Are there any data to support administration of a second course of intravenous immunoglobulin in patients with Guillain-Barré syndrome unresponsive to a first course?
Guillain-Barré syndrome (GBS) refers to several related autoimmune conditions that affect the peripheral nerves.1,2 It is relatively rare in North America, with an estimated incidence of 0.81 to 1.89 cases per 100,000 person-years. Its onset is acute, sometimes fulminant, and occurs after infection in about 70% of cases.1-3 The classic symptoms of GBS are progressive, bilateral muscle weakness and hyporeflexia or areflexia. Muscle weakness typically begins in the lower extremities before ascending to other areas of the body. The severity of muscle weakness varies considerably among GBS patients, with some experiencing loss of mobility and others having paralysis of the respiratory muscles. Pulmonary complications lead to mechanical ventilation in about 25% to 30% of individuals.1 Other common signs and symptoms may be sensory or autonomic in nature.1-3 About half of GBS patients experience pain, which may occur in the back, shoulders, and neck.3 Paresthesia has also been observed in some patients.1,2 Autonomic dysfunction may appear as tachycardia, variable blood pressure, and orthostatic hypotension, among other presentations.1-3 Patients usually require hospitalization and close monitoring to reduce the risk for disease-related morbidity and mortality. Clinical manifestations of GBS appear about 4 to 6 weeks following exposure to an immune system trigger.1 The disease usually reaches its nadir in 2 to 4 weeks, and recovery starts 2 weeks to 6 months afterward.
Common illnesses causing GBS are gastrointestinal and respiratory infections.1-3 Campylobacter jejuni is the infectious agent most frequently associated with GBS cases in Europe, North America, and Australia.³ Other infections that can precipitate GBS include sickness caused by cytomegalovirus, Epstein-Barr virus, and Influenza A virus, among others.1-3 Additional causes of GBS include trauma and vaccines.1 The latter rarely trigger GBS; however, vaccines protecting against infection from influenza and tetanus should be administered cautiously in some individuals.1,4 Although the specific mechanism for GBS remains unclear, it is thought that molecular mimicry plays a significant role.1-3 Gangliosides are glycoconjugates commonly found on the cell surface of human nervous tissue. It is thought that these gangliosides resemble infectious antigens, leading to attack by the immune system and subsequent peripheral nerve damage.
It takes about a year for most patients to fully recover from GBS.1 Symptoms such as fatigue, pain, and muscle weakness may continue following recovery. The mortality rate of GBS is estimated to be between 3% and 7%, with infectious, respiratory, and cardiac complications being the most common causes of death. Factors conferring a poorer prognosis include fulminant disease, need for mechanical ventilation, delayed treatment, and older age, among others.1-3
Initial Management and Guideline Recommendations
Timely diagnosis and treatment of GBS patients increase well-being while minimizing complications.2,5 According to an international consensus document on management of GBS, which was published in 2019 and included representative members from the United States, treatment should be initiated when one or more of the following symptoms has occurred: incapable of walking a short distance, increased weakness in a short period of time, intense involuntary body function or dysphagia, or difficulty breathing.5 Validated tools like the Modified Erasmus GBS Outcome Score (mEGOS) are useful prognostically and may assist clinicians with treatment selection.1,6 This model considers age, antecedent diarrhea, and muscle strength to predict the likelihood of independent ambulation at various time points.
Plasma exchange (PE) and intravenous immunoglobulin (IVIG) are immunotherapies that have been shown to improve disease prognosis, accelerate recovery, and reduce complications when used to treat GBS, although their mechanisms for treatment of GBS are not fully understood.7 The mechanism for PE may involve nonspecific targeting of pathogenic autoantibodies and other pro-inflammatory mediators. Intravenous immunoglobulin is theorized to work via several possible mechanisms, including interrupting autoantibody production or altering various other aspects of the immune response. Both the international consensus document and guidelines from the American Academy of Neurology generally recommend initiation of treatment for GBS with IVIG or PE within 2 to 4 weeks from the onset of symptoms.5,8 Intravenous immunoglobulin is typically dosed at 0.4 g/kg and given once daily for 5 days; PE is administered with approximately 40 to 50 mL of plasma/kg exchanged over 5 to 7 sessions occurring over a period of up to 2 weeks.1,3,5 Common adverse events associated with IVIG include fever, myalgia, headache, and hypotension.9 Plasma exchange is associated with blood pressure instability, transfusion reactions, and infections or other complications related to the need for intravenous or central line access.10,11 While the risk of adverse events is generally similar among patients treated with PE or IVIG, use of IVIG may be preferable since it is easier to administer and generally better tolerated.9,10,11
Persistent Symptoms and Recurrence
Up to 50% of patients who receive treatment with PE or IVIG do not show an improvement in symptoms after 4 weeks.12 In addition, as many as 10% of patients with GBS will experience at least 1 relapse.3,13 Compared to supportive care alone, plasma exchange has been shown to accelerate recovery; however, it has also been associated with a significant, albeit small, increase in risk of relapse.10 Additionally, approximately 10% of patients will have treatment-related fluctuations (ie, worsening of symptoms after an initial response to therapy).2 It is important to note that treatment-related fluctuations are distinct from inadequate treatment response or disease recurrence. Immunotherapy with IVIG over 5 days hastens recovery, while therapy over 2 days increases rates of treatment-related fluctuation in adults.14
Overall, there are a lack of evidence-based recommendations for management of patients that respond poorly to initial therapy; however, these patients are sometimes managed with a repeated course of therapy.1,5 Guidelines do not make specific recommendations for treatment after the first course of PE or IVIG, and the American Academy of Neurology has acknowledged that this is an area requiring further research. In light of the lack of guidance on repeat courses of therapy for GBS, and considering the ease of administration and preferable adverse event profile of IVIG, a search was conducted to identify relevant literature assessing the efficacy of administering a second course of IVIG in patients with unresolved symptoms after an initial course.
A literature search identified a single randomized, double-blinded, placebo-controlled, multicenter study evaluating the efficacy of a second course of IVIG in patients with a poor prognosis.15 The study, which was conducted at 59 hospitals in the Netherlands, included 327 patients aged 12 years and older with GBS. All patients received initial treatment with IVIG 2 g/kg total given over 5 consecutive days. Ninety-nine patients who were determined to have a poor prognosis based on the mEGOS score (score >6) 7 to 9 days after the first day of treatment with IVIG were further randomized to receive either a second course of IVIG over 5 days (n=53) or placebo (n=46). Patients with a good prognosis based on an mEGOS score (score of 0 to 5) were not randomized to additional treatment but continued with follow-up and assessment throughout the remainder of the study period. The primary outcome measured was the GBS disability scale score at 4 weeks after the start of the first course of IVIG. The GBS disability scale score ranks an individual patient’s disability from GBS from 0 to 6, with a score of 0 indicating no symptoms and a score of 6 indicating death. Secondary outcomes included the GBS disability scale score and other related scores at various time points up to 26 weeks, the need for and duration of mechanical ventilation, intensive care and hospital admission rates, and mortality; safety was also assessed via reporting of adverse events. The median age of patients who received a second course of IVIG ranged from 59 to 66 years; the majority of patients were men, and most patients had a GBS disability scale score of 4 or 5 at randomization. No difference was found between groups for the primary outcome (the GBS disability scale score was 4 in both groups), or any of the secondary outcomes; however, the rate of serious adverse events was significantly higher in patients who received a second course of IVIG (51%) compared to those who received placebo (23%; odds ratio, 3.54; 95% confidence interval, 1.44 to 8.72; p=0.0050). The sample size calculation for this trial was based on an assumed 20% difference in a secondary outcome, the improvement in the GBS disability scale score by at least 1 point at 4 weeks, rather than the primary outcome. A 10% difference between groups was reported for this outcome, thus, it seems that the study may have been underpowered to detect a difference between groups.
Guillain-Barré syndrome is a relatively rare autoimmune disorder that is most often provoked by a preceding infection. The nerve damage rapidly progresses causing myopathy and sometimes paralysis. Current treatment strategies include the immunotherapies PE and IVIG. While both PE and IVIG have been shown to have similar effectiveness, IVIG is easier to administer and generally better tolerated. Up to 50% of patients do not experience improvement of symptoms after a first course of therapy, and the evidence is lacking to guide treatment in patients who do not improve after an initial course of IVIG. A multicenter, randomized controlled trial assessing the efficacy of administration of a second course of IVIG in patients with a poor prognosis after an initial course found no difference in outcomes, and an increase in serious adverse events, when compared to placebo. Although the study was limited by its small sample size, it is unlikely that larger studies will be conducted due to the rarity of GBS.
- Sheikh KA. Guillain-Barré syndrome. Continuum. 2020;26(5):1184-1204. doi:10.1212/CON.0000000000000929
- Kwan J, Biliciler S. Guillain-Barré syndrome and other acute polyneuropathies. Clin Geriatr Med. 2021;37(2):313-326. doi:10.1016/j.cger.2021.01.005
- Hauser SL, Amato AA. Guillain-Barré syndrome and other immune-mediated neuropathies. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. McGraw-Hill; 2018:chap 439. Accessed July 30, 2021. https://accesspharmacy.mhmedical.com/
- General best practice guidelines for immunization: contraindications and precautions. Centers for Disease Control and Prevention. Updated August 5, 2021. Accessed August 9, 2021. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/contraindications.html
- Leonhard SE, Mandarakas MR, Gondim FAA, et al. Diagnosis and management of Guillain-Barré syndrome in ten steps. Nat Rev Neurol. 2019;15(11):671-683. doi:10.1038/s41582-019-0250-9
- Walgaard C, Lingsma HF, Ruts L, van Doorn PA, Steyerberg EW, Jacobs BC. Early recognition of poor prognosis in Guillain-Barré syndrome. Neurology. 2011;76(11):968-975. doi:10.1212/WNL.0b013e3182104407
- Liu S, Dong C, Ubogu EE. Immunotherapy of Guillain-Barré syndrome. Hum Vaccin Immunother. 2018;14(11):2568-2579. doi:10.1080/21645515.2018.1493415
- Hughes RA, Wijdicks EF, Barohn R, et al. Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003;61(6):736-740. doi:10.1212/wnl.61.6.736
- Hughes RAC, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2014;2014(9):CD002063. doi:10.1002/14651858.CD002063.pub6
- Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2017;2(2):CD001798. doi:10.1002/14651858.CD001798.pub3
- Muley SA. Guillain-Barré syndrome in adults: treatment and prognosis. UpToDate. UpToDate; 2021. Accessed August 10, 2021. https://www.uptodate.com/
- Verboon C, van Doorn PA, Jacobs BC. Treatment dilemmas in Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry. 2017;88(4):346-352. doi: 10.1136/jnnp-2016-314862
- Guillain-Barré syndrome fact sheet. National Institute of Neurological Disorders and Stroke. Published June 2018. Updated March 16, 2020. Accessed August 4, 2021. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Guillain-Barr%C3%A9-Syndrome-Fact-Sheet
- Shahrizaila N, Lehmann HC, Kuwabara S. Guillain-barré syndrome. Lancet. 2021;397:1214-1228. doi:10.1016/S0140-6736(21)00517-1
- Walgaard C, Jacobs BC, Lingsma HF. Second intravenous immunoglobulin dose in patients with Guillain-Barre syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-283. doi:10.1016/S1474-4422(20)30494-4
Suany Jass, PharmD Candidate Class of 2022
Kyoung Kim, PharmD Candidate Class of 2022
University of Illinois at Chicago College of Pharmacy
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
The information presented is current as of August 4, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.