Intravenous Immunoglobulin-Induced Dyspnea and Bradycardia in a Patient with Guillain–Barre Syndrome

BackgroundGuillain‐Barré syndrome is an acute, paralysing, inflammatory peripheral nerve disease. Intravenous immunoglobulin is beneficial in other autoimmune diseases.ObjectivesWe aimed to determine the efficacy of intravenous immunoglobulin for Guillain‐Barré syndrome.Search strategyWe updated the searches of the Cochrane Neuromuscular Disease Group Trials Specialized Register, MEDLINE and EMBASE in June 2009 using the terms 'Guillain‐Barré syndrome' and 'acute polyradiculoneuritis' combined with 'intravenous immunoglobulin'.Selection criteriaWe included randomised and quasi‐randomised trials.Data collection and analysisTwo authors independently selected papers, extracted data and assessed quality.Main resultsAnother Cochrane systematic review has shown that plasma exchange significantly hastens recovery. In this review, five trials compared intravenous immunoglobulin with plasma exchange in 536 severely affected, mostly adult participants. The mean difference of change in a seven‐grade disability scale after four weeks was not significantly different between the two treatments: 0.02 (95% CI 0.25 to ‐0.20) of a grade more improvement in the intravenous immunoglobulin than the plasma exchange group. There were also no statistically significant differences in the other measures considered. Three studies including a total of 75 children suggested that intravenous immunoglobulin significantly hastens recovery compared with supportive care.In one trial involving 249 participants comparing plasma exchange followed by intravenous immunoglobulin with plasma exchange alone, the mean grade improvement was 0.2 (95% CI ‐0.14 to 0.54) more in the combined treatment group than in the plasma exchange alone group, not significantly different but not excluding the possibility of significant extra benefit. Another trial with 37 participants comparing immunoabsorption followed by intravenous immunoglobulin with immunoabsorption alone did not reveal significant extra benefit from the combined treatment.Small trials in children showed a trend towards more improvement with high‐dose compared with low‐dose intravenous immunoglobulin and no significant difference when the standard dose was given over two days rather than five days.Authors' conclusionsA previous Cochrane review has shown that plasma exchange hastens recovery compared with supportive treatment alone. There are no adequate comparisons of intravenous immunoglobulin with placebo in adults but this review provides moderate quality evidence that, in severe disease, intravenous immunoglobulin started within two weeks from onset hastens recovery as much as plasma exchange. Adverse events were not significantly more frequent with either treatment but intravenous immunoglobulin is significantly much more likely to be completed than plasma exchange. Also according to moderate quality evidence, giving intravenous immunoglobulin after plasma exchange did not confer significant extra benefit. In children, according to low quality evidence, intravenous immunoglobulin probably hastens recovery compared with supportive care alone. More research is needed in mild disease and in patients whose treatment starts more than two weeks after onset. Dose‐ranging studies are also needed.Plain Language SummaryIntravenous immunoglobulin for Guillain‐Barré syndromeGuillain‐Barré syndrome is an uncommon disease of the peripheral nerves. It causes weakness, numbness and breathing difficulty. Another Cochrane review has shown that plasma exchange (taking blood from one vein, separating the plasma from the blood cells and then returning the blood cells with a plasma substitute into another vein) is more effective than supportive care alone. In adults, moderate quality evidence shows that receiving intravenous immunoglobulin (antibodies that have been purified from donated blood) speeds recovery from severe Guillain‐Barré syndrome as much as plasma exchange. Intravenous immunoglobulin is slightly safer and much easier to give than plasma exchange. According to moderate quality evidence, intravenous immunoglobulin added to plasma exchange is not significantly more effective than either alone. A small amount of evidence suggests that intravenous immunoglobulin is also beneficial in children. More research is needed to determine the best dose in adults and children.

Guillain-Barre syndrome (GBS) is the most common cause of acute neuromuscular paralysis, usually due to acute inflammatory demyelinating polyradiculoneuropathy. The presence of activated T lymphocytes and antibodies against peripheral nerve myelin suggests an autoimmune pathogenesis, although there is wide heterogeneity. Gangliosides are sialylated glycolipids widely distributed in nervous system membranes. GBS is usually preceded by an infection, most frequently Campylobacter jejuni enteritis, but also cytomegalovirus, Mycoplasma pneumoniae or Epstein-Barr virus. Patients with GBS and C. jejuni infection are more likely to have neurophysiological features of axonal neuropathy, antibodies to ganglioside GM1, pure motor GBS, a less elevated CSF protein concentration and a worse outcome than other GBS patients. Although molecular mimicry between peripheral nerve gangliosides and epitopes present on C. jejuni lipopolysaccharide could explain some of these associations, this hypothesis is inadequate to account for many aspects of the pathogenesis of GBS.

Background: Autoimmune polyglandular syndrome type 2 (APS2) is defined by the occurrence of two or more autoimmune diseases, with Addison’s disease being most prevalent, and autoimmune thyroid disease and type 1 diabetes mellitus also being common. Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculopathy that is also autoimmune in nature, resulting in ascending muscle weakness or paralysis.Clinical Case: A 49 year old female with past medical history of vitiligo, subclinical hyperthyroidism, and Guillain-Barré syndrome (GBS) presented to our institution with fatigue, nausea, vomiting, polyuria, and polydipsia. She had no history of diabetes. Her history was also significant for GBS, diagnosed 5 months prior to her current admission. She was treated with intravenous immunoglobulin (IVIG) and had partial improvement of motor impairment. On exam, she was noted to have dry mucous membranes, epigastric tenderness, and patches of hyopigmented skin. Laboratory studies were consistent with diabetic ketoacidosis, and she was admitted to the ICU for management.Labs from 5 months prior were significant for a HbA1c of 6.4% (4.0-5.6%), TSH <0.002 mIU/L (0.350-4.7 mIU/L), total T3 154.9 ng/dL (79-149 ng/dL), and free T4 1.7 ng/dL (0.7-1.9 ng/dL), and elevated thyroid stimulating immunoglobulin.During the current admission, HbA1c had risen to 13.6%, C-Peptide 0.6 ng/mL (1.1-4.4 ng/mL) and GAD-65 antibody >250 IU/mL (<5 IU/mL), consistent with a diagnosis of late-onset type 1 diabetes. Repeat thyroid function tests (TSH <0.002 mIU/L, total T3 74 ng/dL, and free T4 1.2 ng/dL), were consistent with subclinical hyperthyroidism. A 21-hydoxylase antibody level was 13 U/mL (<1 U/mL), but cortisol rose appropriately in response to cosyntropin. Based on the patient’s constellation of vitiligo, autoimmune thyroid disease, type 1 diabetes, and elevated 21-hydroxylase antibodies, she was diagnosed with APS2.Conclusion: We present an unusual case of a patient with APS2, who was diagnosed with type 1 diabetes 5 months after developing GBS and being treated with IVIG. Prior reports demonstrate an association between GBS and other autoimmune diseases, including one case report of GBS in a patient with APS2. HLA DR3 has been associated with APS2, type 1 diabetes, Addison’s disease and Grave’s disease. Its association with GBS is less clear, although HLA DR3 was increased in one Mexican cohort with GBS. This case report adds to the literature suggesting an association with GBS and other autoimmune diseases, specifically, with APS2.

Immunoglobulin G Fc N-glycosylation in Guillain-Barré syndrome treated with intravenous immunoglobulin.

Guillain-Barré syndrome (GBS) is an acute, paralysing, inflammatory peripheral nerve disease. Intravenous immunoglobulin (IVIg) is beneficial in other autoimmune diseases. This is an update of a review first published in 2001 and previously updated in 2003, 2005, 2007, 2010 and 2012. Other Cochrane systematic reviews have shown that plasma exchange (PE) significantly hastens recovery in GBS compared with supportive treatment alone, and that corticosteroids alone are ineffective. We had the following four objectives.1. To examine the efficacy of intravenous immunoglobulin (IVIg) in hastening recovery and reducing the long-term morbidity from Guillain-Barré syndrome (GBS).2. To determine the most efficacious dose of IVIg in hastening recovery and reducing the long-term morbidity from GBS.3. To compare the efficacy of IVIg and plasma exchange (PE) or immunoabsorption in hastening recovery and reducing the long-term morbidity from GBS.4. To compare the efficacy of IVIg added to PE with PE alone in hastening recovery and reducing the long-term morbidity from GBS. We searched the Cochrane Neuromuscular Disease Group Specialized Register (2 December 2013), CENTRAL (2013, Issue 12 in The Cochrane Library), MEDLINE (January 1966 to November 2013) and EMBASE (January 1980 to November 2013). We checked the bibliographies in reports of the randomised trials and contacted the authors and other experts in the field to identify additional published or unpublished data. Randomised and quasi-randomised trials of IVIg compared with no treatment, placebo treatment, PE, or other immunomodulatory treatments in children and adults with GBS of all degrees of severity. We also included trials in which IVIg was added to another treatment. Two authors independently selected papers, extracted data and assessed quality. We collected data about adverse events from the included trials. Twelve trials were found to be eligible for inclusion in this review. Seven trials with a variable risk of bias compared IVIg with PE in 623 severely affected participants. In five trials with 536 participants for whom the outcome was available, the mean difference (MD) of change in a seven-grade disability scale after four weeks was not significantly different between the two treatments: MD of 0.02 of a grade more improvement in the intravenous immunoglobulin than the plasma exchange group; 95% confidence interval (CI) 0.25 to -0.20. There were also no statistically significant differences in the other measures considered. Three studies including a total of 75 children suggested that IVIg significantly hastens recovery compared with supportive care. The primary outcome for this review, available for only one trial with 21 mildly affected children, showed significantly more improvement in disability grade after four weeks with IVIg than supportive treatment alone, MD 1.42, 95% CI 2.57 to 0.27.In one trial involving 249 participants comparing PE followed by IVIg with PE alone, the mean grade improvement was 0.2 (95% CI -0.14 to 0.54) more in the combined treatment group than in the PE alone group; not clinically significantly different, but not excluding the possibility of significant extra benefit. Another trial with 34 participants comparing immunoabsorption followed by IVIg with immunoabsorption alone did not reveal significant extra benefit from the combined treatment.Adverse events were not significantly more frequent with either treatment, but IVIg is significantly much more likely to be completed than PE.Small trials in children showed a trend towards more improvement with high-dose compared with low-dose IVIg, and no significant difference when the standard dose was given over two days rather than five days. A previous Cochrane review has shown that PE hastens recovery compared with supportive treatment alone. There are no adequate comparisons of IVIg with placebo in adults, but this review provides moderate quality evidence that, in severe disease, IVIg started within two weeks from onset hastens recovery as much as PE. Adverse events were not significantly more frequent with either treatment but IVIg is significantly much more likely to be completed than PE. Also, according to moderate quality evidence, giving IVIg after PE did not confer significant extra benefit. In children, according to low quality evidence, IVIg probably hastens recovery compared with supportive care alone. More research is needed in mild disease and in patients whose treatment starts more than two weeks after onset. Dose-ranging studies are also needed and one is in progress.

This review covers the major advances in the therapeutic potential of intravenous immunoglobulin (IVIg) as a steroid-sparing agent in autoimmune diseases utilizing a structured search of Medline (1992–2007). IVIg is a potent biological drug, utilized routinely for idiopathic thrombocytopenic purpura, Kawasaki’s diseases, Guillain–Barre syndrome and dermatomyositis. In addition, however, IVIg is an adjunct second-line therapy in neuroimmunologic, infectious, dermatologic, hematologic, obstetric, autoimmune, inflammatory and idiopathic disorders. Compared with immunosuppressive agents administered routinely for systemic autoimmune diseases, IVIg is advantageous, owing to its few and transient minor adverse effects. Hence, it is logical to deliver IVIg with steroids as a sparing agent. All the published material on IVIg and its steroid-sparing effect was reviewed. Currently, there is insufficient evidence to confirm that IVIg has a significant steroid-sparing effect. Based on the available information, IVIg has the potential to act as a steroid-sparing agent in systemic lupus erythematosus and autoimmune blistering diseases, but its effect in other autoimmune diseases remains uncertain. Further investigation is warranted where this issue will be addressed as a primary endpoint and in controlled trials.

Invited commentary

Intravenous immunoglobulin (IVIg) is the treatment of choice for Guillain-Barré syndrome (GBS), an immune-mediated peripheral neuropathy causing rapidly progressive limb weakness and respiratory failure. The working mechanism of IVIg in autoimmune diseases has not been elucidated, but previous studies indicate that some anti-inflammatory effects may be mediated by the N-glycosylation of the Fc-portion of IgG. GBS is a model disease to investigate these effects because GBS is an acute and monophasic disorder usually affecting healthy persons, which is treated with a standard course of IVIg, although the clinical response is highly variable. In the current study, the N-glycosylation of the Fc-portion of serum IgG was investigated in patients with GBS before and after treatment with IVIg in relation to clinical course and outcome. Glycoforms of serum IgG1 and IgG2 were determined separately by liquid chromatography mass spectrometry. These IgG subclasses were purified from the serum of 174 GBS patients before and in 150 patients 2 weeks after standard IVIg treatment regimen. Treatment-naive GBS patients compared with age- and sex-matched controls had lower levels of galactosylation of IgG1 and IgG2. IVIg preparations contained relatively high levels of galactosylated and sialylated IgG Fc glycoforms compared with serum IgG in patients. Treatment with IVIg resulted in an increase in serum of the Fc-galactosylation and -sialylation of both IgG1 and IgG2. The extent of normalization in serum IgG Fc glycosylation varied between patients. Multiple logistic regression analysis showed that patients with persistent low IgG galactosylation and sialylation despite IVIg treatment had the most severe forms of GBS and needed ventilator support more often. Kaplan-Meier analysis showed that these patients also needed more time to be able to walk again compared with patients with a normalized IgG Fc glycosylation profile. In conclusion, our results suggest that serum IgG Fc glycosylation in GBS is related to disease severity and clinical recovery after IVIg and may help to develop new measures to monitor the efficacy of treatment.

Guillain-Barré syndrome (GBS) is an acute, paralysing, inflammatory peripheral nerve disease. Intravenous immunoglobulin (IVIg) is beneficial in other autoimmune diseases. This is an update of a review first published in 2001 and previously updated in 2003, 2005, 2007 and 2010. Other Cochrane systematic reviews have shown that plasma exchange (PE) significantly hastens recovery in GBS compared with supportive treatment alone, and that corticosteroids alone are ineffective. To determine the efficacy of IVIg for GBS. We searched the Cochrane Neuromuscular Disease Group Specialized Register (15 August 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (January 1966 to August 2011) and EMBASE (January 1980 to August 2011). We checked the bibliographies in reports of the randomised trials and contacted the authors and other experts in the field to identify additional published or unpublished data. Randomised and quasi-randomised trials of IVIg compared with no treatment, placebo treatment, PE, or other immunomodulatory treatments in children and adults with GBS of all degrees of severity. We also included trials in which IVIg was added to another treatment. Two authors independently selected papers, extracted data and assessed quality. We collected data about adverse events from the included trials. In this review, seven trials with a variable risk of bias compared IVIg with PE in 623 severely affected participants. In five trials with 536 participants for whom the outcome was available, the mean difference (MD) of change in a seven-grade disability scale after four weeks was not significantly different between the two treatments: MD of 0.02 of a grade more improvement in the intravenous immunoglobulin than the plasma exchange group; 95% confidence interval (CI) 0.25 to -0.20. There were also no statistically significant differences in the other measures considered. Three studies including a total of 75 children suggested that IVIg significantly hastens recovery compared with supportive care.In one trial involving 249 participants comparing PE followed by IVIg with PE alone, the mean grade improvement was 0.2 (95% CI -0.14 to 0.54) more in the combined treatment group than in the PE alone group; not clinically significantly different, but not excluding the possibility of significant extra benefit. Another trial with 37 participants comparing immunoabsorption followed by IVIg with immunoabsorption alone did not reveal significant extra benefit from the combined treatment.Adverse events were not significantly more frequent with either treatment, but IVIg is significantly much more likely to be completed than PE.Small trials in children showed a trend towards more improvement with high-dose compared with low-dose IVIg, and no significant difference when the standard dose was given over two days rather than five days. A previous Cochrane review has shown that PE hastens recovery compared with supportive treatment alone. There are no adequate comparisons of IVIg with placebo in adults, but this review provides moderate quality evidence that, in severe disease, IVIg started within two weeks from onset hastens recovery as much as PE. Adverse events were not significantly more frequent with either treatment but IVIg is significantly much more likely to be completed than PE. Also, according to moderate quality evidence, giving IVIg after PE did not confer significant extra benefit. In children, according to low quality evidence, IVIg probably hastens recovery compared with supportive care alone. More research is needed in mild disease and in patients whose treatment starts more than two weeks after onset. Dose-ranging studies are also needed.

Introduction: The off-label clinical use of Intravenous Immunoglobulin (IVIG) has increased despite the existence of its approved indications by drug regulatory agencies. IVIG is an expensive drug and its availability is also limited; hence, judicious use of IVIG is highly recommended. Aim: To evaluate the utilisation pattern and cost burden of IVIG in the In-Patient Departments (IPD) of a tertiary healthcare facility. Materials and Methods: This record-based cross-section observational study was carried out in the IPD of MKCG Medical College, Department of Pharmacology, MKCG, MCH, Berhampur, Odisha, India, from September 2022 to September 2023, where a total of 108 patients who were prescribed and received IVIG for any clinical condition were included. Clinical data, like clinico-demographic profile, diagnosis, dosage and duration of IVIG, were collected in a predesigned structured Case Record Form (CRF). The utilisation pattern was compared with the drug regulatory agencies’ United States Food and Drug Administration (USFDA) approved IVIG conditions to determine the proportion of such use. Data were collected, compiled and analysed using MICROSOFT (MS) Excel and Statistical Package for Social Sciences (SPSS) version 25.0. Data were expressed as frequency, percentages, median and interquartile range. Results: The median age of patients who received IVIG was 12 years and Interquartile Range (IQR) was 29 (Q1=3, Q3=32). Majority of the cases receiving IVIG, i.e., 59 (54.6%), were from paediatrics IPD. The proportion of male patients was higher at 57 (52.7%). Guillain-Barré Syndrome (GBS) was the most common off-label indication, accounting for 55 (50.9%), followed by Multisystem Inflammatory Syndrome (MIS-C) in 12 (11.1%) children. In 73 (67.59%) of cases, IVIG was administered for offlabel indication, 8 (6.48%) of cases for FDA-approved indication and remaining for others. The highest expenditure was done on diseases with off-label indications, which accounted for 88.63% of total expenditure for IVIG. Conclusion: In the present study, the use of IVIG for off-label indications was higher than for approved indications. National or local drug protocols are needed to prescribe more rational IVIG utilisation and assist physicians to use IVIG for approved or high evidence-based indications.

Intravenous immunoglobulin (IVIg) treatment ameliorates the course of Guillain-Barré syndrome (GBS), but its specific mode of action is unknown. We attempted to delineate the effect of IVIg on neuromuscular blocking antibodies in GBS. A total of seven GBS serum samples were examined for blocking antibodies and the effect of IVIg with a macro-patch-clamp technique in mouse hemidiaphragms. First, serum was tested before and after treatment with IVIg. Second, we investigated with coincubation experiments whether the IVIg was capable of neutralizing neuromuscular blocking antibodies in GBS serum or affinity-purified immunoglobulin G (IgG) fractions. Finally, the mechanism of the neutralizing effect was studied by the coincubation of active blocking GBS IgG with Fab and Fc fragments prepared from IVIg. All GBS sera (two adults and two children) and GBS IgG fractions (three adults) taken before treatment with IVIg blocked evoked quantal release by approximately 90%. Blocking activity was markedly reduced in sera obtained after treatment with IVIg. Coincubation of the pretreatment blocking serum with the posttreatment serum, or with the IVIg preparation used for treatment, reduced the blocking activity of the pretreatment GBS serum. When GBS IgG was coincubated with IVIg, the blocking activity of GBS IgG was diminished dose-dependently. Monovalent and divalent Fab fragments prepared from the IVIg were as effective as whole IVIg, but Fc fragments were ineffective. Therapeutic IVIg is capable of neutralizing neuromuscular blocking antibodies in GBS by a dose-dependent, antibody-mediated mechanism. This may, in part, explain its therapeutic efficacy.

The Case Files

Guillain-Barre syndrome (GBS) is an acute immune-mediated demyelinating polyneuropathy that often results in severe muscular weakness. Most patients have an antecedent infection within the weeks before the onset of disease. GBS patients generally tend to recover spontaneously, but 20% of patients are still unable to walk independently at 6 months after the onset of disease. General medical care is essential for patients with GBS, but more specific treatment with plasma exchange significantly hastens recovery. High dosage intravenous immunoglobulin (IVIg) is at least as effective as plasma exchange, and may be superior. IVIg has some additional advantages over plasma exchange, because it is widely available, easy to administer and has hardly any contraindications. In clinical trials it was shown that relapse or treatment-related clinical fluctuation occurs in around 10% of GBS patients, irrespective of whether the patients were treated with plasma exchange or IVIg. When a GBS patient deteriorates during or shortly after a course of plasma exchange or IVIg, we recommend not to switch to the other treatment because plasma exchange, and probably IVIg also, is only effective when applied within the first 2 weeks of disease. It is impossible to decide for a single GBS patient whether a particular treatment is effective or not. This is partly due to the large clinical variation in the natural course of disease between individual patients. Subgroups of patients responding particularly favourably to plasma exchange or IVIg have not been identified. Although plasma exchange and IVIg treatment are important advances in the treatment of GBS, a considerable proportion of patients have significant clinical deficit many months or years after the onset of disease. The results of a recently completed nonblinded study suggest that the addition of methylprednisolone to IVIg is even more effective than IVIg alone. Whether this combined treatment is definitely superior to IVIg alone will be investigated in a randomised trial.

ObjectiveTo compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses.MethodsFrom the International GBS Outcome...

Guillain-Barré syndrome: surveillance and cost of treatment strategies – Authors' reply