barre syndrome who received 15 g of IVIg at 5 g/hour before she developed a maculopapular rash. She had no previous renal disease; urine analysis and BUN/Cr were normal on the morning of treatment. On the day after treatment, proteinuria was noted and quantified at 1.9 g/24hr, which disappeared within 1 week.

Fifty-two (59%) of our patients had some adverse effect of IVIg therapy. Besides the four with major complications, these included 40 (45%) with vasomotor symptoms, shortness of breath, headache, or fever that could be reduced with slowing the rate of infusion or using symptomatic medications. Five (6%) had laboratory abnormalities including neutropenia, leukopenia, or proteinuria and seven (8%) had other adverse effects including rash, pruritus, or viral-like syndrome. Of patients with diabetes mellitus, nine of 17 (53%) had some adverse effect of IVIg therapy.

Treatment was terminated in nine (10%) patients, because of vasomotor symptoms in two patients, headache four, heart failure one, renal failure one, rash 1. Treatment was temporarily interrupted in five (6%) patients, because of vasomotor symptoms in three patients, headache one, hypotension 1.

Discussion.

Our frequency of side effects (59%) is higher than the often cited 1 to 15%. ^[1] However, our frequency of side effects was similar to that of Bertorini et al., ^[44] who found an 81% frequency of complications in 42 patients with neuromuscular disease. Sekul et al. ^[27] reported headaches in 56% of their patients compared with our 26%. In earlier series, the patients may have been younger, without accompanying diabetes mellitus, heart disease, vascular disease, and renal insufficiency. Also doses were often lower ^[41,42] than the customary 2.0 g/kg for immune-mediated diseases.

The use of IVIg was associated with frequent adverse effects, but serious adverse reactions occurred in only four (4.5%) of our patients and included hypotension, congestive heart failure, renal failure, and deep venous thrombosis. All patients had an identifiable risk factor: preexisting heart disease, diabetic nephropathy, or confinement to bed. All patients who developed acute renal failure, including ours, had mild preexisting renal insufficiency. ^[16-22] However, one of our patients, age 19, and with no prior renal disease, developed reversible proteinuria of 1.9 g/24 hours after a small dose of IVIg at a slow rate for only 1 day. Therefore it is not always possible to predict renal complications. This patient had Guillain-Barre syndrome, which may be associated with membranous glomerulonephritis that could explain the proteinuria, ^[45,46] but the temporal correlation with IVIg and the quick resolution made that explanation unlikely.

Previous reports of acute renal failure occurred in patients given Sandoglobulin, ^[16-20] which contains sucrose as a stabilizing agent. Renal biopsies showed swelling and vacuolization of the proximal tubular epithelial cytoplasm typical of damage from a highsolute load, attributed to sucrose. ^[20] In our case of renal failure, the patient received Gammar (Armour), which also contains sucrose.

Both patients with cardiac complications had preexisting cardiac disease. The exacerbation of heart failure was likely due to the volume overload from IVIg.

Most adverse effects included vasomotor symptoms or headache that was usually controlled by reducing the flow rate or using symptomatic medications, even though these effects sometimes led to discontinuation of therapy. Acetaminophen and diphenhydramine were effective. Most headaches were mild but seven patients had severe headache and four patients with severe headache later received prophalactic steroids (100 to 200 mg hydrocortisone intravenously or 100 mg prednisone orally) as premedication, ^[47] which was effective. In five patients therapy stopped because of headache. In the series of Sekul et al., ^[27] 50% of patients with migraine had aseptic meningitis with IVIg therapy. Similarly, three of seven (43%) of our patients with migraine developed headaches during an infusion, compared with 25% of those without migraine. We did not identify aseptic meningitis, in contrast to a frequency of 11% in the series of Sekul et al. ^[27] We may have missed some cases by not performing lumbar puncture in all patients with headache. However, none of our patients had nuchal rigidity, drowsiness or lethargy, fever, photophobia, or painful eye movements. ^[27]

One patient developed a reversible neutropenia during his second exposure to IVIg. Neutropenia is a rare complication of IVIg. ^[30-32] During his third course 3 months later, he again developed neutropenia. Other patients have had recurrent episodes of neutropenia, which may be secondary to serum factors in individual patients in concert with the globulin preparation. ^[31] The recurrent episodes in our patient support this theory. During his first course of IVIg, he had a reactive leukocytosis while being treated for osteomyelitis and after receiving IVIg his WBC dropped by more than 50% to 3.9 10³/mm³. Though not defined as a complication, we noted a drop of 50% or more in the peripheral WBC in 12 of 41 patients (29%), with cell counts available within 1 week before and within 2 weeks after the first infusion. Koffman and Dalakas ^[48] reported a 33% drop in the lymphocyte count in 44 of 46 patients. We did not have differential counts on all patients to determine which white cell types were affected. Only four of our patients became leukopenic, always transient and asymptomatic. In one reported patient mouth ulcers developed during neutropenic episodes. ^[32]

There are previous reports of eczema, ^[34] erythema multiforme, ^[36,37] purpuric erythema, ^[37] and alopecia. ^[35] Rash occurred in five (6%) of our patients: (1) An urticarial eruption on the arms recurred in other courses of IVIg and was controlled with diphenhydramine. (2) A maculopapular rash on the trunk and proximal limbs arose during the first dose of IVIg, and treatment was terminated. (3) A nonpruritic petechial rash with a normal platelet count occurred on the fifth infusion day and began to resolve the next day. (4) Biopsy-proven eczematous dermatitis arose on the palmar surface of the hands during the second course of IVIg; it did not recur with future courses. (5) A rash developed after the fifth and last treatment, involving the face and hands.

There were no cases of anaphylaxis. Only one of our patients had IgA deficiency and she had no adverse reaction.

We identified no cases of hepatitis B or C transmission, a reported risk in particular IVIg preparations. ^[23,24] Most available preparations are now treated to prevent hepatitis B and C viral transmission. ^[24,49,50]

Headache and vasomotor symptoms, usually considered minor adverse effects, led to interruption in therapy of 10 patients and permanent discontinuation in six (7%). Sixteen percent of all patients had therapy interrupted either temporarily or permanently because of adverse effects.

There was no mortality or long-term morbidity in our series, but one patient (with renal failure) required dialysis and another was given warfarin for venous thrombosis. Potentially serious complications, as with all forms of immunosuppressive therapy, must be recognized and anticipated.