Guillain-Barré Syndrome

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;.

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 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; 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. 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 Other pains in GBS include dysesthetic pain in the extremities as a manifestation of sensory nerve fiber involvement
Several subtypes of GBS are recognized, as determined primarily by electrodiagnostic and pathologic distinctions. 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). 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.

Antecedent Events

Approximately 70% of cases of GBS occur 1–3 weeks after an acute infectious process, usually respiratory or gastrointestinal.A similar proportion is preceded by a human herpes virus infection, often CMV or Epstein-Barr virus. Other viruses and also Mycoplasma pneumoniae have been identified as agents involved in antecedent infections, as have recent immunizations. 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).

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 .
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, interferonit 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.
Antiganglioside antibodies, most frequently to GM1, are common in GBS (20–50% of cases), particularly in those preceded by C. jejuni infection
Anti-GQ1b IgG antibodies are found in >90% of patients with MFS , 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 involvementTaken together, these observations provide strong but still inconclusive evidence that autoantibodies play an important pathogenic role in GBS. 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

Pathophysiology

In the demyelinating forms of GBS, the basis for flaccid paralysis and sensory disturbance is conduction block. This finding, demonstrable electrophysiologically, implies that the axonal connections remain intact. Hence, recovery can take place rapidly as remyelination occurs. In severe cases of demyelinating GBS, secondary axonal degeneration usually occurs; its extent can be estimated electrophysiologically. More secondary axonal degeneration correlates with a slower rate of recovery and a greater degree of residual disability. When a severe primary axonal pattern is encountered electrophysiologically, the implication is that axons have degenerated and become disconnected from their targets, specifically the neuromuscular junctions, and must therefore regenerate for recovery to take place. In motor axonal cases in which recovery is rapid, the lesion is thought to be localized to preterminal motor branches, allowing regeneration and reinnervation to take place quickly. Alternatively, in mild cases, collateral sprouting and reinnervation from surviving motor axons near the neuromuscular junction may begin to reestablish physiologic continuity with muscle cells over a period of several months.

Laboratory Features

CSF findings are distinctive, consisting of an elevated CSF protein level (100–1000 mg/dL)] without accompanying pleocytosis. The CSF is often normal when symptoms have been present for 48 h; by the end of the first week, the level of protein is usually elevated. A transient increase in the CSF white cell count (10–100/L) occurs on occasion in otherwise typical GBS; however, a sustained CSF pleocytosis suggests an alternative diagnosis (viral myelitis) or a concurrent diagnosis such as unrecognized HIV infection, leukemia or lymphoma with infiltration of nerves, or neurosarcoidosis.

NCS:

In AIDP, the earliest features are prolonged F-wave latencies, prolonged distal latencies and reduced amplitudes of compound muscle action potentials Later, slowing of conduction velocity, conduction block, and temporal dispersion may be appreciated. Occasionally, sensory nerve action potentials (SNAPs) may be normal in the feet (e.g., sural nerve) when abnormal in the arms. This is also a sign that the patient does not have one of the more typical “length-dependent” polyneuropathies

Diagnosis

GBS is a descriptive entity. The diagnosis of AIDP is made by recognizing the pattern of rapidly evolving paralysis with areflexia, absence of fever or other systemic symptoms, and characteristic antecedent events (Table ). Other disorders that may enter into the differential diagnosis include acute myelopathies (especially with prolonged back pain and sphincter disturbances); diphtheria (early oropharyngeal disturbances); Lyme polyradiculitis and other tick-borne paralyses; porphyria (abdominal pain, seizures, psychosis); vasculitic neuropathy (check erythrocyte sedimentation rate, described below); poliomyelitis (fever and meningismus common); West Nile virus; CMV polyradiculitis (in immunocompromised patients); critical illness neuropathy or myopathy; neuromuscular junction disorders such as myasthenia gravis and botulism (pupillary reactivity lost early); poisonings with organophosphates, thallium, or arsenic; paralytic shellfish poisoning; or severe hypophosphatemia (rare.

Table Diagnostic Features of Acute Inflammatory Demyelinating Polyneuropathy (AIDP)

  • Required for Diagnosis
    • Progressive weakness of variable degree from mild paresis to complete paralysis
    • Generalized hypo- or areflexia
  • Supportive of Diagnosis
    • Clinical Features
      • Symptom progression: Motor weakness rapidly progresses initially but ceases by 4 weeks. Nadir attained by 2 weeks in 50%, 3 weeks 80%, and 90% by 4 weeks.
      • Demonstration of relative limb symmetry regarding paresis.
      • Mild to moderate sensory signs.
      • Frequent cranial nerve involvement: Facial (cranial nerve VII) 50% and typically bilateral but asymmetric; occasional involvement of cranial nerves XII, X, and occasionally III, IV, and VI as well as XI.
      • Recovery typically begins 2–4 weeks following plateau phase.
      • . Autonomic dysfunction can include tachycardia, other arrhythmias, postural hypotension, hypertension, other vasomotor symptoms.
      • A preceding gastrointestinal illness (e.g., diarrhea) or upper respiratory tract infection is common.
    • Cerebrospinal Fluid Features Supporting Diagnosis
      • Elevated or serial elevation of CSF protein.
      • CSF cell counts are
    • Electrodiagnostic Medicine Findings Supportive of Diagnosis
      • 80% of patients have evidence of NCV slowing/conduction block at some time during disease process
      • Patchy reduction in NCV attaining values less than 60% of normal.
      • Distal motor latency increase may reach 3 times normal values.
      • F-waves indicate proximal NCV slowing.
      • About 15–20% of patients have normal NCV findings.
      • No abnormalities on nerve conduction studies may be seen for several weeks.
  • Findings Reducing Possibility of Diagnosis
    • Asymmetric weakness
    • Failure of bowel/bladder symptoms to resolve
    • Severe bowel/bladder dysfunction at initiation of disease
    • Greater than 50 mononuclear cells/mm3 in CSF
    • Well-demarcated sensory level
  • Exclusionary Criteria
    • Diagnosis of other causes of acute neuromuscular weakness (e.g., myasthenia gravis, botulism, poliomyelitis, toxic neuropathy).
    • Abnormal CSF cytology suggesting carcinomatous invasion of the nerve roots

Abbreviations:

CSF, cerebrospinal fluid; NCV, nerve conduction velocity. Source: AA Amato, D Dumitru, in D Dumitru et al (eds): Electrodiagnostic Medicine, 2nd ed, Philadelphia, Hanley & Belfus, 2002.

Treatment:

Guillain-Barré Syndrome(GBS)

In the vast majority of patients with GBS, treatment should be initiated as soon after diagnosis as possible. Each day counts; 2 weeks after the first motor symptoms, it is not known whether immunotherapy is still effective. If the patient has already reached the plateau stage, then treatment probably is no longer indicated, unless the patient has severe motor weakness and one cannot exclude the possibility that an immunologic attack is still ongoing. Either high-dose intravenous immune globulin (IVIg) or plasmapheresis can be initiated, as they are equally effective for typical GBS. A combination of the two therapies is not significantly better than either alone. IVIg is often the initial therapy chosen because of its ease of administration and good safety record. Anecdotal data has also suggested that IVIg may be preferable to PE for the AMAN and MFS variants of GBS. IVIg is administered as five daily infusions for a total dose of 2 g/kg body weight. There is some evidence that GBS autoantibodies are neutralized by anti-idiotypic antibodies present in IVIg preparations, perhaps accounting for the therapeutic effect. A course of plasmapheresis usually consists of 40–50 mL/kg plasma exchange (PE) four to five times over a week. Meta-analysis of randomized clinical trials indicates that treatment reduces the need for mechanical ventilation by nearly half (from 27% to 14% with PE) and increases the likelihood of full recovery at 1 year (from 55% to 68%). Functionally significant improvement may occur toward the end of the first week of treatment, or may be delayed for several weeks. The lack of noticeable improvement following a course of IVIg or PE is not an indication to treat with the alternate treatment. However, there are occasional patients who are treated early in the course of GBS and improve, who then relapse within a month. Brief retreatment with the original therapy is usually effective in such cases. Glucocorticoids have not been found to be effective in GBS. Occasional patients with very mild forms of GBS, especially those who appear to have already reached a plateau when initially seen, may be managed conservatively without IVIg or PE.
In the worsening phase of GBS, most patients require monitoring in a critical care setting, with particular attention to vital capacity, heart rhythm, blood pressure, nutrition, deep vein thrombosis prophylaxis, cardiovascular status, early consideration (after 2 weeks of intubation) of tracheotomy, and chest physiotherapy. As noted, 30% of patients with GBS require ventilatory assistance, sometimes for prolonged periods of time (several weeks or longer). Frequent turning and assiduous skin care are important, as are daily range-of-motion exercises to avoid joint contractures and daily reassurance as to the generally good outlook for recovery.

Prognosis and Recovery

Approximately 85% of patients with GBS achieve a full functional recovery within several months to a year, although minor findings on examination (such as areflexia) may persist and patients often complain of continued symptoms, including fatigue. The mortality rate is 5% in optimal settings; death usually results from secondary pulmonary complications. The outlook is worst in patients with severe proximal motor and sensory axonal damage. Such axonal damage may be either primary or secondary in nature), but in either case successful regeneration cannot occur. Other factors that worsen the outlook for recovery are advanced age, a fulminant or severe attack, and a delay in the onset of treatment. Between 5 and 10% of patients with typical GBS have one or more late relapses; such cases are then classified as chronic inflammatory demyelinating polyneuropathy (CIDP).