Guillain-Barre Syndrome Treatments

Number: 0732

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses Guillain-Barre syndrome treatments.

1. Medical Necessity

   Aetna considers any of the following therapies medically necessary for the treatment of Guillain-Barre syndrome (GBS):

   1. Intravenous immunoglobulin (IVIG) when criteria in CPB 0206 - Parenteral Immunoglobulins are met.
   2. Outpatient pulmonary rehabilitation program when criteria listed in CPB 0032 - Pulmonary Rehabilitation are met.
   3. Plasmapheresis when criteria in CPB 0285 - Plasmapheresis/Plasma Exchange/Therapeutic Apheresis are met.

2. Experimental, Investigational, or Unproven

   Aetna considers the use of any of the following therapies for the treatment of GBS experimental, investigational, or unproven because their effectiveness for this indication has not been established (not an all-inclusive list).

   1. Acupuncture (CPB 0135 - Acupuncture and Dry Needling)
   2. Amantadine
   3. Bifidobacterium infantis
   4. Brain-derived neurotrophic factor
   5. Cerebrospinal fluid filtration
   6. Corticosteroids
   7. Eculizumab (CPB 0807 - Eculizumab (Soliris))
   8. Interferons (CPB 0404 - Interferons)
   9. Leukocyte trafficking inhibitors (e.g., efalizumab, etrolizumab, natalizumab and vedolizumab)
   10. Neuromuscular electrical stimulation in rehabilitation of GBS
   11. Per-oral endoscopic myotomy (for the treatment of GBS-associated achalasia)
   12. Rituximab (CPB 0314 - Rituximab)
   13. Sugammadex.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
36514	Therapeutic apheresis; for plasma pheresis
90283	Immune globulin (IgIV), human, for intravenous use
CPT codes not covered for indications listed in the CPB:
Per-oral endoscopic myotomy - no specific code:
97810 - 97814	Acupuncture, 1 or more needles
HCPCS codes covered if selection criteria are met:
J1561	Injection, immune globulin, (Gamunex/Gamunex-C/Gammaked), nonlyophilized (e.g., liquid), 500 mg
J1566	Injection, immune globulin, intravenous, lyophilized, (e.g., powder), 500 mg
J1568	Injection, immune globulin, (Octagam), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1569	Injection, immune globulin, (Gammagard liquid), nonlyophilized, (e.g., liquid), 500 mg
S9473	Pulmonary rehabilitation program, non-physician provider, per diem
HCPCS codes not covered for indications listed in the CPB:
Sugammadex; Bifidobacterium infantis - no specific code:
J0202	Injection, alemtuzumab, 1 mg
J0702	Injection, betamethasone acetate and betamethasone sodium phosphate, per 3 mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1 mg
J1299	Injection eculizumab 2 mg
J1700	Injection, hydrocortisone acetate, up to 25 mg (Hydrocortone acetate)
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J2323	Injection, natalizumab, 1 mg
J2650	Injection, prednisolone acetate, up to 1 ml
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg
J3300	Injection, triamcinolone acetonide, preservative free, 1 mg
J3301	Injection, triamcinolone acetonide, per 10 mg
J3302	Injection, triamcinolone diacetate, per 5 mg
J3303	Injection, triamcinolone hexacetonide, per 5 mg
J3380	Injection, vedolizumab, 1 mg
J7509	Methylprednisolone, oral, per 4 mg
J7510	Prednisolone, oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J8540	Dexamethasone, oral, 0.25 mg
J9212	Injection, interferon alfacon-1, recombinant, 1 mcg
J9213	Interferon alfa-2A, recombinant, 3 million units
J9214	Interferon alfa-2B, recombinant, 1 million units
J9215	Interferon alfa-N3, (human leukocyte derived), 250,000 IU
J9216	Interferon gamma-1B, 3 million units
J9312	Injection, rituximab, 10 mg
Q3027	Injection, interferon beta-1a, 1 mcg for intramuscular use
Q5134	Injection, natalizumab-sztn (tyruko), biosimilar, 1 mg
S8930	Electrical stimulation of auricular acupuncture points; each 15 minutes of personal one-on-one contact with the patient
S9559	Home injectable therapy, interferon, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drug and nursing visits coded separately), per diem
ICD-10 codes covered if selection criteria are met:
G61.0	Guillian-Barre syndrome

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Background

Guillain-Barré syndrome (GBS) is an acquired acute peripheral neuropathy that causes limb weakness, progressing over a period of days to weeks. It occurs with a median annual incidence of 1.3 cases per 100,000 population, with men being more frequently affected than women. The prognosis for GBS is generally favorable, but it is a serious disease with a mortality rate of about 10%, and approximately 20% of patients are left with severe disability. GBS is considered an autoimmune disease triggered by a preceding bacterial or viral infection, with common antecedent pathogens including Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae. It is a heterogeneous disorder representing at least five different entities: three predominantly motor forms—acute inflammatory demyelinating polyneuropathy (AIDP), acute motor sensory axonal neuropathy (AMSAN), and acute motor axonal neuropathy (AMAN)—and two variants, Fisher syndrome and acute panautonomic neuropathy (Lindenbaum et al., 2001; Kuwabara, 2004).

In the AMAN form of GBS, the infecting organisms likely share homologous epitopes with components of the peripheral nerves, leading to immune responses that cross-react with the nerves and cause axonal degeneration. The target molecules in AMAN are likely gangliosides GM1, GM1b, GD1a, and GalNAc-GD1a expressed on the motor axolemma. In contrast, in the AIDP form of GBS, immune system reactions against target epitopes in Schwann cells or myelin result in demyelination; however, the exact target molecules in AIDP have not yet been identified. Acute inflammatory demyelinating polyneuropathy is by far the most common form of GBS in Europe and North America, whereas AMAN occurs more frequently in Eastern Asia, particularly in China and Japan (Kuwabara, 2004).

Treatment of GBS involves managing severely paralyzed patients with intensive care and ventilatory support, along with specific immunomodulating therapies that shorten the progressive course of GBS, presumably by limiting nerve damage. High-dose intravenous immunoglobulin (IVIG) and plasmapheresis (PP)/plasma exchange (PE)/therapeutic apheresis facilitate more rapid resolution of the disease. The predominant mechanisms by which IVIG exerts its action appear to involve a combined effect of complement inactivation, neutralization of idiotypic antibodies, cytokine inhibition, and saturation of Fc receptors on macrophages.

There is insufficient evidence that patients with GBS respond to corticosteroids (Lindenbaum et al., 2001; Czaplinski and Steck, 2004; Newswanger and Waren, 2004; Kuwabara, 2004). Furthermore, a Cochrane review on corticosteroids for GBS (Hughes et al., 2006) stated that limited evidence demonstrates that oral corticosteroids markedly slow recovery from GBS. Substantial evidence shows that intravenous methylprednisolone alone does not produce significant benefit or harm. The authors noted that further investigation is needed, and more effective treatments for GBS should be sought.

In a multi-center, randomized controlled study (n = 233), van Koningsveld et al. (2004) reported no significant difference between methylprednisolone plus IVIG and IVIG alone in the treatment of patients with GBS. Odaka et al. (2005) compared side effects in nine patients with GBS treated with standard IVIG only and in nine patients treated with combined methylprednisolone and IVIG therapy. Headache occurred in two patients in both groups, suggesting that pre-infusion with steroids does not prevent headache.

In a Cochrane review, Hughes and colleagues (2010) examined the effectiveness of corticosteroids in the treatment of GBS. These investigators searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (June 2009), Medline (January 1966 to June 2009), and Embase (January 1980 to June 2009). They included quasi-randomized or randomized controlled trials of any form of corticosteroid or adrenocorticotropic hormone. The primary outcome was the change in disability grade on a 7-point scale after 4 weeks of treatment; secondary outcomes included time from randomization until recovery of unaided walking, time from randomization until discontinuation of ventilation (for those ventilated), death, death or disability (inability to walk without aid) after 12 months, relapse, and adverse events. Two authors extracted the data. No new trials were discovered in the new search in June 2009; six trials with 587 subjects provided data for the primary outcome. According to moderate-quality evidence, the change in disability grade following 4 weeks in the corticosteroid groups was not significantly different from that in the control groups, with a weighted mean difference (WMD) of 0.36 less improvement (95% confidence intervals [CI]: 0.16 more to 0.88 less improvement). In four trials of oral corticosteroids with a total of 120 participants, there was significantly less improvement after 4 weeks with corticosteroids than without corticosteroids, with a WMD of 0.82 disability grades less improvement (95% CI: 0.17 to 1.47). In two trials with a combined total of 467 participants, there was no significant difference, with a WMD of 0.17 (95% CI: -0.06 to 0.39) of a disability grade more improvement after 4 weeks with intravenous corticosteroids. According to moderate-to-high quality evidence, there were no significant differences between the corticosteroid-treated and control groups in any of the secondary outcomes. Diabetes was significantly more common, and hypertension significantly less common, in the corticosteroid-treated participants. The authors concluded that according to moderate-quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome. According to low-quality evidence, oral corticosteroids delay recovery. Diabetes requiring insulin was significantly more common, and hypertension less common, with corticosteroids.

Interferon has not been shown to be effective for GBS. Pritchard et al. (2003) performed a pilot double-blind, randomized, placebo-controlled safety trial of interferon beta-1a on patients with GBS. Participants received interferon beta-1a or placebo subcutaneously three times weekly, starting with 22 µg for the first week and then 44 µg for up to 24 weeks, in addition to IVIG. These researchers reported that interferon beta-1a did not have any unexpected interaction with IVIG, and there was no significant difference in the rate of improvement.

Practice parameter on immunotherapy for GBS furnished by the Quality Standards Subcommittee of the American Academy of Neurology (Hughes et al., 2003) has the following recommendations:

• Corticosteroids are not recommended for the management of GBS;
• IVIG is recommended for non-ambulant adult patients with GBS within 2 or possibly 4 weeks of the onset of neuropathic symptoms.  The effects of PE and IVIG are equivalent;
• PE and IVIG are treatment options for children with severe GBS;
• PE is recommended for non-ambulant adult patients with GBS who seek treatment within 4 weeks of the onset of neuropathic symptoms.  PE should also be considered for ambulant patients examined within 2 weeks of the onset of neuropathic symptoms; and
• Sequential treatment with PE followed by IVIG, or immuno-absorption followed by IVIG is not recommended for patients with GBS.

Monaco and colleagues (2004) stated that in Guillain-Barré syndrome (GBS) and related variants, randomized clinical trials show that plasmapheresis (PE) and intravenous immunoglobulin (IVIG) are equally effective as disease-modifying treatments, although IVIG has been adopted as the preferred treatment in most centers. Finsterer (2005) noted that there is no significant difference between IVIG, PE, and PE followed by IVIG in the treatment of GBS. Due to its convenience and non-invasive nature, IVIG is usually preferred.

A Cochrane review (Hughes et al., 2006) indicated that randomized trials in severe cases of GBS show that IVIG started within 2 weeks from onset hastens recovery as much as PE, which is known to be more effective than supportive care. Treatment with IVIG is significantly more likely to be completed than PE. Administering IVIG after PE did not confer any significant extra benefit. In children, IVIG likely hastens recovery compared to supportive care alone. The authors stated that more research is needed in mild disease and in treatments starting more than 2 weeks after the onset of the condition. These findings align with the recommendations of the American Academy of Neurology.

Raphael (2005) noted that PE is the first-line treatment for GBS. Two sessions of PE are recommended for patients who are able to walk (mild), with two additional sessions if they deteriorate. For patients who are unable to walk without assistance (moderate), four sessions of PE are sufficient, as are four sessions for those requiring mechanical ventilation (severe form). It is not useful to add further sessions of PE in more severe disease or if there is no response. High-dose IVIG (0.4 g/kg daily for 5 days) and PE are equally effective in treating intermediate and severe forms of GBS. The choice between the two options depends on their respective contraindications and local availability.

Amantadine has not been proven effective for the treatment of GBS. In a randomized, double-blind, placebo-controlled, cross-over trial (n = 80), Garssen et al. (2006) examined the effect of amantadine on severe fatigue related to GBS. During the pre-treatment phase, all patients were monitored for 2 weeks. Only patients with severe fatigue, defined as a mean fatigue score of greater than or equal to 5.0 on the Fatigue Severity Scale (FSS), were included in this study. The primary outcome measure was improvement of at least 1 point on the FSS. Secondary outcome measures included the impact of fatigue, anxiety and depression, handicap, and quality of life. A total of 80 patients were randomized, of whom 74 were included for analysis. Fatigue appeared to be reduced during the pre-treatment phase (p = 0.05), likely due to increased attention provided to the patients. No significant differences in any of the primary and secondary outcome measures were found. These researchers concluded that amantadine was not superior to placebo.

A multi-disciplinary consensus group reviewed the published medical literature and made recommendations regarding the supportive care of individuals with GBS (Hughes et al., 2005). In the acute phase for bed-bound adult patients, the group recommended the use of heparin and graduated pressure stockings to prevent deep vein thrombosis, monitoring for blood pressure, pulse, autonomic disturbances, and respiratory failure, and the timely institution of artificial ventilation and tracheostomy. The group noted that pain management is challenging, but carbamazepine or gabapentin may help. The cautious use of narcotic analgesics may also be necessary. Disabled patients should be treated by a multi-disciplinary rehabilitation team and should receive an assistive exercise program. Persistent fatigue following GBS is common and may be alleviated by an exercise program. The group stated that, due to a very small and possibly only theoretical increase in the risk of recurrence following immunization, the need for immunization should be reviewed on an individual basis. They reported that more research is needed to identify optimal methods for all aspects of supportive care.

van Doorn (2009) noted that epidemiological studies have shown that the incidence of GBS remains stable at about 2 per 100,000 per year; however, there have been changes in hospitalization use, likely due to the widespread availability of IVIG. Research into mechanisms has highlighted the importance of single amino acids in Campylobacter jejuni and the significance of ganglioside conformation. In a murine model of anti-ganglioside antibody-mediated neuropathy, eculizumab was effective in reversing clinical disease and preventing pathology, suggesting that trials of eculizumab in GBS should be considered. However, there are no new randomized controlled trials in GBS to report.

In a Cochrane review, Hughes et al. (2011) systematically reviewed the evidence from randomized controlled trials for pharmacological agents other than PE, IVIG, and corticosteroids. These investigators searched the Cochrane Neuromuscular Disease Group Specialized Register (July 5, 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), MEDLINE (January 1966 to June 2010), and EMBASE (January 1980 to June 2010) for treatments for GBS. They included all randomized or quasi-randomized controlled trials of acute (within 4 weeks from onset) GBS of all types, ages, and degrees of severity, and excluded trials that only tested corticosteroids, IVIG, or PE. The researchers included other pharmacological treatments or combinations of treatments compared with no treatment, placebo treatment, or another treatment. Change in disability after 4 weeks was the primary outcome. Two authors checked references and extracted data independently. One author entered and another checked data in Review Manager (RevMan). They assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. They calculated mean differences and risk ratios with their 95% confidence intervals. Only very low-quality evidence was found for four different interventions. One randomized controlled trial with 13 participants showed no significant difference in any outcome between interferon (IFN) beta-1a and placebo. Another trial with 10 participants showed no significant difference in any outcome between brain-derived neurotrophic factor and placebo. A third trial with 37 participants showed no significant difference in any outcome between cerebrospinal fluid filtration and PE. In a fourth trial with 20 participants, the risk ratio of improving by one or more disability grades after 8 weeks was significantly greater with the Chinese herbal medicine tripterygium poly-glycoside than with corticosteroids (risk ratio 1.47; 95% CI: 1.02 to 2.11). The authors concluded that the quality of the evidence was very low. Three small randomized controlled trials of IFN beta-1a, brain-derived neurotrophic factor, and cerebrospinal fluid filtration showed no significant benefit or harm. A fourth small trial indicated that the Chinese herbal medicine tripterygium poly-glycoside hastened recovery significantly more than corticosteroids, but this result needs confirmation. It was not possible to draw useful conclusions from the few observational studies.

In a Cochrane review, Liu and colleagues (2013) evaluated the safety and effectiveness of pharmacological treatments for various pain symptoms associated with GBS during both the acute and convalescent (3 months or more after onset) phases of GBS. On August 27, 2012, these investigators searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, Issue 8) in The Cochrane Library, MEDLINE (January 1966 to August 2012), and EMBASE (January 1980 to August 2012). Additionally, they searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform. These researchers included randomized controlled trials (RCTs) and quasi-RCTs in participants with confirmed GBS, with pain assessment as either the primary or secondary outcome. For cross-over trials, an adequate washout period between phases was required for inclusion. Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed the risk of bias of each study. A total of three short-term RCTs, which enrolled 277 randomized participants with acute phase GBS, were included. Risk of bias in the included studies was generally unclear due to insufficient information. None of the included studies reported the primary outcome selected for this review, which was the number of patients with self-reported pain relief of 50% or greater. One small study investigated 7-day regimens of gabapentin versus placebo. Pain was rated on a scale from 0 (no pain) to 10 (maximum pain). Among the 18 participants, significantly lower mean pain scores were found at the end-point (day 7) in the gabapentin phase compared to the end-point of the placebo phase (mean difference -3.61, 95% CI: -4.12 to -3.10) (very low-quality evidence). For adverse events, no significant differences were found in the incidence of nausea (risk ratio (RR) 0.50, 95% CI: 0.05 to 5.04) or constipation (RR 0.14, 95% CI: 0.01 to 2.54). A second study enrolling 36 participants compared gabapentin, carbamazepine, and placebo, all administered over 7 days. Participants in the gabapentin group had significantly lower median pain scores on all treatment days compared to the placebo and carbamazepine groups (p < 0.05). There were no statistically significant differences in the median pain scores between the carbamazepine and placebo groups from day 1 to day 3, but from day 4 until the end of the study, significantly lower median pain scores were noted in the carbamazepine group (p < 0.05) (very low-quality evidence). There were no adverse effects of gabapentin or carbamazepine reported other than sedation. One large RCT (223 participants, all also treated with IVIG) compared a 5-day course of methylprednisolone with placebo and found no statistically significant differences in the number of participants developing pain (RR 0.89, 95% CI: 0.68 to 1.16), the number of participants with decreased pain (RR 0.95, 95% CI: 0.63 to 1.42), or the number of participants with increased pain (RR 0.85, 95% CI: 0.52 to 1.41) (low-quality evidence). The study did not report whether there were any adverse events. The authors concluded that while management of pain in GBS is essential and pharmacotherapy is widely accepted as an important component of treatment, this review did not provide sufficient evidence to support the use of any pharmacological intervention for people with pain in GBS. Although reductions in pain severity were found when comparing gabapentin and carbamazepine with placebo, the evidence was limited and of very low quality. They stated that larger, well-designed RCTs are needed to further investigate the safety and effectiveness of potential interventions for patients with pain in GBS. Additionally, interventions for pain in the convalescent phase of GBS should be explored.

Pena et al. (2015) noted that pain is a common symptom in patients with Guillain-Barré syndrome (GBS), with intensity ranging from moderate to severe in most cases, and pain may persist even after the resolution of the disease. These researchers aimed to identify the most appropriate analgesic therapy for pain management in GBS patients by performing a systematic review of scientific articles on the treatment of pain in these patients, published between January 1985 and December 2012. They included only double-blind randomized controlled trials (RCTs) assessing the effectiveness of drugs for pain management in GBS patients. A total of four articles met the inclusion criteria: one evaluated the use of gabapentin, another evaluated carbamazepine, a third compared gabapentin to carbamazepine, and the last evaluated the use of methylprednisolone. Both carbamazepine and gabapentin were found to be useful for pain management, with patients experiencing lower-intensity pain with gabapentin treatment in the study comparing the two drugs. Methylprednisolone was not shown to be effective for reducing pain. The published data did not allow for the completion of a meta-analysis. The authors concluded that there is currently no robust evidence pointing to a single treatment option for this disorder and emphasized the need for further clinical studies with larger patient samples and longer durations to characterize types of pain for each patient and measure pain intensity objectively.

Tzachanis et al. (2014) reported on the case of a 79-year-old man with chronic lymphocytic leukemia who presented with GBS, exhibiting features overlapping with Miller Fisher syndrome and Bickerstaff brainstem encephalitis, along with positive anti-ganglioside GQ1b antibody, about six months after treatment with bendamustine and rituximab. His clinical and neurologic condition continued to deteriorate despite sequential treatment with corticosteroids, IVIG, and plasmapheresis; however, he ultimately achieved a complete and durable response to treatment with alemtuzumab. The findings of this single-case study need to be validated by well-designed studies.

Zhang et al. (2014) stated that GBS is an immune-mediated acute inflammatory disorder of the peripheral nervous system (PNS) in humans, characterized by inflammatory infiltration and damage to myelin and axons. Experimental autoimmune neuritis (EAN) serves as a useful animal model for studying the pathogenesis and treatment of GBS. Immunocompetent cells, along with cytokines produced by various cells, contribute to the inflammatory process of GBS and EAN by acting as mediators or effectors. Both GBS and EAN have long been attributed to T helper (Th) 1 cell-mediated autoimmune disorders. Interferon-gamma (IFN-γ) acts as a central mediator of Th1-mediated autoimmune disorders by steering the immune response toward a Th1 phenotype, inducing the differentiation of T cells to a Th1 phenotype, and inhibiting the development of Th2 cells in autoimmune disorders such as GBS. These investigators presented an overview of current knowledge on the inflammatory and immune-regulatory role of IFN-γ in GBS and EAN, which is important for evaluating whether IFN-γ can become a potential therapeutic target in GBS. The authors concluded that the analysis of the immunopathogenesis of GBS and EAN revealed the significance of IFN-γ in both diseases, although the complex mechanism of the delicate modulation of the cytokine remains under debate. They stated that more work is needed to explore its potential in immune-regulatory functions and to pave the way for new therapeutic strategies for GBS.

Pritchard and colleagues (2016) noted that PE and IVIG, but not corticosteroids, are beneficial in the treatment of GBS, while the effectiveness of other pharmacological agents remains unknown. This review was first published in 2011 and updated in 2013 and 2016. These researchers evaluated the effects of pharmacological agents other than PE, IVIG, and corticosteroids for GBS. On January 18, 2016, they searched the Cochrane Neuromuscular Specialized Register, Cochrane Central Register of Controlled Trials, Medline, and Embase for treatments for GBS, as well as clinical trials registries. They included all RCTs or quasi-RCTs of acute GBS (within 4 weeks from onset) of all types and degrees of severity, and in individuals of all ages, while discarding trials that investigated only corticosteroids, IVIG, or PE. They included other pharmacological treatments or combinations of treatments compared with no treatment, placebo, or another treatment. The authors concluded that the quality of the evidence was very low; three small RCTs comparing IFN beta-1a or brain-derived neurotrophic factor with placebo, and cerebrospinal fluid filtration with PE, showed no significant benefit or harm for any of the interventions. A fourth small trial indicated that the Chinese herbal medicine tripterygium poly-glycoside hastened recovery in people with GBS to a greater extent than corticosteroids, but this result requires confirmation. The authors stated that they were unable to draw any useful conclusions from the few observational studies they identified.

Plasmapheresis Versus Intravenous Immunoglobulin in the Management of Guillain-Barre Syndrome

Nandeesha et al. (2024) noted that GBS is a rare and debilitating autoimmune disorder that affects the PNS. Although the exact etiology of GBS is still unknown, it is thought to be triggered by a preceding gastro-intestinal (GI) infection in most of the cases. Clinical manifestations include limb weakness, areflexia, and sensory loss that can further progress to neuromuscular paralysis affecting the respiratory, facial, and bulbar functions. Both PE and IVIG have shown effectiveness in the treatment of GBS; however, it is still unclear which treatment approach is superior in terms of effectiveness. These researchers carried out a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. For appropriate studies and research, these investigators searched PubMed, PubMed Central (PMC), Medical Literature Analysis and Retrieval System Online (Medline), Science Direct, and Google Scholar.  Screening of studies was carried out based on relevance and inclusion and exclusion criteria. To check for bias, these researchers used relevant quality appraisal tools. Initially, they retrieved 2,454 articles. After removing duplicates and irrelevant papers, these researchers finalized 31 studies based on titles, abstracts, and reading entire articles. They excluded 14 studies because of poor quality; the remaining 17 papers were included in this review.  IVIG was equally effective as PE in improving primary outcomes and secondary outcomes. IVIG showed a slight advantage over PE in reducing the need for mechanical ventilation (MV) and hospital length of stay (LOS). However, in children, PE showed a slight edge in improving secondary outcomes. PE was associated with a slightly higher risk of AEs and post-treatment worsening symptoms compared to IVIG. IVIG was considered more user-friendly with a significantly lower patient discontinuation rate than PE.

Rescue Treatment (Intravenous Immunoglobulin or Plasma Exchange)

Walgaard and associates (2018) noted that a standard treatment for Guillain-Barré syndrome (GBS) patients who are unable to walk independently is one course of intravenous immunoglobulin (IVIG) at a dosage of 2 g/kg. Despite this treatment, some patients experience poor recovery, which may be partly due to the rapid consumption of IVIG, suggesting that they could benefit from a second course of IVIG. These investigators examined whether a second course of IVIG, administered one week after the start of the first course in patients with GBS and a predicted poor outcome, improves functional outcomes on the GBS disability scale after four weeks. Secondary outcome measures included adverse events (AEs), the Medical Research Council sum score, and GBS disability scores after 8, 12, and 26 weeks, as well as the length of hospital and intensive care unit (ICU) admissions, mortality, and changes in serum IgG levels. GBS patients aged 12 years and older with a poor prognosis, based on the modified Erasmus GBS outcome score (mEGOS) at one week after the start of the first IVIG course, are eligible for randomization in this double-blind, placebo-controlled clinical trial (IVIG or albumin). This study aims to determine if a second course of IVIG administered in the acute phase of the disease is safe, feasible, and effective in patients with GBS and a poor prognosis.

Alboudi and colleagues (2019) examined the effectiveness of rescue treatment (IVIG or plasmapheresis [PE]) in patients with GBS who did not respond or deteriorated after initial management with IVIG. These investigators conducted a retrospective review of the medical records of patients who responded poorly or did not respond to IVIG treatment. They compared the disability parameters of those who received second-line treatment with IVIG or PE (20 patients) to those who did not receive second-line treatment (19 patients). There was a statistically significant improvement in disability scores at one month for patients who received the rescue treatment (p = 0.033). However, there was no significant difference in disability scores at three and six months, nor in the length of ICU stay. The authors concluded that the optimal strategy for GBS patients who do not respond to the first course of treatment remains to be determined. Some trials have shown benefits or trends of benefit from a second modality of treatment. They noted that this study indicated that a second course of treatment for carefully selected patients may be beneficial. The researchers stated that randomized controlled trials (RCTs) should be conducted, including only patients who did not respond to first-line treatment, to be randomized to either a second-line treatment or supportive management.

The authors acknowledged several drawbacks of this study. First, it was a retrospective study, and there were no clear criteria established for selecting patients who should receive the rescue treatment; instead, the decision was made by the responsible physician based on their interpretation of the patient's clinical situation. Second, follow-up was limited because most patients were expatriates. Additionally, it was evident that more patients in the control group were lost to follow-up, and the increasing disability scores at follow-up suggested that less severely affected patients were the ones lost. Third, the wide range of ages introduced more variability in the results. Finally, financial issues sometimes influenced the decision not to provide a second course of treatment to some patients who might have otherwise benefited from it.

Second Course of IVIG

Algahtani and associates (2020) stated that Guillain-Barré syndrome (GBS) is a life-threatening form of inflammatory polyneuropathy. Immunotherapy with intravenous immunoglobulin (IVIG) has been successfully used in the treatment of GBS. In this case report, the researchers presented a severe axonal form of GBS that showed improvement after three cycles of IVIG. They suggested that repeated cycles of IVIG may be an option for treating severe forms of GBS that do not respond to the first course of treatment. Recent findings indicated that patients who are severely affected and exhibit severe gadolinium enhancement on magnetic resonance imaging (MRI) of the spine should be considered for re-treatment with IVIG. Although the cost of management was high, the outcome was excellent, which the authors deemed a reasonable approach. They concluded that this case report serves as an urgent call for conducting large, multi-center studies on the use of repeated cycles of IVIG in managing severe cases of GBS.

Verboon and colleagues (2020) compared the disease course in patients with GBS who had a poor prognosis (defined as being unable to walk independently) and were treated with either one or two courses of IVIG. From the International GBS Outcome Study, these researchers selected patients whose modified Erasmus GBS Outcome Score at week one predicted a poor prognosis. They compared those treated with one IVIG course to those treated with two IVIG courses. The primary endpoint, the GBS disability scale at four weeks, was evaluated using multi-variable ordinal regression. Of 237 eligible patients, 199 received a single IVIG course, while 20 received an "early" second IVIG course (1 to 2 weeks after the start of the first IVIG course) and 18 patients received a "late" second IVIG course (2 to 4 weeks after the start of IVIG). At baseline and one week, those receiving two IVIG courses were more disabled than those receiving one course. Compared to the one-course group, the adjusted odds ratio (OR) for a better GBS disability score at four weeks was 0.70 (95% CI: 0.16 to 3.04) for the early group and 0.66 (95% CI: 0.18 to 2.50) for the late group. The secondary endpoints did not favor a second IVIG course. The authors concluded that this observational study did not demonstrate better outcomes after a second IVIG course in GBS patients with poor prognosis. They noted that the study was limited by small sample sizes and baseline imbalances, and the lack of improvement likely motivated the decision to initiate a second IVIG course. The researchers stated that a prospective, randomized trial is needed to determine if a second IVIG course would improve outcomes in GBS, and such a trial is currently being conducted in the SID-GBS RCT.

Acupuncture

Fan and colleagues (2020) noted that GBS is the most common acute paralytic neuropathy. Many clinical trials indicated acupuncture provides a good effect as a complementary therapy of Western medicine for GBS. The objective of this systematic review protocol is to provide the evidence to examine the safety and effectiveness of acupuncture for the treatment of GBS. These investigators will search relevant RCTs examining the effect of acupuncture for GBS in following data-bases from start to October 2019: PubMed, Embase, the Cochrane Library, CINAHL Complete, National Digital Science Library, China National Knowledge Infrastructure, and Wanfang Database without language restriction. For articles that meet inclusion criteria, 2 researchers will extract the data information independently, and evaluate the risk of bias and trial quality by the Cochrane collaboration's tool. All data will be analyzed by RevMan V.5.3.3 statistical software. According to the Barthel index of activities of daily living (ADL) and the Medical Research Council (MRC) muscle scale, the safety and efficacy of acupuncture for GBS will be determined in this study. The authors concluded that this systemic review will provide high quality evidence to examine if acupuncture provides benefits for the treatment of GBS.

Bifidobacterium infantis

Shi and colleagues (2018) stated that GBS is a rare, autoimmune-mediated disease. The use of Bifidobacterium infantis is reportedly effective in alleviating GBS since they act by regulating T helper (Th) cells. In this study, these researchers explored the differentiation of T helper cell subsets in patients with GBS. They also evaluated the effect of GBS on Bifidobacterium levels in patients and the likely protective influence of this bacterium in alleviating the disease in an animal model. These investigators used flow cytometry, and real-time polymerase chain reaction (PCR) to determine the T cell subsets differentiation among 30 GBS patients and 20 healthy controls (HC). The concentration of Bifidobacterium was assayed by real-time PCR. Experimental autoimmune neuritis (EAN) animal model was established to support the protective role of Bifidobacterium in GBS. The expression of Th cells, Th2 and Th17 in the patients was significantly higher than that in the HC, while Treg cells decreased substantially. Moreover, the levels of Bifidobacterium in the GBS patients were considerably lower than those in the HC, the concentration of Bifidobacterium correlating with Th2 and Th17 subsets negatively. Treatment with Bifidobacterium significantly reduced the levels of Th2 and Th17 and promoted the levels of Treg cells. The authors concluded that Bifidobacterium alleviated GBS by regulating Th cells, although in-depth studies are needed to fully understand the mechanism of action.

Eculizumab

In a multi-center, double-blind, randomized phase-II clinical trial, Misawa and colleagues (2018) examined the safety and efficacy of eculizumab, a humanized monoclonal antibody against the complement protein C5, in patients with severe GBS. This was a 24-week, placebo-controlled trial carried out at 13 hospitals in Japan. Eligible patients with GBS were aged 18 years or older and could not walk independently (GBS functional grade 3 to 5). Patients were randomly assigned (2:1) to receive 4 weeks of IVIG plus either eculizumab (900 mg) or placebo; randomization was done via a computer-generated process and web response system with minimization for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade of less than or equal to 2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy end-point, these investigators pre-defined a response rate threshold of the lower 90% CI boundary exceeding 50%. Between August 10, 2015 and April 21, 2016, a total of 34 patients were assigned to receive either eculizumab (n = 23) or placebo (n = 11). At week 4, the proportion  of the patients able to walk independently (functional grade of less than or equal to 2) was 61% (90% CI: 42 to 78; n = 14) in the eculizumab group, and 45% (20 to 73; n = 5) in the placebo group. Adverse events (AEs) occurred in all 34 patients; 3 patients had serious AEs: 2 in the eculizumab group (anaphylaxis in 1 patient and intra-cranial hemorrhage and abscess in another patient) and 1 in the placebo group (depression). The possibility that anaphylaxis and intra-cranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. The authors concluded that the primary outcome measure did not reach the pre-defined response rate. However, these researchers noted that because this was a small study without statistical comparison with the placebo group, the safety and efficacy of eculizumab need to be examined in larger RCTs.

Efgartigimod

Zhang et al. (2024) noted that Guillain-Barré syndrome (GBS) is caused by immunoglobulin G (IgG) autoantibodies. Efgartigimod (Vyvgart) has the potential to increase IgG degradation, making it a promising therapeutic drug for GBS. In this case report, the researchers presented findings from two patients with post-infectious and acute flaccid paralysis who were bed-ridden upon admission. Nerve conduction studies indicated peripheral neuropathy, leading to a suspicion of GBS. The subjects were treated with two doses of efgartigimod (10 mg/kg) within five days. Their muscle strength improved gradually, and four weeks after the initial dose, they were able to walk independently. Following the first dose, Patient 1 reported muscle soreness, which subsided the next morning. Patient 2 was intubated due to respiratory failure the day after the initial dose but did not report any other adverse effects. The investigators noted that in GBS patients, two doses of efgartigimod (10 mg/kg) were effective in rapidly improving muscle strength, with a satisfactory safety profile. These findings suggested a potential role for efgartigimod in modifying the disease process in patients with GBS. The authors concluded that efgartigimod appeared safe and effective in the treatment of GBS and highlighted its potential as a novel therapeutic option. They emphasized the need for well-designed clinical trials to validate these preliminary findings.

Hughes (2024) stated that since the early 1900s, the clinical picture of GBS has been illustrated in multiple series, culminating in the ongoing International Guillain-Barré Syndrome study involving 2,000 patients. In the 1950s and 1960s, the inflammatory nature of the most common form, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), was described. In the 1990s, two axonal forms—acute motor-sensory axonal neuropathy and acute motor axonal neuropathy—were recognized. During the 1990s and early 2000s, it was demonstrated that these forms were due to antibodies against Campylobacter jejuni glycans that cross-react with glycolipids on axonal membranes. While the pathogenesis of AIDP remains unknown, T-cell responses to the compact myelin proteins P2 and P0, which cause experimental autoimmune neuritis, suggest that T cells play an important role. Randomized controlled trials (RCTs) in the 1970s and 1980s showed no benefit from corticosteroids, while trials in the 1980s demonstrated benefits from plasmapheresis (PE) and in the 1990s from IVIG. The author concluded that future research should focus on identifying biomarkers to distinguish subgroups with different treatment responses, defining the true natural history of the disease through population-based epidemiological studies, studying pathology in autopsies early in the disease, seeking causative antibodies, and confirming autoimmune T-cell responses in AIDP. In particular, the author mentioned planned or ongoing studies of complement inhibitors, imlifidase (an IgG-cleaving enzyme purified from Streptococcus pyogenes), and efgartigimod alfa (a neonatal Fc receptor blocker), which aim to reduce IgG levels. These treatments are contingent on the underlying pathogenesis of GBS being IgG- and complement-dependent.

Chen et al. (2025) noted that GBS is a serious neurological condition with limited therapeutic options. In a case-series study, these investigators examined the effects of sequential efgartigimod administration in patients with different GBS phenotypes and varying levels of disease severity. All three subjects tested positive for IgG antibodies against serum gangliosides. In Case 1, the patient was treated with 0.4 g/kg of IVIG for five days, showing minimal recovery. After receiving three weekly doses of efgartigimod (10 mg/kg), the patient achieved independent ambulation 19 days post-onset, along with a reduction in serum ganglioside antibody titers and total IgG levels. Case 2 involved a middle-aged man with Miller Fisher syndrome (MFS)-GBS overlap, who experienced worsened autonomic dysfunction following IVIG treatment. After three doses of efgartigimod, the patient showed symptom improvement within one month, alongside a reduction in IgG antibody levels. In Case 3, a 27-year-old man with MFS-GBS overlap, initially unresponsive to IVIG, showed significant improvement in ophthalmoplegia following two doses of efgartigimod, with his serum ganglioside antibodies eventually becoming undetectable. The authors concluded that these findings suggested that sequential efgartigimod treatment may reduce serum anti-ganglioside antibody titers and potentially shorten the disease course in severe GBS and MFS-GBS overlap syndrome. Furthermore, it may offer clinical benefits for patients with GBS who have a poor or no response to IVIG, especially in treating ophthalmoplegia. The researchers stated that further investigations are needed to validate these preliminary findings.

These investigators noted that a previous study (Zhang et al., 2024) indicated that efgartigimod alone was effective in treating GBS, positioning it as a potential new therapeutic option. However, given the limited current research on efgartigimod for GBS, further studies are necessary to clarify the specific mechanisms underlying this therapy. They mentioned that a randomized-controlled, double-blind, phase-II clinical trial is currently underway, comparing the safety and effectiveness of efgartigimod and IVIG as independent treatments for GBS; the findings from this study may provide further insights.

Leukocyte Trafficking Inhibitors

Liu and co-workers (2018) noted that GBS, the most common cause of acute neuromuscular weakness and paralysis worldwide, encompasses a group of acute immune-mediated disorders restricted to peripheral nerves and roots. Immune-mediated attack of peripheral nervous system myelin, axons or both is presumed to be triggered by molecular mimicry, with both cell- and humoral-dependent mechanisms implicated in disease pathogenesis. Good circumstantial evidence exists for a pathogenic role for molecular mimicry in GBS pathogenesis, especially with its axonal forms, providing insights that could guide future immunotherapy; IVIG and PE are the most commonly prescribed immunotherapies for GBS with variable efficacy dependent on GBS subtype, severity at initial presentation and other clinical and electrophysiologic prognostic factors. The mechanisms of action of IVIG and PE are not known definitely. Despite recent significant advances in molecular biology that provide insights into GBS pathogenesis, no advances in therapeutics or significant improvements in patient outcomes have occurred over the past three decades. We summarize the clinical aspects of GBS, its current pathogenesis and immunotherapy, and highlight the potential of leukocyte trafficking inhibitors as novel disease-specific immunotherapeutic drugs.

Neuromuscular Electrical Stimulation in Rehabilitation of Guillain-Barre Syndrome

Harbo and colleagues (2019) noted that in GBS, patients often develop muscle atrophy from denervation and immobilization. In a pilot study, these researchers examined the feasibility, safety, and effectiveness of neuromuscular electrical stimulation (NMES) on muscle wasting in the early phase of GBS. A total of 17 patients were randomized to receive 20 mins of muscle fiber stimulation followed by 40 mins of NMES of the right or left quadriceps muscle with the untreated side as control. Cross-sectional area (CSA) of the muscle measured by ultrasound (US) and isometric knee extensor strength were the primary and secondary outcome measures. No treatment related adverse effects were recorded. Change in CSA was -0.25 cm2 (CI: -0.93 to 0.42) on the stimulated side versus -0.60 cm2 (CI: -1.32 to 0.11) on the non-stimulated side (p = 0.08).  No effect was observed on muscle strength. The authors concluded that NMES appeared safe and feasible in the early phase of GBS. Moreover, these researchers stated that further studies are needed to examine the effect on muscle function.

Per-Oral Endoscopic Myotomy for Guillain-Barre Syndrome-Associated Achalasia

Shin and colleagues (2017) stated that GBS-associated achalasia is a very rare disease of uncertain cause. These researchers reported the case of a patient diagnosed with GBS-associated type I achalasia who was successfully treated with per-oral endoscopic myotomy (POEM). A 30-year old man who was diagnosed with GBS 3 months before was referred to the authors’ department with dysphagia and meal-related regurgitation. The results of esophagography, endoscopy, and high-resolution manometry (HRM) revealed type I achalasia. POEM that utilized a sub-mucosal tunneling technique was performed to treat the GBS-associated type I achalasia. After POEM, smooth passage of a contrast agent into the stomach was shown in follow-up esophagography, and follow-up HRM revealed a decrease in the mean integrated relaxation pressure of 22.9 mmHg to 9.6 mmHg. The patient remained without dysphagia for 7 months, even though the patient's neurological problems were not fully resolved. The authors concluded that POEM may be a safe and effective treatment for GBS-associated type I achalasia.

Rituximab for the Treatment of Guillain-Barre Syndrome

Motamed-Gorji and colleagues (2017) addressed emerging biological approaches for the treatment of Guillain-Barré syndrome (GBS). They conducted an extensive electronic literature search from April 2016 to July 2016, selecting original articles, clinical trials, systematic reviews (with or without meta-analysis), and case reports. Reviewers screened the titles and abstracts of the papers to determine eligibility, and full texts of the remaining articles were retrieved. The researchers focused on data concerning emerging biological therapeutic agents, including anti-C5 monoclonal antibody (eculizumab), anti-C1q monoclonal antibody, anti-T cell monoclonal antibody, anti-CD2 monoclonal antibody, anti-L-selectin monoclonal antibody, anti-CD20 monoclonal antibody (rituximab), anti-CD52 monoclonal antibody (alemtuzumab), and various cytokine targets. None of these agents has been approved for the treatment of GBS by the Food and Drug Administration (FDA). The authors concluded that the findings presented in their review herald promising results for the use of these biological targets.

In a systematic review and meta-analysis, MacIsaac and colleagues (2018) examined the safety and efficacy of rituximab in autoimmune diseases that are also treated with IVIG. The most common indications for immune modulation with IVIG, as identified from a 2012 regional audit in Canada, included chronic inflammatory demyelinating polyneuropathy (CIDP), immune thrombocytopenia (ITP), myasthenia gravis (MG), multifocal motor neuropathy, GBS, systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and pemphigus vulgaris. These investigators searched Medline, Embase, and the Cochrane Library until July 2016 for studies evaluating rituximab in each of these conditions. The primary outcome in this meta-analysis was clinical response at 6 months, defined by disease-specific criteria in randomized trials. The researchers also calculated pooled proportions of responders within disease types from observational studies. A total of 95 rituximab studies were identified: 86 were observational studies involving patients with ITP (n = 1,746), SLE (n = 1,047), pemphigus vulgaris (n = 564), SS (n = 138), MG (n = 66), and CIDP (n = 31), while 9 were randomized controlled trials (RCTs) (n = 992) in patients with ITP, SLE, and SS that compared rituximab with placebo plus standard care. Among the randomized trials, response rates were higher with rituximab (RR, 1.38; 95% CI: 1.05 to 1.83). The pooled proportion of rituximab responses ranged from 94% (95% CI: 88% to 98%) for pemphigus vulgaris to 48% (95% CI: 30% to 66%) for CIDP. Rituximab was generally well-tolerated in observational studies; however, in the randomized trials, adverse events (AEs) were more common in the rituximab group. The authors concluded that rituximab is an immune-modulating agent with biological activity across many autoimmune conditions. They stated that these findings support the use of comparative trials with broad eligibility criteria to evaluate rituximab as an alternative to IVIG in autoimmune diseases.

Sugammadex for the Treatment of Guillain-Barre Syndrome

Tezcan and colleagues (2017) noted that sugammadex encapsulates and inactivates rocuronium and vecuronium. It is used to reverse neuromuscular blockade from these non-depolarizing agents. The safety of sugammadex in patients with neuromuscular disease has not been established. Guillain-Barre Syndrome (GBS) is a neuromuscular disease characterized by acute inflammatory polyneuropathy. Patients with GBS may exhibit autonomic dysfunction, chronic pain, abnormal reactions to neuromuscular blocking agents, and may require post-operative mechanical ventilation. These investigators reported the successful use of sugammadex to reverse rocuronium in a patient with chronic GBS, who presented for a hemi-colectomy. These findings need to be validated in well-designed studies.

The Zipper Method

Kesici and colleagues (2019) noted that IVIG and PE are proven treatments for GBS. Despite these treatments, the prognosis for severe GBS is still unsatisfactory. These researchers sought for a logical timing for PE-IVIG synergy, which may improve outcome in severe GBS requiring mechanical ventilation. In an open-label study, a total of 9 pediatric severe GBS patients requiring mechanical ventilation were treated with novel treatment strategy named as "zipper method". In this method, following diagnosis of GBS, PE was started immediately. In the 1st session of PE, 1.5 volume of patients' plasma was removed by using 5% albumin as replacement solution. At the end of the PE session, 0.4 g/kg IVIG infusion was started immediately; 2nd PE session was applied with 1 volume change after 24 hours from the end of the IVIG infusion. Each PE session was followed by IVIG infusions. This PE-IVIG cycle was repeated for 5 times. Among the 9 patients, the mean mechanical ventilation duration was 7 (5 to 14) days and the mean hospital stay was 18 (10 to 30) days. Medical Research Council sum score was increased in all patients, especially after the 3rd session. All patients survived and all patients were able to walk unaided on the 28th day of admission. The authors concluded that the zipper method as a novel treatment modality appeared to reduce mortality, expedite weaning from mechanical ventilation, and shorten hospital stay, with excellent outcome in severe GBS patients, who required intensive care. These researchers stated that this technique stands as a promising immunomodulation strategy for various scenarios.

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References