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179

Guillain-Barré Syndrome Ximena Arcila-Londono, M.D. 1

Richard A. Lewis, M.D. 2

1 Henry Ford Health System Department of Neurology 2 Department of Neurology, Wayne State University School of

Medicine, Detroit, MI

Address for correspondence and reprint requests Ximena Arcila-Londono, 2799 West Grand Blvd., Detroit, MI, 48202 (e-mail: [email protected]).

Abstract Keywords

► Guillain-Barré syndrome ► acute inflammatory demyelinating polyradiculoneuropathy ► acute motor axonal neuropathy ► acute motor and sensory axonal neuropathy ► Fisher syndrome

Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy, which has various clinical presentations and both axonal and demyelinating forms. The original description of “ascending paralysis” encompasses the most common varieties: the primary demyelinating form, acute inflammatory demyelinating polyneuropathy (AIDP), and some of the axonal forms, acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN). However, there are now welldocumented acute “monophasic” polyneuropathies that have a different clinical phenomenology than that described originally by Guillain, Barré, and Strohl: Miller Fisher syndrome, pure sensory neuropathy/neuronopathy, pandysautonomia, and oropharyngeal variant. Here the authors review both typical GBS (AIDP, AMAN, and AMSAN), and variant syndromes with a focus on clinical and diagnostic features, pathologic findings, pathogenesis, and treatment.

Epidemiology What we now recognize as Guillain-Barré syndrome (GBS) was first described in detail in 1859, by the French physician Jean Baptiste Landry. However, Guillain, Barré, and Strohl provided the first comprehensive description, including clinicopathologic features and cerebrospinal fluid (CSF) findings. Additional reports of similar cases followed, and in 1949 a clinicopathologic report of 50 cases of fatal areflexic paralysis showed that the clinical presentation may correlate with axonal or demyelinating findings.1 It is now clear that GBS is a true syndrome that encompasses several specific disorders, including the demyelinating form, acute inflammatory demyelinating polyneuropathy (AIDP) and axonal forms, acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN). Other clinical presentations include the Miller Fisher syndrome (a triad of ophthalmoplegia, ataxia, and areflexia),2 pure sensory neuropathy/neuronopathy, pandysautonomia, oropharyngeal variant, and overlap syndromes.3 The incidence of GBS in North America and Europe is 1–2/100,000/year in adults, and 0.4–1.4/100,000/year in

Issue Theme Neuromuscular Therapy from Bench to Bedside; Guest Editor, A. Gordon Smith, MD

children.(4) Annual incidence estimates from other world regions vary from as low as 0.40/100,000 in Brazil 5 to 2.5/ 100,000 in Curacao.6 More importantly, the relative frequency of axonal versus demyelinating types varies by location. In North America and Europe, AIDP is the predominant form, observed in up to 90% of GBS cases.7 By contrast, axonal variants account for 40 to 60% of cases in Asia.8–10 In North America, Miller Fisher syndrome is uncommon, accounting for 1 to 7% of all GBS cases,11,12 but in Japan and Taiwan it is much more common, accounting for up to 19% of cases.13,14 Half of GBS patients have an antecedent infection, usually less than 4 weeks prior to symptom onset. The most common infections in adults are respiratory (22–53%) and gastrointestinal (6–26%). Preceding infections are more common in children (67–85%) with a greater percentage of respiratory (50–70%) than gastrointestinal (7–14%).15 The most commonly recognized pathogens include Campylobacter jejuni, Cytomegalovirus, Epstein–Barr virus, and Mycoplasma pneumoniae.16 Most cases of GBS are sporadic, although rare clusters have been reported after bacterial enteritis.6 The association of vaccination and GBS is controversial. Detailed analysis of the combined 1992–1993 and 1993–1994

Copyright © 2012 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0032-1329196. ISSN 0271-8235.

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Semin Neurol 2012;32:179–186.

Guillain-Barré Syndrome

Arcila-Londono, Lewis

influenza vaccine campaigns in the United States reported a marginally increased risk of GBS (one extra case of GBS for every 1 million vaccines) during the 6 weeks following immunization.17 However, a large epidemiologic study from the General Practice Research Database in the United Kingdom suggests influenza vaccination carries no increase in GBS risk (relative risk 0.74, 95% confidence interval [CI] 0.41–1.4), whereas acute influenza carries a significantly increased relative risk of GBS of 16.64 (95% CI 9.37–29.54) within 30 days of infection.18

The differential diagnosis of GBS is that of other etiologies of acute quadriparesis, including myelopathies and other acute neuropathies and polyradiculopathies. The diagnosis of GBS, and evaluation for other potential diagnoses, is based on clinical features as supportive tests, such as CSF studies and nerve conduction studies, often remain normal within the first week. Serologic studies for antecedent infections are occasionally useful and antiganglioside antibody titers are associated with specific axonal or variant syndromes.

Electrodiagnostic Features

Clinical Features of Guillain-Barré Syndrome The diagnosis of GBS is usually straightforward, although it may be more challenging with variant syndromes and atypical presentations. Guillain-Barré syndrome is a monophasic illness that nadirs in less than 4 weeks. Key features include four-limb weakness, hyporeflexia or areflexia, and raised CSF protein concentrations without pleocytosis (►Table 1).19 Back and neck pain are common and may be severe. Most patients note paresthesias, although prominent sensory signs are atypical (except in sensory variants). Approximately 50% of GBS patients reach their nadir in 2 weeks and over 85% in 3 weeks, differentiating it from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), which continues to progress for 8 weeks or longer.20 One or more episodes of worsening after initial therapy and improvement are observed in 8 to 16% of GBS patients. Worsening more than 9 weeks after onset, or occurrence of two episodes of worsening suggest a diagnosis of CIDP.21

Table 1 Assessment of Current Diagnostic Criteria for Guillain-Barré Syndrome (GBS)

Electrodiagnostic studies are helpful in confirming the localization and confirming axonal versus demyelinating physiology. Early abnormalities are observed in over 80% of patients, and most will become abnormal with serial studies.7 Frequent early findings include prolonged F-wave latencies, absent H-reflexes, and the pattern of a normal sural but abnormal median sensory response.22 Patients with primary axonal forms may have early reduction in compound muscle action potentials (CMAP) amplitudes.23,24 It is important that multiple nerves be evaluated. The cardinal features of primary demyelination (prolonged motor distal latencies, slowed motor conduction velocities, prolonged minimal F wave latencies, and partial motor conduction block and/or abnormal temporal dispersion) typically evolve over the first one to two weeks after presentation. Recognition of these features is critical in confirming a diagnosis of AIDP and in differentiation from AMAN and AMSAN (and other axonal radiculoneuropathies). There are over 15 published criteria for AIDP and CIDP and the clinician must be aware that these criteria were largely developed for research studies, and not all patients with AIDP will fulfill them. The interested reader is referred to a recent review.25

The Spectrum of Guillain-Barré Syndrome Required for diagnosis of GBS Progressive motor weakness of more than one limb plus areflexia/hyporeflexia Strongly supportive of the diagnosis of GBS Clinical features Peak onset is reached within 4 weeks. Relative symmetry Mild sensory symptoms or signs Cranial nerve involvement, usually symmetric Autonomic dysfunction may be present. Absent fever at onset of symptoms Cerebrospinal fluid Elevated protein concentration within one week, or rising Less than 10 mononuclear leukocytes/mm3 Other potential etiologies have been determined unlikely due to clinical features and/or negative testing as necessary. Source: Modified from Asbury and Cornblath, 1990.24 Note. The mean cerebrospinal fluid cell count of patients with human immunodeficiency virus (HIV) and lower CD4 counts is 23 cells/ mm3.47 Seminars in Neurology

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As already noted, GBS encompasses a spectrum of physiologic and regional/anatomic variants. Although these variants share key clinical features, they have distinct, though sometimes overlapping, clinical phenomenology and pathophysiology. An understanding of disease mechanism informs the following discussion of therapeutic strategy.

Acute Inflammatory Demyelinating Polyneuropathy Acute inflammatory demyelinating polyneuropathy (AIDP) is the most common form of GBS in the United States and Western Europe. Pathologic studies reveal patchy multifocal mononuclear cell infiltrates throughout the peripheral nervous system, more prominent in areas with clinical involvement, such as distal intramuscular nerve segments and proximal nerve roots. Macrophages are recruited and mediate segmental demyelination.26 Reports of complement activation in autopsies of patients who died within 9 days of symptom onset suggests the antibodies may bind to epitopes of Schwann cells, leading to complement activation and macrophage invasion.27 Proving this theory has been challenging and studies are conflicting. More recent data suggest antibodies

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Guillain-Barré Syndrome

AMAN and AMSAN Differentiating axonal variants from AIDP in an individual patient can be difficult based on clinical features alone, although AMSAN is often more severe with an early nadir and more frequent autonomic dysfunction. However, axonal forms have a unique pathophysiology. In AMAN, macrophages attack the nodes of Ranvier and invade periaxonally early in the disease,32 The degree of macrophage-related axonal degeneration correlates with clinical outcomes.33 AMAN patients may have high titers of IgG anti-GD1a antibodies. Because most of these gangliosides are expressed in both sensory and motor nerves, there appears to be a “structural” requirement for target recognition.34 Several other antibodies have been described (►Table 2). GM1 is expressed at the paranode and is important in architectural maintenance and clustering of voltage-gated sodium channels.35 Anti-GM1 antibodies may bind to and block these

channels, causing transient conduction block, explaining the rapid recovery of some patients with AMAN following therapy. AMSAN most likely has similar pathophysiology, but dorsal as well as ventral roots are involved. The reason AMSAN is typically more severe than other GBS forms is unknown.

Regional Variants Although typical GBS can be categorized by physiology (axonal vs demyelinating), other GBS variants are classified based on specific system (e.g., sensory) or anatomic features. Many variants are associated with specific antibodies (►Table 2). Miller Fisher syndrome: Miller Fisher syndrome is named for Charles Miller Fisher. The classic triad of Miller Fisher syndrome is areflexia, ataxia, and ophthalmoplegia2 The clinical features are variable and sometimes include facial weakness, oropharyngeal weakness (dysarthria), and internal ophthalmoparesis. Pupillary abnormalities, blepharoptosis, dysesthesias, minimal weakness and sensory abnormalities (despite profound ataxia), and problems with micturition can be seen. In general, most patients recover well and are able to go back to their routine lives.36 Electrodiagnostic findings vary with some patients demonstrating low amplitude or absent sensory nerve action potential amplitudes, rare demyelinating features or normal nerve conduction studies.37 When a similar syndrome occurs with encephalitis and/or corticospinal tract signs, it is recognized as Bickerstaff’s brainstem encephalitis.38

Table 2 Antibodies in Guillain-Barré Syndrome (GBS) Disorders Clinical Presentation

Target Antigen

Acute inflammatory demyelinating polyneuropathy (AIDP)

Unknown

Acute motor axonal neuropathy (AMAN)

181

Localization in Humans

Localization in Animals

GM1, GD1a, GalNac-GD1a, GM1b

Myelinated axons in both motor and sensory nerves, node of Ranvier, abaxonal Schwann cell surfaces*

Axolemma at node/ paranode/myelin of motor nerve, dorsal root ganglia, motor nerve terminals

GD1a

Motor myelinated fibers in ventral root cross section

Motor nerve terminal

GalNAc-GD1a

Close to nodes of Ranvier: nodal and paranodal axolemma

Axon, motor nerve terminal

GM1b (distal weakness)

Undetermined

Undetermined

Acute motor and sensory axonal neuropathy (AMSAN)

GM1, GM1b, GD1a

Undetermined

Undetermined

Fisher syndrome

GQ1b

Paranodal myelin of ocular motor nerves, part of DRG neurons

Large neurons in DRG and motor nerve terminals

Sensory ataxic GBS

GD1b

Large Neurons in DRG, paranodal myelin

Large neurons in DRG, paranodal myelin

Bulbar palsy, pharyngealcervical-brachial variant GBS

GT1a

Undetermined

Undetermined

Acute Pandysautonomia

Unknown

Source: Modified from Kaida K, Ariga T, Yu RK.71  Proposed. Seminars in Neurology

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may react to ganglioside epitopes, including some present in the lipid membrane.28 Results of studies with the “combinatorial glycoarrays” are underway.29 Cell-mediated immunity is also important. T cells reactive to gangliosides and myelin proteins have been found in patients with AIDP.30 Activated CD4 T-helper cells may bind to specific antigens. The number, but not the function, of CD4 þ CD25þ regulatory T cells is reduced in the acute phase of GBS.(31)

Arcila-Londono, Lewis

Guillain-Barré Syndrome

Arcila-Londono, Lewis

Over 95% of Miller Fisher syndrome and two-thirds of Bickerstaff’s brainstem encephalitis patients have anti-GQ1b IgG antibodies.39 The presence of anti-GQ1b antibodies in both Bickerstaff’s brainstem encephalitis and Miller Fisher syndrome implies a common pathologic process, called by some as “GQ1 b antibody syndrome.”40 Hyperintense lesions may be seen on T2-weighted magnetic resonance images (MRIs) of the brainstem, thalamus, and/or cerebellum in 10 to 30% of patients. The primary pathologic process has been difficult to define. Single reports of patients with Miller Fisher syndrome with little weakness showed very mild inflammation and segmental demyelination in the spinal roots (sensory and motor), as well as cranial nerves III, VII, X, and XI.41,42 GQ1b antibodies have been implicated in abnormalities at the motor nerve terminal, either pre- or postsynaptic (alteration of quantal release, reduced postsynaptic currents).43 More recently, complement activation at the presynaptic terminal has been proposed as a primary mechanism.44 Pharyngeal-cervical-brachial GBS presents with neck, arm, and oropharyngeal weakness, and upper extremity areflexia. Leg strength and reflexes are usually preserved. Findings may be asymmetric.45 Electrophysiologic features may include mild conduction velocity slowing,10 low upper extremity CMAP amplitudes,46 or can be normal. Up to 40% of patients have anti-GQ1b IgG antibodies. Other antibodies include anti-GT1a IgG antibodies and others.47,48 Most case reports report improvement with various treatments, with poor response of bulbar palsy.48 There are no pathologic descriptions of this variant. Sensory variants often present as an acute sensory ataxic neuropathy (ASAN). Some patients have antibodies to GD1b and GQ1b gangliosides supporting autoimmunity. Antibody positive patients may respond to immunotherapy.49 Detailed pathologic studies are lacking. Acute pandysautonomia presents with orthostatic hypotension, gastroparesis, constipation, diarrhea, ileus, micturition problems, sudomotor/pupillary abnormalities, and neuropathic pain, at times severe, reaching its peak within 1 to 3 weeks. Some, but not all, patients experience sensory loss.50 Symptoms are mostly due to parasympathetic and cholinergic dysfunction. Half of patients experience significant disability.50 Various immunotherapies have been tried for this condition, including intravenous immunoglobulin (IVIg) and high-dose steroids.51,52

Treatment Strategies The therapeutic strategy for GBS incorporates both supportive and disease-altering therapies such as IVIg and plasma exchange (PEx). Recent studies have focused on maximizing currently available therapies, development of new immunomodulatory approaches, or enhancing axon regeneration or axonal function.

Supportive Care Management of symptoms and systemic consequences of GBS and prevention of complications is a critical and often underSeminars in Neurology

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appreciated aspect of therapy. Mortality in GBS is often related to failure in other organ systems. ►Table 3 provides a list of the important aspects of care as outlined by a consensus group.53 An early and critical issue is management of respiratory weakness and deciding if and when to intubate a patient. Until the respiratory status is stable, the patient should be monitored very closely, preferably in an intensive care unit. There should be a low threshold for intubation and if forced vital capacity (FVC) falls below 1200 ml or 15 ml/kg and/or negative inspiratory force drops below 20 cm H2O, intubation and respiratory support should be considered. Although noninvasive ventilation can provide some support in certain instances, if there is bulbar dysfunction it is not advisable to use noninvasive ventilation. It is particularly important to closely monitor the trend in ventilatory function. Patients with rapidly declining FVC often require intubation at values well above 1200 ml. Intubation is required in 25% of patients. One study found that 22% of 377 patients required ventilator support in the first week of hospitalization with another 4% after the first week. The major predictors of mechanical ventilation were admission within 3 days of onset of symptoms, presence of facial or bulbar weakness, and the presence of marked global weakness. The investigators developed a 7-point scoring system, the Erasmus GBS Respiratory Insufficiency Score (EGRIS) that can determine the relative risk of needing mechanical ventilation.54

Immunotherapy There is consensus that patients who are unable to walk unassisted should be treated as soon as possible. Although there is no absolute evidence about ambulatory patients, it is rational to consider intervention for patients who are continuing to progress or have limb weakness, impaired pulmonary function, moderate-to-severe swallowing problems, or autonomic dysfunction. PEx was the first evidence-based therapy for GBS. PEx has demonstrated efficacy when used within the first 4 weeks of symptoms. The response may be better within 2 weeks, especially in patients unable to walk.55 PEx results in a 50% reduction in the need for mechanical ventilation and a 13% higher chance of recovering full strength at one year.56 The treatment typically consists of five exchanges (plasma volumes) administered every other day. The mechanism of action is not clearly known, but may involve the removal of autoantibodies, cytokines, and other inflammatory mediators.57 IVIg was found to have equivalent efficacy with PEx in 1992.58 A Cochrane Review found that there was no significant difference between the two treatments in regards to mechanical ventilation, death, or residual disability.59 Although most studies administered 0.4 g/kg bodyweight daily for 5 consecutive days, many centers now deliver the total dose over a briefer period, often 2 days. The mechanism of action is yet to be proven, but theories include neutralization of autoantibodies, inhibition of complement, and modulation of Fc-receptor effects (including phagocytosis).60

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183

Medical Issue

Recommendation

Prophylaxis for deep vein thrombosis

Subcutaneous unfractionated or fractionated heparin and support stockings for nonambulatory adult patients

Monitor of heart rate and blood pressure

Monitor pulse and blood pressure in severely affected patients until extubation or improvement begins

Respiratory monitoring, airway protection

1. Close monitoring of ventilatory function 2. Consider artificial ventilation if vital capacity > 15–20 ml/kg13 3. Weaning from the ventilator should be guided by improvement in strength and serial pulmonary function tests.

Timing and method of tracheostomy

Assess need after 2 weeks of mechanical ventilation. 1. Perform tracheostomy if pulmonary function tests do not show any significant improvement. 2. If pulmonary function test improves above baseline, tracheostomy may be deferred for one additional week. 3. Percutaneous tracheostomy may be preferred in centers with adequate experience in using the technique.

Pain management

1. Simple analgesics or nonsteroidal antiinflammatory drugs may be tried, but often do not provide adequate pain relief. 2. Single small randomized controlled trials support the use of gabapentin or carbamazepine in in the acute phase of GBS. 3. Appropriate narcotic analgesics may be used, but require careful monitoring of adverse effects in the setting of autonomic denervation. 4. Adjuvant therapy with tricyclic antidepressant medication, tramadol, gabapentin, carbamazepine, or mexiletine for chronic pain

Management of bowel dysfunction

1. 2. 3. 4.

Management of bladder dysfunction

Bladder catheterization is often needed for severely affected patients. A sterile, closed urinary drainage system should be used with avoidance of breaking the seal to obtain urine samples and irrigation of the bladder.

Rehabilitation

Acute treatment should include an individual program of gentle strengthening involving isometric, isotonic, isokinetic, and manual resistive and progressive resistive exercises. Rehabilitation should be focused on proper limb positioning, posture, orthotics, and nutrition.

Management of fatigue

An exercise program may be beneficial for persistent fatigue.

Future immunizations

1. Immunizations are not recommended during the acute phase and should be avoided for one year after onset. 2. After that, potential risks of having the vaccine should be balanced against risk of infection for the individual patient. 3. If GBS occurs within 6 weeks after a specific immunization, the vaccine should be avoided in the future.

Daily abdominal auscultation for development of gut silence Suspension of gut-feeding nasogastric and rectal tubes Erythromycin or neostigmine may be effective in treating adynamic ileus. Promotility agents are contraindicated in patients with dysautonomia.

The response to IVIg is variable. A recent study examined the relationship between postinfusion immunoglobulin (Ig) levels and response to therapy. Those patients with the higher postinfusion Ig levels were significantly more likely to be able to walk unaided 6 months later.61 Ongoing natural history and therapeutic studies are exploring this issue. Uncontrolled series have suggested some benefit of a second course of IVIg in patients with poor prognosis (defined as a low probability of walking: 85% chance of not walking at 4 weeks and 35% at 6 months).62 To answer this clinically important question, a randomized placebo controlled trial is ongoing in the Netherlands (SID-GBS Trial). In this trial, patients will receive standard treatment with IVIg. After 1 week, patients with poor prognosis will be randomized to receive either placebo or IVIg for a second course of therapy. Hopefully, this trial will help us define its usefulness.57

A goal of the SID-GBS trial is to determine which patients are likely to have a poor outcome. The Erasmus Guillain Barré Outcome Scale (EGOS) performed at 2 weeks after onset has been shown to predict ability to walk at 6 months. This simple 7-point scale is based on age, whether the patient had diarrhea and the GBS disability scale at 2 weeks (►Table 4). Older age, presence of diarrhea, and most importantly the higher GBS disability scale (5 of the 7-point scale) were predictors of nonambulation. These patients may be particularly appropriate for a second course of IVIg or other interventions.63 IVIg and PEx are considered equally effective therapies for Guillain-Barré syndrome, including both the demyelinating and axonal forms. Because IVIg is available in more centers and is not associated with the risks of placing and maintaining a central dialysis catheter, it is more often Seminars in Neurology

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Table 3 Consensus Multidisciplinary Therapy for Guillain-Barré Syndrome (GBS)53

Guillain-Barré Syndrome

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Table 4 The Erasmus Guillain-Barré Syndrome Outcome Score: EGOS(65) Category Guillain-Barré syndrome (GBS) disability score 2 weeks after entry

Age at onset

Diarrhea (within 4 weeks)

Score

Requiring assisted ventilation part of the day

5

5

Bedridden, chair bound

4

4

Able to walk 10 m with help

3

3

Able to walk >10 m without assistance, unable to run

2

2

Able to run, minor problems

1

1

Healthy

0

1

>60 years

1

1

41–60 years

0.5

0.5