Guillain-Barré syndrome (GBS) is an acute, frequently severe, and fulminant polyradiculoneuropathy that is autoimmune in nature. It occurs year-round at a rate of between 1 and 4 cases per 100,000 annually; in the United States, ~5000–6000 cases occur per year. Males are at slightly higher risk for GBS than females, and in Western countries, adults are more frequently affected than children.

Clinical manifestations

GBS manifests as a rapidly evolving areflexic motor paralysis with or without sensory disturbance. The usual pattern is an ascending paralysis that may be first noticed as rubbery legs. Weakness typically evolves over hours to a few days and is frequently accompanied by tingling dysesthesias in the extremities. The legs are usually more affected than the arms, and facial diparesis is present in 50% of affected individuals. The lower cranial nerves are also frequently involved, causing bulbar weakness with difficulty handling secretions and maintaining an airway; the diagnosis in these patients may initially be mistaken for brainstem ischemia. Pain in the neck, shoulder, back, or diffusely over the spine is also common in the early stages of GBS, occurring in ~50% of patients. Most patients require hospitalization, and in different series, up to 30% require ventilatory assistance at some time during the illness. The need for mechanical ventilation is associated with more severe weakness on admission, a rapid tempo of progression, and the presence of facial and/or bulbar weakness during the first week of symptoms. Fever and constitutional symptoms are absent at the onset and, if present, cast doubt on the diagnosis. Deep tendon reflexes attenuate or disappear within the first few days of onset. Cutaneous sensory deficits (e.g., loss of pain and temperature sensation) are usually relatively mild, but functions subserved by large sensory fibers, such as deep tendon reflexes and proprioception, are more severely affected. Bladder dysfunction may occur in severe cases but is usually transient. If bladder dysfunction is a prominent feature and comes early in the course, diagnostic possibilities other than GBS should be considered, particularly spinal cord disease. Once clinical worsening stops and the patient reaches a plateau (almost always within 4 weeks of onset), further progression is unlikely.

Autonomic involvement is common and may occur even in patients whose GBS is otherwise mild. The usual manifestations are loss of vasomotor control with wide fluctuation in blood pressure, postural hypotension, and cardiac dysrhythmias. These features require close monitoring and management and can be fatal. Pain is another common feature of GBS; in addition to the acute pain described above, a deep aching pain may be present in weakened muscles that patients liken to having overexercised the previous day. Other pains in GBS include dysesthetic pain in the extremities as a manifestation of sensory nerve fiber involvement. These pains are self-limited and often respond to standard analgesics (Chap. 8).

Several subtypes of GBS are recognized, as determined primarily by electrodiagnostic (Edx) and pathologic distinctions (Table 54-1). The most common variant is acute inflammatory demyelinating polyneuropathy (AIDP). Additionally, there are two axonal variants, which are often clinically severe—the acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN) subtypes. In addition, a range of limited or regional GBS syndromes are also encountered. Notable among these is the Miller Fisher syndrome (MFS), which presents as rapidly evolving ataxia and areflexia of limbs without weakness, and ophthalmoplegia, often with pupillary paralysis. The MFS variant accounts for ~5% of all cases and is strongly associated with antibodies to the ganglioside GQ1b (see “Immunopathogenesis,” below). Other regional variants of GBS include (1) pure sensory forms; (2) ophthalmoplegia with anti-GQ1b antibodies as part of severe motor-sensory GBS; (3) GBS with severe bulbar and facial paralysis, sometimes associated with antecedent cytomegalovirus (CMV) infection and anti-GM2 antibodies; and (4) acute pandysautonomia (Chap. 41).

Antecedent events

Approximately 70% of cases of GBS occur 1–3 weeks after an acute infectious process, usually respiratory or gastrointestinal. Culture and seroepidemiologic techniques show that 20–30% of all cases occurring in North America, Europe, and Australia are preceded by infection or reinfection with Campylobacter jejuni. A similar proportion is preceded by a human herpes virus infection, often CMV or Epstein-Barr virus. Other viruses (e.g., HIV, hepatitis E) and also Mycoplasma pneumoniae have been identified as agents involved in antecedent infections, as have recent immunizations. The swine influenza vaccine, administered widely in the United States in 1976, is the most notable example. Influenza vaccines in use from 1992 to 1994, however, resulted in only one additional case of GBS per million persons vaccinated, and the more recent seasonal influenza vaccines appear to confer a GBS risk of <1 per million. Epidemiologic studies looking at H1N1 vaccination demonstrated at most only a slight increased risk of GBS. Meningococcal vaccinations (Menactra) do not appear to carry an increased risk. Older-type rabies vaccine, prepared in nervous system tissue, is implicated as a trigger of GBS in developing countries where it is still used; the mechanism is presumably immunization against neural antigens. GBS also occurs more frequently than can be attributed to chance alone in patients with lymphoma (including Hodgkin’s disease), in HIV-seropositive individuals, and in patients with systemic lupus erythematosus (SLE). C. jejuni has also been implicated in summer outbreaks of AMAN among children and young adults exposed to chickens in rural China.

Immunopathogenesis

Several lines of evidence support an autoimmune basis for acute inflammatory demyelinating polyneuropathy (AIDP), the most common and best-studied type of GBS; the concept extends to all of the subtypes of GBS (Table 54-1).

It is likely that both cellular and humoral immune mechanisms contribute to tissue damage in AIDP. T cell activation is suggested by the finding that elevated levels of cytokines and cytokine receptors are present in serum (interleukin [IL] 2, soluble IL-2 receptor) and in cerebrospinal fluid (CSF) (IL-6, tumor necrosis factor α, interferon γ). AIDP is also closely analogous to an experimental T cell–mediated immunopathy designated experimental allergic neuritis (EAN). EAN is induced in laboratory animals by immune sensitization against protein fragments derived from peripheral nerve proteins, and in particular against the P2 protein. Based on analogy to EAN, it was initially thought that AIDP was likely to be primarily a T cell–mediated disorder; however, abundant data now suggest that autoantibodies directed against nonprotein determinants may be central to many cases.

Circumstantial evidence suggests that all GBS results from immune responses to nonself antigens (infectious agents, vaccines) that misdirect to host nerve tissue through a resemblance-of-epitope (molecular mimicry) mechanism (Fig. 54-1). The neural targets are likely to be glycoconjugates, specifically gangliosides (Table 54-2; Fig. 54-2). Gangliosides are complex glycosphingolipids that contain one or more sialic acid residues; various gangliosides participate in cell-cell interactions (including those between axons and glia), modulation of receptors, and regulation of growth. They are typically exposed on the plasma membrane of cells, rendering them susceptible to an antibody-mediated attack. Gangliosides and other glycoconjugates are present in large quantity in human nervous tissues and in key sites, such as nodes of Ranvier. Antiganglioside antibodies, most frequently to GM1, are common in GBS (20–50% of cases), particularly in AMAN and AMSAN and in those cases preceded by C. jejuni infection. Furthermore, isolates of C. jejuni from stool cultures of patients with GBS have surface glycolipid structures that antigenically cross react with gangliosides, including GM1, concentrated in human nerves. Sialic acid residues from pathogenic C. jejuni strains can also trigger activation of dendritic cells via signaling through a toll-like receptor (TLR4), promoting B cell differentiation and further amplifying humoral autoimmunity. Another line of evidence is derived from experience in Europe with parenteral use of purified bovine brain gangliosides for treatment of various neuropathic disorders. Between 5 and 15 days after injection, some recipients developed acute motor axonal GBS with high titers of anti-GM1 antibodies that recognized epitopes at nodes of Ranvier and motor endplates. Experimentally, anti-GM1 antibodies can trigger complement-mediated injury at paranodal axon-glial junctions, disrupting the clustering of sodium channels and likely contributing to conduction block (see “Pathophysiology,” below).

Anti-GQ1b IgG antibodies are found in >90% of patients with MFS (Table 54-2; Fig. 54-2), and titers of IgG are highest early in the course. Anti-GQ1b antibodies are not found in other forms of GBS unless there is extraocular motor nerve involvement. A possible explanation for this association is that extraocular motor nerves are enriched in GQ1b gangliosides in comparison to limb nerves. In addition, a monoclonal anti-GQ1b antibody raised against C. jejuni isolated from a patient with MFS blocked neuromuscular transmission experimentally.

Taken together, these observations provide strong but still inconclusive evidence that autoantibodies play an important pathogenic role in GBS. Although antiganglioside antibodies have been studied most intensively, other antigenic targets may also be important. One report identified IgG antibodies against Schwann cells and neurons (nerve growth cone region) in some GBS cases. Proof that these antibodies are pathogenic requires that they be capable of mediating disease following direct passive transfer to naïve hosts; this has not yet been demonstrated, although one case of possible maternal-fetal transplacental transfer of GBS has been described.

In AIDP, an early step in the induction of tissue damage appears to be complement deposition along the outer surface of the Schwann cell. Activation of complement initiates a characteristic vesicular disintegration of the myelin sheath and also leads to recruitment of activated macrophages, which participate in damage to myelin and axons. In AMAN, the pattern is different in that complement is deposited along with IgG at the nodes of Ranvier along large motor axons. Interestingly, in cases of AMAN, antibodies against GD1a appear to have a fine specificity that favors binding to motor rather than sensory nerve roots, even though this ganglioside is expressed on both fiber types.