Guillain-Barré Syndrome

Kazim A. Sheikh, MBBS Peripheral Nerve and Motor Neuron Disorders p. 1184-1204 October 2020, Vol.26, No.5 doi: 10.1212/CON.0000000000000929
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PURPOSE OF REVIEW This article reviews the clinical features, diagnosis and differential diagnosis, prognosis, pathogenesis, and current and upcoming treatments of Guillain-Barré syndrome (GBS).

RECENT FINDINGS GBS is an acute inflammatory neuropathic illness with striking clinical manifestations and significant morbidity. A substantial proportion of patients with GBS do not respond to current immunomodulatory therapies (ie, plasma exchange and IV immunoglobulin [IVIg]), highlighting the need for new therapies. Prognostic models that can accurately predict functional recovery and the need for artificial ventilation have emerged. These models are practical, and online calculators are available for clinical use, facilitating early recognition of patients with poor outcome and the opportunity to personalize management decisions. Clinical and experimental studies have identified innate immune effectors (complement, macrophage lineage cells, and activating Fcγ receptors) as important mediators of inflammatory nerve injury. Two complement inhibitors are undergoing clinical testing for efficacy in GBS.

SUMMARY GBS is the most common cause of acute flaccid paralysis in the United States and worldwide. New treatments for GBS have not emerged since the 1990s. Our understanding of the pathogenesis of this disorder has progressed, particularly over the past decade; as a result, new therapeutic agents targeting different components of the complement cascade are at advanced stages of clinical development.

Address correspondence to Dr Kazim Sheikh, Department of Neurology, University of Texas-Medical School at Houston, 6431 Fannin St, Houston, TX 77030, Kazim.Sheikh@uth.tmc.edu.

RELATIONSHIP DISCLOSURE: Dr Sheikh serves on the medical advisory board of the GBS/CIDP Foundation International and on the editorial board of Scientific Reports. Dr Sheikh has received personal compensation for speaking engagements from CSL Behring and research/grant support from the Department of Defense (W81XWH-18-1-0422) and the National Institute of Neurological Disorders and Stroke (R21NS107961).

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Sheikh reports no disclosure.

INTRODUCTION

The term Guillain-Barré syndrome (GBS) encompasses a group of heterogeneous but related disorders of peripheral nerves that have acute onset and almost always a monophasic course. GBS is often postinfectious and usually paralytic, and a large body of inferred evidence supports the autoimmune nature of the syndrome. The two most common forms of GBS are acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). The incidence rate of GBS in the United States and Europe is estimated to be 0.81 to 1.89 (median 1.1) cases per 100,000 person-years. The incidence increases steadily with advancing age, and the disorder is marginally more frequent in males than females. The lifetime risk of developing GBS is 1 in 1000.

AIDP is the most common form of the disease in North America and Europe, accounting for up to 90% of patients, whereas AMAN accounts for less than 10%. The relative incidence of AMAN is much higher in Asia, South America, and Central America. These variations in incidence of AIDP and AMAN may reflect differences in the immunogenetic repertoire and infectious pressures in different geographic regions.

Most commonly used diagnostic criteria for GBS were developed at the behest of the National Institute of Neurological Disorders and Stroke (NINDS) in the context of the swine flu vaccine and GBS in 1976–1977. These criteria are only relevant to major/paralytic forms of GBS; they have been reaffirmed and remain convenient for research and clinical use. Two clinical features are requisite for the diagnosis of paralytic GBS: progressive muscle weakness that must occur in more than one limb with relative symmetry on both sides of the body and areflexia, implying loss of reflexes and/or hypoactive reflexes. Features that strongly support, cast doubt upon, or rule out the diagnosis of GBS are summarized in table 3-1. The Brighton Collaboration set forth diagnostic criteria that provide different levels of certainty for the standardization of case definitions to improve vaccine safety. A limitation of these criteria is the inclusion of a monophasic course that becomes evident after follow-up, which limits their use in clinical diagnosis at the time of presentation.

CLINICAL FEATURES

The diagnosis of GBS and related syndromes remains primarily clinical. Early recognition is crucial because diagnostic tests such as nerve conduction studies and CSF analysis may not be positive in the first week, and immune therapies should be initiated as soon as possible. This section focuses on the clinical features and diagnosis of GBS; subsequent sections discuss diagnostic testing and therapies.

The clinical manifestations of GBS are diverse, reflecting various degrees of injury to motor, sensory, and autonomic nerve fibers along the spinal roots and cranial and peripheral nerves. The majority of patients with AIDP present with sensory symptoms or pain (eg, backache, radicular painful paresthesia); however, findings on sensory examination are less frequent. Although the first symptoms are often sensory, AIDP is a predominantly motor polyradiculoneuropathy characterized by acute progressive symmetric weakness of proximal and distal muscles. The classic pattern of limb muscle weakness is ascending, but weakness can start in proximal muscles. Rarely, the weakness can be confined to the legs in the so-called paraparetic variant. These motor and sensory symptoms are associated with reduced or absent deep tendon reflexes. Approximately 25% to 30% of patients develop respiratory muscle weakness and require mechanical ventilation. More than half of patients have cranial nerve involvement, most commonly facial weakness, ophthalmoplegia, difficulty swallowing, and altered taste. Dysautonomia of highly variable severity is seen in the majority of patients and can manifest as reduced sinus arrhythmia, sinus tachycardia, and other arrhythmias; labile blood pressure; orthostatic hypotension; abnormal sweating; and pupillary abnormalities. Bladder and bowel involvement can be seen, but if patients have severe sphincter dysfunction at presentation, spinal cord or cauda equina disorders should be considered.

Among the axonal variants, the AMAN form of GBS is most common and is characterized by motor findings with weakness typically beginning in the legs but, in some patients, affecting arms or cranial muscles initially. Loss of deep tendon reflexes corresponds to the severity of muscle weakness, likely reflecting relative sparing of muscle afferent fibers (type Ia sensory fibers), which are prominently affected in AIDP. A small proportion of Japanese patients with AMAN are reported to have normal or exaggerated reflexes. Sensory impairment is minimal, and autonomic involvement is less common than in AIDP. The acute motor-sensory axonal neuropathy (AMSAN) subtype is a less common and, in general, considered more severe form of axonal GBS. Patients with AMSAN typically have severe involvement of sensory and motor nerve fibers, a greater likelihood of autonomic involvement, and a poor prognosis.

Miller Fisher syndrome, the most common minor subtype of GBS, is characterized by a triad of ophthalmoplegia, ataxia, and areflexia. Double vision is the typical presenting symptom. In practice, facial and bulbar weakness have been included as part of the syndrome. A significant proportion of patients do not have the classic triad or have overlapping features that are beyond the triad. Those who have features beyond the classic triad have Miller Fisher syndrome–related disorder. An altered level of consciousness or hyperreflexia with external ophthalmoplegia and ataxia reflects central nervous system involvement indicative of Bickerstaff brainstem encephalitis. It has been proposed that Miller Fisher syndrome–related disorders are a clinical continuum of conditions with Bickerstaff brainstem encephalitis on one end and Miller Fisher syndrome on the other. The inclusion of Bickerstaff brainstem encephalitis under the rubric GBS is debated as clinically discernible peripheral nerve involvement may not be obvious by bedside examination. Overlapping forms of Miller Fisher syndrome and AIDP can also be seen and are termed Miller Fisher syndrome–GBS overlap syndromes. Other formes frustes of GBS include the pharyngeal-cervical-brachial variant and acute autonomic neuropathy. Pure sensory neuropathies with an acute onset, a monophasic course (in the absence of systemic disorders) with either axonal or demyelinating electrophysiology, or small fiber involvement may be viewed as part of the GBS spectrum.

GBS has a monophasic course in more than 95% of patients, and recurrence has been reported in less than 5% of cases. About two-thirds of patients with GBS have an antecedent respiratory or diarrheal illness in the 4 to 6 weeks before the onset of neurologic symptoms. By definition, the disease nadir is reached within 4 weeks, although two-thirds of patients reach nadir within 14 days. The progressive phase of the disease is followed by a highly variable static period before the onset of recovery (figure 3-1). Recovery typically begins within 2 to 4 weeks of nadir but can be delayed up to 6 months. The majority of patients make a complete recovery over 6 to 12 months.

Residual deficits affecting activities of daily living and quality of life are not uncommon. The most common residual features include fatigue, pain, paresthesia, and reduced muscle strength. Serious disability includes inability to walk independently in approximately 20% of patients. Modern intensive care has significantly reduced the mortality rate of GBS, but it remains 3% to 7% in recent series. Advanced age, severity of disease, mechanical ventilation, pulmonary and cardiac complications, and systemic infections increase the risk of mortality. Death can occur during the acute progressive phase or during the recovery phase. Most deaths are attributed to cardiac arrest secondary to autonomic disturbance, respiratory failure or infection, or pulmonary embolism.

INVESTIGATIONS

Laboratory testing for the diagnosis of GBS includes nerve conduction studies and EMG, CSF analysis, and serologic studies, if warranted. Nerve conduction studies and EMG, particularly relevant for paralytic forms, provide supportive data by confirming the involvement of peripheral spinal roots and/or nerves to differentiate between axonal and demyelinating subtypes and may provide prognostic information by estimating the extent and location of axonal injury. A single study around the time of admission may not be sufficient to accurately discriminate between axonal and demyelinating variants, and serial studies may be necessary, which are also required for prognostic information. Although serial nerve conduction studies and EMG are useful diagnostically, they are not always practical; at present, the treatment of axonal and demyelinating variants is similar, and, as discussed below, useful clinical prognostic tools are available. The main purpose of CSF analysis is to exclude other diagnoses. The utility of antiglycan (ganglioside) serology for the diagnosis and management of GBS is not established and, thus, is not necessary for routine clinical care of patients with AIDP. The presence of specific antiganglioside antibodies can support the diagnosis of minor variants or formes frustes of GBS, but, because of the turnaround time of the results in the United States, these studies often do not influence treatment decisions.

Nerve conduction studies are often normal early in the disease course, although prolonged minimal F-wave latencies (or absent responses) reflecting involvement of proximal nerve trunks or roots is a common finding during the first week. A sural sparing pattern, in which the sural sensory response is preserved but the upper limb sensory responses are absent or of reduced amplitude, is another nerve conduction study finding that can be present early in the course of AIDP. Other nerve conduction changes peak around 2 weeks after symptom onset in the majority of patients. The typical demyelinating changes on motor nerve conductions in AIDP include prolonged distal motor latencies, reduced motor nerve conduction velocities, prolonged F-wave latencies (or absent responses), increased temporal dispersion, and conduction blocks at noncompressible sites. In contrast, axonal variants of GBS show decreased compound muscle action potential (CMAP) amplitudes in AMAN and decreased CMAP and sensory nerve action potential (SNAP) amplitudes in AMSAN in the absence of typical demyelinating features except conduction block. Motor nerve conduction changes mimicking reversible conduction block without temporal dispersion can be seen in AMAN and can be a cause of confusion in classifying AMAN and AIDP early in the disease course. This feature is attributed to pathologic alterations at the nodes of Ranvier and is termed reversible conduction failure. Serial nerve conduction studies may be required to accurately distinguish between AMAN and AIDP as improvement in the conduction block in AMAN is not associated with the development of abnormal temporal dispersion.

CSF analysis characteristically shows normal cell counts and elevated protein levels, termed albuminocytologic dissociation. This feature is seen in more than 80% of patients after the first week. Lumbar puncture after initiation of IV immunoglobulin (IVIg) therapy can be diagnostically challenging as IVIg can increase CSF protein and white blood cell counts. In 10% to 15% of patients, a mild (<50 cells/mm3) increase in white blood cell count can be present. CSF cell counts greater than 50 cells/mm3 should raise suspicion for Lyme disease, human immunodeficiency virus (HIV), cytomegalovirus, or an infiltrative leptomeningeal process; an increased cell count may also raise suspicion for paralytic rabies (in certain clinical settings) or poliomyelitis (in certain geographic locations).

Antiglycan antibodies (mostly antigangliosides) are the most commonly recognized autoimmune markers in all forms of GBS. Gangliosides are sialic acid–containing glycosphingolipids enriched in peripheral nerves. Antiganglioside antibodies are complement-fixing IgG isotypes (IgG1 and IgG3). GM1, GD1a, GalNAc-GD1a, and GM1b gangliosides are implicated as target antigens in AMAN. IgG anti-GM1 and anti-GD1a antibodies can be detected in up to 50% to 60% of patients with AMAN in Japanese and northern Chinese populations, respectively. The frequency of anti–GalNAc-GD1a and anti-GM1b antibodies in motor-predominant syndromes is 10% to 15%. Anti-GQ1b antibodies (often cross-reactive with GT1a) occur in more than 80% of patients with Miller Fisher syndrome, providing the strongest association between antibodies to a specific ganglioside and a GBS subtype. Antiglycan antibodies with various specificities (mostly LM1 and GM1) also occur in up to 25% to 30% of patients with AIDP. Recent studies have suggested that antibodies to mixtures of gangliosides and other glycolipids can be correlated with different variants of GBS, but this does not substantially increase sensitivity or positive reactivity. Antiganglioside antigen testing for GM1, asialo-GM1, GD1b, GD1a, GalNAc-GD1a, GT1a, and GQ1b is commercially available in the United States.

PROGNOSIS

A number of factors, including age (older than 40 years), preceding diarrhea, short interval from onset to nadir of the disease, need for mechanical ventilation, high-grade deficits on the GBS disability scale (table 3-2), and persistently low CMAP amplitudes, are considered poor prognostic factors. Predictability of two issues is of importance: the need for mechanical ventilation acutely (during the admission for GBS) and the long-term functional outcome (arbitrarily defined as at 6 or more months after GBS onset). A Dutch group has developed validated clinical models with relatively high accuracy to predict the need for ventilation and long-term functional outcome, and an online calculator is available. The Erasmus GBS Respiratory Insufficiency Score (EGRIS) is based on the severity of weakness (quantified as the Medical Research Council [MRC] sum score), the number of days between the onset of weakness and admission, and facial or bulbar weakness; it allows prediction of the need for mechanical ventilation during the first week after admission. This model can be used at the time of admission to triage patients with a high EGRIS score to an intensive care unit setting. The Modified Erasmus GBS Outcome Score (mEGOS) is a long-term functional outcome model that is based on three parameters: age, severity of weakness quantified as the MRC sum score, and the presence or absence of preceding diarrhea. This model can be applied at the time of admission or 1 week after admission and predicts the probability of walking independently at 1, 3, and 6 months. The severity of weakness quantified by the MRC sum score is a common denominator in these models and is emerging as an important variable for predicting acute and long-term prognosis. Efforts are under way to correlate the MRC sum score and serum neurofilament light chain levels (reflecting cumulative axonal injury) with prognosis.

PATHOLOGY

The pathology of AIDP and axonal variants of GBS is well defined. AIDP is characterized by demyelination and multifocal perivascular and endoneurial T-cell infiltrations with patchy involvement of spinal roots and nerve trunks and distal nerve segments. In some series, a proportion of cases showed immunopathologic changes suggestive of antibody- and complement-mediated demyelinating nerve injury. Macrophages are particularly prominent at sites of extensive myelin breakdown and contain fragments of degenerating myelin, and macrophage-mediated myelin stripping (contact-dependent injury) is considered a hallmark of AIDP pathology (figure 3-2). The spectrum of pathologic changes in AIDP supports the role of T-cell– and antibody-mediated immune injury, but the contribution of humoral and cellular mechanisms may substantially vary in individual cases.

The pathology of AMSAN was initially described in Canadian patients who had severe axonal degeneration in nerve roots and distal nerves without inflammation or demyelination. The pathology of AMAN was characterized in a series of ultrastructural and immunopathologic studies in patients from northern China (figure 3-3). These studies indicated a paucity of T-cell inflammation and evidence of antibody and complement deposition. The earliest pathologic changes were centered on motor nodes of Ranvier and included nodal lengthening with distortion of paranodal myelin. This change was associated with macrophages overlying nodes of Ranvier, which extended their processes through the Schwann cell basal lamina covering the node and apposed the axolemma. Macrophages then extended beneath the myelin terminal loops and entered the periaxonal space, dissecting the axon from the adaxonal Schwann cell plasmalemma and advancing into the internodal periaxonal space, where they typically surrounded a condensed-appearing axon. This arrangement appeared to be stable for some time, but the axon subsequently underwent wallerianlike degeneration (contact-dependent injury). Immunohistology showed IgG and C3d (membrane-bound cleaved product of C3) at the nodes of Ranvier initially and later at paranodal and internodal axolemma. In some cases of AMAN, nodal changes were not associated with significant axon degeneration; this restricted nodal injury is believed to correlate with quick recovery in patients with AMAN, in particular, those with reversible conduction failure.

In sum, the pathology of AIDP, AMAN, and AMSAN shares endoneurial inflammatory effectors, including components of the innate immune system (complement and macrophage lineage cells) that have upregulation of activating FcγRs, and macrophages that induce contact-dependent Schwann cell/myelin (AIDP) and axon (AMAN/AMSAN) injury. Detailed pathologic characterization of AIDP and AMAN has prompted the development of new therapeutics targeting innate immune effectors, particularly the complement cascade.

PATHOGENESIS

GBS is considered to be an autoimmune disorder. Autoimmune conditions are characterized by an aberrant activation of the adaptive immune response, with T cells and B cells reacting (independently or in concert) to tissue-specific self-antigens in the absence of any direct microbial or tumor invasion of the affected tissue(s), in this case, peripheral nerves. The precise mechanisms for the development of GBS remain incompletely understood. There is general consensus that GBS is triggered by environmental agents in genetically susceptible hosts. It is likely that a single gene does not impart susceptibility to develop GBS but that multiple genes are needed to induce aberrant immunity, and environmental exposures may need to occur in a particular sequence, or in tandem, to provoke autoimmunity. The genes that impart host susceptibility to develop GBS are not firmly established. Additionally, random correct alignment of multiple genetic and environmental risk factors must occur in a correct sequence, with relatively short latencies, before the development of an acute autoimmune disorder such as GBS. Alternatively, multiple exposures, including possible infectious or noninfectious events, occurring during a critical window when individuals are more susceptible to them, are necessary to overcome tolerance. Breakdown of self-tolerance (the unresponsiveness of the adaptive immune system to self-antigens) is an important variable for the development of autoimmune disorders such as GBS. Regulatory T cells function to maintain tolerance and suppress other immune cells, such as B cells, T cells, and dendritic cells, to prevent autoimmune disease. In human studies, the number of regulatory cells present during the acute phase of GBS is decreased, and these cells are increased following treatment. Stimulation or modulation of the immune system from a triggering event can disrupt the balance needed to maintain immunologic homeostasis, making the host susceptible to autoimmune disease. This complex construct provides a potential explanation for the extreme rarity with which GBS develops in an individual after exposure to common environmental triggers.

Environmental and Other Triggers

Infections of the gastrointestinal and upper respiratory tract are common triggers of GBS, and Campylobacter jejuni, a gram-negative rod, is the most common trigger of GBS (particularly for axonal forms), reported in 13% to 72% of patients in different series, with an overall prevalence estimated around 30%.C. jejuni is one of the most common causes of bacterial gastroenteritis worldwide, but GBS is an extremely rare complication of this infection. It is estimated that less than 2 in 10,000 cases of C. jejuni infection develop GBS within a 2-month period. The exact susceptibility factors of human host or attributes of C. jejuni that determine whether GBS follows the infection are not known. Case control studies have shown that upper respiratory tract infection caused by cytomegalovirus, Epstein Barr virus, Mycoplasma pneumoniae, and Haemophilus influenzae are also triggering events, as is nonrespiratory infection with hepatitis E. C. jejuni, M. pneumoniae, and H. influenzae have been shown to express glycolipid antigens either by structural methods or by cross-reactive binding of antiglycolipid antibodies in GBS sera. Cytomegalovirus can induce the expression of GM2 gangliosidelike antigens in cell cultures.

Recently, Zika virus, a mosquito-borne RNA flavivirus, was also identified as a potential trigger for GBS; a French Polynesian study reported an increase in GBS cases during a Zika virus outbreak in 2013-2014. Most post–Zika virus cases in this series were AMAN, and a substantial proportion had antiglycan antibodies. Similarly, post-Zika GBS was observed in South America during a major outbreak in 2015-2016. Many patients with post-Zika GBS show a parainfectious rapid disease onset.

In late 2019, an outbreak of illness caused by the novel coronavirus SARS-CoV-2 was identified, and the disease was labeled COVID-19. In March 2020, the World Health Organization declared the illness a pandemic. A number of neurologic complications have been reported in association with COVID-19 infections, and hypogeusia and hyposmia are perhaps the most common. A number of case reports and series from China and Europe have also reported GBS in association with COVID-19 infection, including demyelinating, axonal, and Miller Fisher variants. CSF studies have generally shown albuminocytologic dissociation and negative polymerase chain reaction (PCR) for COVID-19. Patients with GBS who present with fever, cough, hypogeusia, or hyposmia should be tested for COVID-19. Moreover, there should be disease vigilance for GBS in patients with COVID-19 infection, which could allow early initiation of immune therapy.

Less common noninfectious triggering events for GBS include trauma, vaccinations, immunosuppression, and pregnancy. In 1968, Arnason and Asbury reported a series of cases from Massachusetts General Hospital that developed postsurgical polyneuritis after surgical trauma, and release of sequestered peripheral nerve antigens was implicated as a trigger. A large 2018 French study that examined the association of GBS and recent surgery using nationwide French data concluded that GBS was moderately associated with any type of recent surgery and more strongly associated with bone and digestive organ surgery. Rare sporadic cases of GBS have been described following a number of vaccines. In 1976, influenza vaccination was causatively implicated with exposure to the swine flu vaccine, although subsequent surveillance found only one additional case of GBS for every 1 million vaccines. The risk of developing GBS is much higher following influenza infection than it is from vaccination. Patients who develop their first attack of GBS within 6 to 8 weeks after any vaccination (postvaccination cases) may be at particularly high risk and should not receive the same vaccine again. The risk of relapse with influenza vaccination in patients who have recovered from GBS not temporally associated with vaccination is extremely low. Individuals aged 65 or older and those with chronic serious disorders, including chronic bronchitis and emphysema, are at increased risk of significant complications from influenza and other infections, and age-appropriate vaccinations should not be withheld unless a clear contraindication exists.

Molecular Mimicry

Antiganglioside antibodies are considered to be pathogenetically relevant to AMAN and Miller Fisher syndrome, but the pathologic relevance of antiglycan (except antigalactocerebroside) antibodies in AIDP is questioned because relevant experimental data are lacking. Several lines of evidence support the molecular mimicry hypothesis and pathogenicity of antiganglioside antibodies in the axonal and Miller Fisher syndrome subtypes of GBS. Work over the past 3 decades has led to the hypothesis that postinfectious molecular mimicry is the predominant pathophysiologic mechanism in GBS, particularly in Miller Fisher syndrome and axonal variants, supported by the following key observations:

  • C. jejuni enteritis is the most commonly recognized antecedent infection in GBS
  • Different variants of GBS, particularly Miller Fisher syndrome and motor axonal variants, are strongly associated with specific antiganglioside antibodies
  • The lipooligosaccharides of C. jejuni isolates from patients with GBS carry relevant gangliosidelike moieties
  • Gangliosides, the purported target antigens, are enriched in nerve fibers
  • Pathologic and immunopathologic studies in the axonal forms indicate antibody-mediated axonal injury or dysfunction
  • Active immunization animal studies have directly linked C. jejuni lipooligosaccharides to the development of antiganglioside antibodies and neuropathy
  • Passive transfer of antiganglioside antibodies can produce nodal and axonal injury in experimental models that mimics the pathology seen in axonal GBS

Although the pathogenesis of AIDP is largely undetermined, evidence of molecular mimicry exists in a small minority of patients with AIDP. A number of patients develop GBS after M. pneumoniae infection. M. pneumoniae expresses antigens that cross-react with galactocerebroside (GalC), a glycolipid that is enriched in the myelin sheath of Schwann cells in peripheral nerves. These patients have anti-GalC antibodies and commonly have the demyelinating/AIDP form of GBS. Experimental animal studies demonstrate that immunization with GalC and passive intraneural administration of anti-GalC antibodies produce inflammatory demyelinating nerve pathology resembling the demyelination seen in patients with AIDP.

Experimental and animal studies have attempted to define the immune effectors that constitute the final common pathway of endoneurial inflammation that mediates nerve injury in demyelinating and axonal variants in an effort to identify therapeutic targets for drug development. That antigen specificity and the nature of adaptive T-cell and B-cell autoimmune responses are not well defined, particularly for AIDP. In contrast, strong evidence exists for the role of specific antiglycan antibodies in the pathogenesis of axonal and the Miller Fisher variants of GBS. Adaptive autoimmunity uses the powerful effector functions of cells of the innate immune system, including monocytes/macrophages, to induce target tissue inflammation and injury in autoimmune disorders. Pathologic studies in demyelinating and axonal GBS indicate a central role for macrophage populations (including contact-dependent injury), which are the key components of the innate immune system and endoneurial inflammation. Recognizing all antigen-specific adaptive immune responses that initiate/orchestrate nerve injury in autoimmune disorders such as GBS may not be necessary if downstream innate immune effectors mediating nerve injury are identified. Cumulatively, clinical and experimental studies have identified innate immune effectors that include classic complement pathway, macrophage-microglia lineage cells, and activating FcγRs as final common pathway(s) of inflammatory nerve injury in GBS.

DIFFERENTIAL DIAGNOSIS AND OTHER ACUTE NEUROPATHIES

The paralytic forms of GBS are relatively easy to recognize with a low probability of diagnostic confusion. The differential diagnosis for GBS is quite wide and depends on the clinical subtype, patient’s age, and geographic locale. It includes central conditions such as encephalomyelitis and rhombencephalitis for Miller Fisher syndrome–Bickerstaff brainstem encephalitis spectrum disorders. Paralytic GBS can be confused with transverse myelitis or myelopathy early on, and clinicians should have a low threshold for spinal cord imaging. The differential diagnosis for paralytic GBS includes the following:

  • Infections affecting anterior horn cells, including West Nile virus, enteroviruses (children more than adults), rabies (paralytic form), and polio (in appropriate geographic regions)
  • Neuromuscular junction disorders, including myasthenic crisis and botulism (particularly in young children)
  • Acute severe myopathies, including immune-mediated necrotizing myopathies (eg, those associated with antibodies against signal recognition particle and 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA]) reductase, acute myositis, and rhabdomyolysis
  • Periodic paralysis
  • A number of other neuropathic and polyradiculopathic conditions that present acutely or subacutely and can be confused with GBS (table 3-3)

TREATMENT

Two immunomodulatory treatments, IVIg and plasma exchange, are used for the treatment of GBS, but provision of multidisciplinary medical supportive care remains the cornerstone of therapy during the acute phase to prevent complications and facilitate recovery. All patients with GBS should be admitted to a hospital with an intensive care unit, except for patients with very mild disease who have reached a plateau phase or are already recovering. The principles of GBS care include monitoring for major risks to avoid complications arising from acute respiratory failure, dysautonomia, bulbar weakness, progressive muscle weakness, and immobility. Close monitoring of forced vital capacity, blood pressure, heart rate and rhythm, and bulbar function is necessary to identify patients with deteriorating respiratory function or autonomic instability or those at risk of aspiration who require intensive care. Close monitoring of respiratory parameters and use of EGRIS should allow elective (preemptive) intubation, which is less traumatic for patients and families and less prone to complications. About one-third of patients require admission to an intensive care unit. Important aspects of medical management include prevention of nosocomial infections, prophylaxis for deep venous thrombosis, management of bowel and bladder dysfunction, pain management, early physical therapy and rehabilitation to avoid complications of immobility (including pressure ulcers), eye care in those with severe facial weakness, and psychosocial support.

Randomized clinical trials have shown the efficacy of plasma exchange up to 4 weeks after the onset of symptoms and IVIg within 2 weeks after onset in hastening recovery. All trials have used the GBS disability scale (table 3-2) for enrollment and as the primary outcome measure. Patients with a GBS disability score of 3 or higher were enrolled in these clinical trials, and an improvement of 1 point on this scale at 4 weeks was considered treatment responsiveness. A standard dose of plasma exchange is to exchange 200 mL/kg to 250 mL/kg in four to five sessions over 7 to 14 days. The clinical trials of IVIg administered a total of 2 g/kg given over 4 to 5 days, although, in practice, this dose is sometimes administered over a shorter period in selected patients. Although head-to-head comparisons of IVIg and plasma exchange in clinical trials have shown equivalent efficacy, IVIg is considered first-line treatment because of the ease of administration and widespread availability. In patients whose treatment is being initiated more than 2 weeks after onset, it may be reasonable to consider plasma exchange, as clinical trials have shown efficacy of this treatment in patients enrolled up to 4 weeks after onset. Conceptually, early treatment is preferable as it could limit endoneurial inflammation and nerve injury; data from North American and French Cooperative Group studies support this notion as the beneficial effects of plasma exchange were most marked in patients enrolled within 1 week after onset.

A large proportion of patients do not show significant response to initial immunomodulatory treatment(s) and pose a special challenge as no evidence-based recommendations are currently available for this group of patients. Randomized controlled trials indicate that 40% to 50% of patients did not improve significantly after plasma exchange or IVIg treatment, defined as improvement by 1 or more points on the GBS disability scale at 4 weeks after treatment (primary outcome measure). Two approaches are sometimes used for this group of patients. One is the use of combination therapy (ie, plasma exchange followed by IVIg or, less commonly, IVIg followed by plasma exchange). The Plasma Exchange/Sandoglobulin GBS Trial compared plasma exchange followed by IVIg to either modality alone and found no significant differences in treatment groups, indicating that combination therapy is not superior to monotherapy with either modality. Although IVIg followed by plasma exchange is counterintuitive (ie, the plasma exchange removes the previously infused circulating immunoglobulin), this approach is sometimes attempted in patients with severe disease who do not respond to IVIg alone. A small retrospective study examined this combination therapy and found that combination therapy was not superior to IVIg alone. In general, the combination of IVIg and plasma exchange, however sequenced, is discouraged. The second approach is the use of high-dose or a second dose of IVIg in patients for whom the first IVIg treatment has failed. This approach carries a risk of complications, and the ISID (International Second IVIg Dose) study, a recently published observational study, did not show better outcomes after a second IVIg course in GBS with poor prognosis. A prospective randomized single-center trial examining whether a second course of IVIg improves outcome is ongoing, and its results are awaited. The author’s approach in such patients is to use a single treatment modality, early tracheostomy and percutaneous endoscopic gastrostomy (if warranted), and early discharge to a rehabilitation or long-term acute care facility (case 3-1).

CASE 3-1

A 36-year-old woman was admitted to the hospital with Guillain-Barré syndrome (GBS) 3 days after the onset of neurologic symptoms. At admission, she had proximal greater than distal weakness in her legs more than her arms, areflexia, and distal sensory loss, and her forced vital capacity was 2.83 L. She reported preceding diarrhea.

Her motor nerve conduction studies (see grid) were notable for prolonged right median nerve distal latency, partial motor conduction block in the right fibular (peroneal) nerve, and prolonged F-wave latencies. Sensory nerve conduction studies (see grid) showed inexcitable median and ulnar nerves, reduced radial evoked sensory nerve action potential (SNAP) amplitude, and relatively preserved sural SNAP, a pattern recognized as sural sparing, as shown in the test results. CSF analysis showed no white blood cells, and protein was elevated at 51 mg/dL.

She was diagnosed with the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) variant of GBS, and IV immunoglobulin (IVIg) was administered for 5 consecutive days without any complications. Her symptoms worsened after initiation of IVIg; she became quadriplegic within 48 hours after admission while on IVIg treatment, and her forced vital capacity dropped to less than 1 L, requiring ventilatory support. No clinical improvement was seen 1 week after completion of IVIg. Her family was extremely concerned about the lack of responsiveness to IVIg. A number of options were considered, including repeat electrical studies and lumbar puncture, nerve biopsy, a second dose of IVIg, and plasma exchange. The multidisciplinary team concluded that none of these approaches were evidence based and decided to consider predictive modeling for GBS prognosis; they shared this information with the patient and her family and instituted supportive medical management. The patient’s Modified Erasmus GBS Outcome Score (mEGOS) score was 10 at 7 days after admission, predicting a 40% probability of walking independently at 3 months and 60% probability by 6 months.

The patient underwent tracheostomy and percutaneous endoscopic gastrostomy and was transferred to a long-term acute care facility. Four weeks later, the patient was on a tracheostomy collar without ventilator support with mild recovery of proximal muscle function in the arms but still confined to bed. Six months later, she was ambulating using a cane.

COMMENT

A substantial proportion of patients with GBS deteriorate during or shortly after treatment with IVIg or plasma exchange, and no evidence has shown that combination therapy or repeat IVIg is helpful. Prognostic modeling is practical for clinical use to make supportive management decisions in such patients. In the past, some experts would prescribe additional IVIg for patients who did not respond to a first dose because a study reported that patients with large increments of serum IgG levels after standard IVIg treatment (2 g/kg) recovered more quickly than those with smaller increments. However, a second course of IVIg can be complicated by anaphylaxis, acute kidney injury, thromboembolic events, or hemolytic anemia. Further, the ISID (International Second IVIg Dose) study, an observational study, did not show better outcomes after a second course of IVIg in GBS with poor prognosis. It is prudent not to use a second dose of IVIg in patients with GBS who do not respond to the first dose of IVIg because of potential risks until evidence-based data are available to support this treatment paradigm.

Treatment-related fluctuations, defined as worsening of at least 1 point on the GBS disability scale after initial improvement or stabilization within 8 weeks after disease onset, are another related aspect. Treatment-related fluctuations can be seen in up to 10% of patients treated with IVIg or plasma exchange. No evidence-based recommendations are available for patients with treatment-related fluctuations, and general consensus is retreatment with the original treatment modality as the preferred approach.

Although the incidence of GBS is slightly lower in children compared to adults, the immunomodulatory treatment recommendations are similar. Clinical trial data show that IVIg hastens total recovery. A total IVIg dose of 2 g/kg can be administered over 2 days instead of a 5-day regimen with the caveat that treatment-related fluctuations can be more common with a shorter infusion paradigm. One trial compared IVIg with plasma exchange in children requiring mechanical ventilation and found that overall recovery was comparable, but plasma exchange was slightly superior in shortening ventilatory support. Both plasma exchange and IVIg can be used in pregnant women; however, IVIg is less likely to cause hemodynamic instability.

Randomized controlled data do not exist for the use of immunotherapy in minor variants of GBS, including Miller Fisher syndrome and related disorders. Some anecdotal observations report beneficial effects of IVIg in the treatment of minor variants. It is not unreasonable to err on the side of using immunomodulatory treatments in patients with minor variants of GBS if the treatment is unlikely to increase the risk of treatment-related adverse events, because these cases reflect immune/inflammatory nerve injury, albeit restricted, and some variants such as Miller Fisher syndrome have a propensity to spread and involve limb muscles.

Trends

An urgent need exists for new immunomodulatory treatments as a substantial proportion of patients with GBS do not respond to current therapies. Emerging therapies with potential for GBS include complement and neonatal Fc receptor (FcRn) inhibitors and hypersialylated IVIg. The development of these therapies is driven by current opinion favoring the role of IgG autoantibodies and innate immune effectors such as complement and activating FcγRs. Complement inhibitors are already in GBS clinical trials. Eculizumab, a humanized antibody against complement component C5, has been studied in a small phase 2 trial in Japan as an add-on therapy with IVIg. This treatment was found to be relatively safe, and significantly more patients were able to run at 6 months in the eculizumab-treated group compared to the placebo group, which was a secondary outcome measure. A phase 3 trial is anticipated with this agent. Another complement inhibitor, a humanized antibody against the C1q component of complement is being studied in a phase 1b trial in the United States as an add-on therapy with IVIg. This trial is currently recruiting. FcRn functions to protect IgG from catabolism, and antagonism of this receptor shortens the half-life of circulating pathogenic antineural autoantibodies, which can reduce antibody-mediated nerve injury in experimental models relevant to GBS. In this context, a number of FcRn inhibitors are at advanced stages of clinical development for various indications, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and a rationale exists to extend the use of these agents to GBS. Another novel agent currently in human safety studies with potential to treat GBS is hypersialylated IgG, an investigational glyco-modified product derived from commercially available IVIg with an approximately tenfold enhanced anti-inflammatory activity compared to IVIg. Preclinical studies indicate that sialylated IgG fractions have tenfold more efficacy than IVIg in animal models of autoantibody-mediated neuropathy relevant to GBS. Hypersialyated IgG likely works via modulation of FcγR functions.

PATIENT SUPPORT AND EDUCATION

Patients with GBS and their families may benefit from community resources and education. The GBS/CIDP Foundation International is a nonprofit organization with the mission to support patients with GBS, CIDP, and related conditions and their families. They are committed to education, research, and advocacy.

CONCLUSION

GBS is the most common acute neuropathic illness requiring hospitalization, which presents as acute flaccid paralysis in the majority of patients. Early diagnosis and treatment are imperative. Medical supportive care, immunomodulatory treatments, and prognostic modeling are vital components of acute management. The need for more potent immunomodulatory therapies still exists, and ongoing research promises to identify new disease-modifying treatments targeting relevant immunopathomechanisms. The need of proregenerative therapies to enhance nerve repair, particularly for patients with severe disease, axonal injury, and residual deficits, is unmet.

KEY POINTS

  • Guillain-Barré syndrome (GBS) encompasses a spectrum of acute neuropathic disorders, with muscle weakness being the cardinal manifestation in the majority of patients. It is the most common cause of acute flaccid paralysis in the United States and worldwide.
  • The National Institute of Neurological Disorders and Stroke diagnostic criteria for paralytic GBS are simple and practical for routine clinical use; the key features of the criteria include symmetric flaccid weakness, decreased deep tendon reflexes, and exclusion of alternative causes.
  • Although the first symptoms of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) are often sensory, it is primarily a motor polyradiculoneuropathy causing symmetric weakness of proximal and distal muscles. The classic pattern is of ascending weakness, but symptoms may also begin proximally.
  • Of patients with GBS, 25% to 30% will require intubation because of respiratory muscle weakness or pharyngeal muscle weakness (airway protection); patients should be closely monitored for the need of mechanical ventilation.
  • Miller Fisher syndrome, the most common minor subtype of GBS, is characterized by a triad of ophthalmoplegia, ataxia, and areflexia.
  • An altered level of consciousness or hyperreflexia with external ophthalmoplegia and ataxia reflects central nervous system involvement indicative of Bickerstaff brainstem encephalitis. Miller Fisher syndrome–related disorders are considered a clinical continuum with Bickerstaff brainstem encephalitis on one end and Miller Fisher syndrome on the other.
  • Residual symptoms after GBS are common and include fatigue, pain, paresthesia, and reduced muscle strength.
  • Nerve conduction studies and EMG provide confirmation of an acute neuropathic process and may differentiate between demyelinating and axonal variants of GBS. They are often relatively normal early in the course; serial studies are often necessary and may be useful for prognostication.
  • Partial motor nerve conduction block without temporal dispersion may be seen in acute motor axonal neuropathy because of reversible conduction failure at the nodes of Ranvier. Other demyelinating features, such as reduced conduction velocity and prolonged minimal F-wave or distal motor latencies, are absent.
  • CSF analysis typically shows albuminocytologic dissociation. A mild pleocytosis (<50 cells/mm3) can be seen in up to 10% to 15% of patients with GBS. A pleocytosis of greater than 50 cells/mm3 suggests an alternative diagnosis.
  • Prognostic models for GBS based on clinical parameters, including Medical Research Council (MRC) sum score, which are collected as part of standard care, can reliably predict the need for mechanical ventilation in the first week and functional outcomes at 4 weeks to 6 months after admission.
  • AIDP, acute motor axonal neuropathy, and acute motor-sensory axonal neuropathy share common pathologic features, including activation of components of the innate immune system such as complement activation and upregulation of Fc receptors for IgG (FcγRs). These are promising therapeutic targets.
  • It is believed that GBS is triggered by environmental exposures in genetically susceptible hosts.
  • Campylobacter jejuni is the most common trigger for GBS, particularly the axonal forms, with an estimated prevalence of 30%. However, the risk of GBS with C. jejuni infection is low (less than 2 in 10,000).
  • Noninfectious events, including trauma, vaccinations, immunosuppression, and pregnancy, may rarely trigger GBS.
  • The risk of developing GBS following influenza infection is much higher than the risk of GBS following vaccination. Patients who develop GBS following influenza or any other vaccine should not receive the same vaccine again.
  • Postinfectious molecular mimicry is the predominant pathophysiologic mechanism in Miller Fisher syndrome and axonal variants and in patients who develop AIDP following Mycoplasma pneumoniae infection.
  • Supportive and intensive care remains the cornerstone of management of patients with GBS during the acute phase of this monophasic illness, and immune therapy with plasma exchange or IV immunoglobulin (IVIg) hastens recovery.
  • Randomized clinical trials indicate that IVIg and plasma exchange hasten recovery in patients with GBS, and both treatments were found to be equally efficacious.
  • Of patients with GBS treated with IVIg or plasma exchange in clinical trials, 40% to 50% did not have a clinical response (ie, did not meet primary end point), emphasizing the need for new therapies.
  • Randomized controlled data indicate that combination treatment with plasma exchange followed by IVIg is not superior to treatment with IVIg or plasma exchange alone, and anecdotal observations indicate that combination treatment with IVIg followed by plasma exchange is no better than IVIg alone. Combination therapy is generally discouraged.
  • No evidence- or consensus-based recommendations are available for additional immunomodulatory treatments for patients with GBS for whom initial IVIg or plasma exchange treatment has failed, and further supportive medical management should be tailored according to individual needs in such cases.
  • Biologics targeting the complement cascade are at various stages of clinical trials in GBS, and neonatal Fc receptor (FcRn) inhibitors (which can reduce IgG autoantibody burden) and modulators of FcγR are at advanced stages of clinical development with potential applicability to GBS.

ACKNOWLEDGMENTS

Dr Sheikh is supported by the US Department of Defense (W81XWH-18-1-0422) and the National Institute of Neurological Disorders and Stroke (R21NS107961).

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