4.1 Introduction
Guillain-Barré syndrome (GBS), also called acute inflammatory demyelinating polyradiculoneuropathy (AIDP), is an inflammatory disorder affecting the peripheral nervous system that is characterized by acute or subacute onset and typically monophasic course of the disease. Some patients with this disorder need hospitalization to an intensive care unit (ICU). Among neuromuscular disorders, only several ones require monitoring and treatment at ICUs, namely, GBS, amyotrophic lateral sclerosis, and acute myasthenia gravis. Management of these patients in ICU normally includes specific therapy, vital signs’ monitoring, treatment of systemic complications, as well as the elimination of autonomic nervous system disorders [1–5].
GBS is considered the most common cause of inflammatory polyneuropathies, the annual frequency of which is estimated as 1–3 cases per 100,000 people. GBS might develop at any age (from 2 months to 95 years); however, there is a tendency of the predominance of male patients aged 15–35 and 50–75 years among those who develop this disorder. The risk of this disease in females reduces during pregnancy and increases after the delivery [6, 7].
The pathogenesis of GBS is based on the autoimmune damage of the myelin sheath of the peripheral nerves. Despite the fact that only sporadic cases of this disease are reported, about two-thirds of patients have a history of infections 1–4 weeks prior to the development of neurological symptoms. These infections are most often caused by viruses (cytomegalovirus, Epstein-Barr, HIV, enteroviruses, herpes simplex, hepatitis A and C viruses) but also may be of bacterial origin (Mycoplasma or Campylobacter jejuni) and are respiratory or gastrointestinal (mainly diarrhea) in 40% and 20% of cases, respectively [8–10]. Zika virus has also been shown to be a possible trigger [11]. GBS might be associated with surgical procedures or vaccination. However, one-third of patients have no prior history of infections or any other relevant factors [12–15]. C. jejuni infection is the most common one and can be found in 25–50% of patients [16]. It is often associated with the motor form of GBS, more severe course, and the positive result of the test for antibodies to GM1 and GD1a gangliosides [17–20]. Anti-GM1 antibodies and antibodies to other gangliosides are observed in 20–40% of GBS patients. Gangliosides are glycosphingolipids that can primarily be found in the nervous system, particularly in neuronal axons. There are several subtypes of gangliosides, for example, GM1, GM2, GM3, GD1a, GD1b, GT1b, and GQ1b [21]. Positive results of the test for these antibodies are generally associated with a poorer outcome [18].
Thus, AIDP is a rapidly progressing post-infection disorder manifested with muscle weakness in the extremities, involvement of cranial nerves accompanied by reduction, and, subsequently, lack of deep tendon reflexes. Other symptoms include specific changes in the cerebrospinal fluid and electroneuromyography findings [22]. Muscle weakness is symmetrical (in some cases, slight asymmetry may be observed during the disease onset) and develops within 5–10 days. Increase in muscle weakness stops in 2, 3, and 4 weeks after the disease onset in 50%, 80%, and 90% of patients, respectively. This is followed by a period of the plateau. There is no special biological marker for the GBS diagnosis; however, such invasive diagnostic procedures as electrodiagnostic testing and lumbar puncture usually help in making this diagnosis [20]. About one-fourth of patients require mechanical ventilation and may develop autonomous system disorders; many of them need admission to critical or intensive care units [1, 20].
4.2 History of Guillain-Barré syndrome
The disease was described for the first time by Octave Laundry in 1859 [23]. Later, in 1916, Guillain, Barré, and Strohl reported two cases of acute ascending weakness associated with good prognosis in respect of recovery [24]. The term “Guillain-Barré syndrome” was suggested by Draganescu and Claudian [25]. The first diagnostic criteria were developed in 1960 by Osler and Sidell [26]. After an epidemic of GBS in the USA following the use of swine flu vaccines, the National Institute of Neurological and Communicative Disorders and Stroke suggested new criteria for the disease, which were revised in 1990 by Asbury and Cornblath [27, 28] and became widely used by both investigators and clinical practitioners. In 2011, the new “Brighton criteria” were published [29–31].
4.3 Clinical Variants
Clinical variants of GBS
Clinical variants | Clinical features |
|---|---|
Typical clinical GBS (acute inflammatory demyelinating polyneuropathy—AIDP) (71–90% of cases) [28, 32–34] | Progressive course of the disease, symmetric muscle weakness, absence of deep tendon reflexes |
Tendon reflexes may be preserved; sensory nerves do not suffer; faster progression, antibodies to the gangliosides GM1, GD1a, GalNac-GD1a, and GD1b are present | |
Acute motor and sensory axonal neuropathy—AMSAN (<1% of cases) [32–36] | A more severe form of AMAN, both sensory and motor fibers are affected |
Miller Fisher syndrome (MFS) (5–17% of GBS cases) [32–34, 37, 38] | Ophthalmoplegia, ataxia, and areflexia with no weakness, antibodies to GQ1b are present in 85–90% of patients with MFS |
Bickerstaff’s brainstem encephalitis (BBE) is a variant of MFS (1–10% of MFS cases) [32–34, 39] | Сonfusion of consciousness, paradoxical hyperreflexia, ataxia, and ophthalmoparesis associated with anti-GQ1b antibodies |
Pharyngeal-cervical-brachial variant (2–5% of cases) [32–34, 40, 41] | The acute weakness of the oropharyngeal, neck, and shoulder muscles with swallowing dysfunction |
Dizziness, vomiting, diarrhea, abdominal pain Orthostatic hypotension, urinary retention, pupillary abnormalities, violation of heart rhythm and sweating, salivation, and lacrimation Decrease or absence of tendon reflexes | |
Ataxia, reflexes are absent, and there may be minor motor involvement, association with antibodies to GD1b |
Other, rarer variants have also been described (acute pharyngeal weakness, paraparetic GBS (1–7%), facial diplegia and distal limb paresthesia (1–2%), pure cranial nerves, acute ophthalmoparesis (1%), etc.) [32–34]. Diagnosis of a typical GBS usually does not cause difficulties, but in some patients, the diagnosis can be more complicated (constant asymmetry of weakness or dysfunction of the bladder or intestine at the beginning, etc.) [44].
4.4 Clinical Features
• Progressive weakness in lower limbs and/or upper limbs • Areflexia (or decreased tendon reflexes) |
and |
• Progressive phase lasts days to 4 weeks (often 2 weeks) • Symmetrical weakness • Mild sensory symptoms (not present in acute motor axonal neuropathy) • Cranial nerve involvement • Autonomic dysfunction • Pain (common) • Albuminocytological dissociation of CSF • Typical electrodiagnostic features |
Patients may have progression of weakness over the course of 4 weeks (sometimes 2 weeks or up to 6 weeks after onset). During the progressive phase, 20–30% of patients develop respiratory failure and need ventilation at an intensive care unit (ICU) [20, 31].
According to the data obtained by Willison et al. [20] and Hughes et al. [47], there may be deterioration of the condition of 25% of patients during or after the immunoglobulin administration or plasma exchange. Therefore, a conclusion was made that the patients’ condition without this therapy would have been worse and that this fact could not be considered resistance to treatment [20, 47].
The severity of clinical manifestations and the duration of the disease may vary greatly among patients: some patients experience mild weakness and spontaneous recovery, while the others develop severe tetraplegia with respiratory disorders that require mechanical ventilation, no signs of recovery within several months. However, almost all patients demonstrate improvement after some time, while it can be the reason for severe disability in very rare cases [48].
About one-third of GBS patients require mechanical ventilation [48]. In two-thirds of AIDP cases, autonomous system disturbances develop, which are especially frequent in mechanically ventilated patients. More than 50% of patients develop sinus tachycardia [5]. Other symptoms of autonomic dysfunction may include bradycardia (mostly observed in intubated patients), orthostatic hypotension (as well as associated syncopal episodes), BP fluctuations (most often hypertension, less often hypotension), and sweating disorders (despite their high frequency, the patients usually do not complain of these disorders). About 10–20% of patients develop transient pelvic floor disorders (often urinary retention, sometimes urinary incontinence) due to dysfunction of the sphincter muscles [5, 48, 49].
Additional tests used in patients with suspected GBS include lumbar puncture with cerebrospinal fluid analysis (cell counts and protein levels) and the electrophysiology studies. However, it should be taken into account that the findings of these investigations may be within the normal ranges in the early stage of the disease. CSF examination allows to rule out other potential causes of progressive weakness (HIV, CMV, Lyme, sarcoid, carcinomatous, or lymphomatous polyradiculoneuropathy) [5, 20, 50]. The most important finding for the diagnosis of GBS is increased protein level (>0.55 g/L), which develops within 1 week from the disease onset and reaches its peak on Weeks 3–4. During the first 2 days, 85% of patients demonstrate normal protein levels; by the end of Week 1, an increase in protein levels is observed in two-thirds of patients; and at Week 2, this is a typical finding in 80% of patients. The phenomenon of combined normal cell count and increased protein concentration is known as cytoalbuminologic dissociation and is typical for patients with Guillain-Barré syndrome [5, 20, 50].
Neurophysiological testing helps confirm the diagnosis GBS; suggests different clinical variants, AIDP, AMAN, and AMSAN; and also determines the type of damage, demyelination or axonal damage. In some cases, the electrodiagnostic test helps to establish a prognosis [51–53]. For the diagnosis it is necessary to study at least four motor nerves, not less than three sensory nerves, and the presence of F-wave and H-reflexes. Demyelination is characterized by prolonged distal motor latency, reduced nerve conduction velocity, prolonged F-wave latency, increased temporal dispersion, and conduction blocks [20].
The GBS Сlassification Group indicates that the diagnosis of GBS, MFS, and their variants can be established clinically in most patients. Existing diagnostic criteria are rigid and often depend on laboratory data. Electrophysiological testing and analysis of cerebrospinal fluid in the onset of the disease do not always confirm this diagnosis. The albuminocytological dissociation of CSF is absent in the first week of symptoms in more than half of patients with GBS, and in approximately 40% of patients, electrophysiological studies conducted during the first week can offer diagnosis of neuropathy without the manifestation of criteria for one of the specific electrophysiological variants [32].
4.5 Differential Diagnosis
Differential diagnosis of Guillain-Barre syndrome (GBS)
The red flags or signs that make one doubt the diagnosis include high cell count (>50 cells/μL) in CSF, severe respiratory failure accompanied by mild or no weakness in the limbs, pronounced sensory disturbances accompanied by no weakness in the limbs at the disease onset, bladder or bowel dysfunction at early stages of the disease, fever at the disease onset, segmental sensory disorders, and persistent asymmetry of weakness or its slow progression [20, 44, 54–56].
Apart from acute transverse myelitis, the differential diagnosis of GBS should include myasthenic crisis (in this case, medical history data, presence of transient ptosis, or other oculomotor disorders, the severity of which depends on physical activity, should be taken into account) or botulism (the typical signs of which include dilated pupils with no light reaction, constipation, and the development of neurological symptoms within 12–36 h after the intake of contaminated products). The development of facial nerve palsy, including facial diplegia, may occur in patients with neuroborreliosis. Other diseases with symptoms similar to those of GBS include polyneuropathies of different origin (related to vasculitis, porphyria, paraneoplastic syndromes), acute polymyositis, acute steroid myopathy, rare cases of heavy metal or organophosphate poisoning, and hypophosphatemia (parenteral nutrition, abstinence syndrome in patients with alcohol abuse, and some other conditions may provoke the development of quadriplegia characterized by hyporeflexia and rapid regression after restoration of phosphate levels). Critically ill patients with sepsis and multiorgan failure may develop axonal polyneuropathy (critical illness polyneuropathy) [20, 44, 54–56].
4.6 Respiratory Failure
In a study by Hughes, it shown that about 30% of patients with AIDP need endotracheal intubation for mechanical ventilation (MV) when they enter the intensive care unit (ICU) [22]. At present, the importance of clinical, immunological, biochemical, and neurophysiological criteria for the prediction of GBS is actively being studied in the world [4, 48, 57–59]. Studies have shown that clinical prognostic factors that require intubation and MV in critical care are inability to walk, inability to raise the head, decreased vital capacity (VC), delay in hospitalization for less than 7 days, and high level of liver enzymes [60].
The need for MV in this disease can vary significantly in different patients—from a few days, months to a year or more. It is considered that the need for tracheostomy occurs when the expected duration of ventilation is more than 14 days. Both delayed and early tracheostomy can lead to undesirable consequences: in the first case, an increased risk of infectious complications (e.g., pneumonia associated with the ventilator) and, in the second case, an unjustified risk of complications in patients with rapid recovery [61–63]. It should be noted that the appointment of specific therapy led to an acceleration of functional recovery and a reduction in the timing of MV.
In a study by Fourrier et al. [60], it was shown that, in patients with GBS, long-term MV can be predicted with a functional marker: the lack of foot flexion ability at the end of immunotherapy was significantly associated with MV lasting more than 15 days. The results of EMG evaluation confirmed the sensitivity of this simple marker. François Fourier suggests using this marker to address the issue of the need for tracheostomy after the completion of immunotherapy [60, 64–66].
4.7 Treatment
The acute phase of GBS (even mild cases) should be considered an emergent condition since decompensation with the development of severe respiratory failure requiring mechanical ventilation may develop within several hours. Therefore, these patients should be urgently hospitalized.
Treatment of Guillain-Barré syndrome can be conventionally divided into supportive care, which is aimed at preventing or managing complications, monitoring of respiratory function, cardiac and hemodynamic monitoring (autonomic dysfunction), prophylaxis for deep vein thrombosis, management of possible bladder and bowel dysfunction, pain management, early initiation of physiotherapy and rehabilitation, psychosocial support, and specific therapy, including the use of intravenous immunoglobulins and plasmapheresis [5, 20, 44, 47, 67, 68].
Plasmapheresis was suggested as a method of GBS treatment in 1978, and its positive effects were subsequently demonstrated in randomized clinical trials [69, 70]. Since 1988, intravenous immunoglobulin has been used for treatment of this disease [71]. In 1992, the first randomized clinical study demonstrated similar efficacy of both these therapeutic methods [72].
4.8 Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE)
The main issues related to the use of intravenous immunoglobulin that concerned clinical practitioners were whether its effect was comparable to that of plasmapheresis, whether addition of corticosteroids was more effective in respect of GBS treatment, and what the optimal dose of immunoglobulin was [67, 68].
EFNS guidelines for the use of intravenous immunoglobulin in the treatment of neurological diseases (2008) | Evidence-based guidelines: intravenous immunoglobulin in the treatment of neuromuscular disorders (AAN) (2012) |
|---|---|
The first line of therapy may include treatment with immunoglobulin (0.4 g/kg/day for 5 days) or plasmapheresis, which are equally effective (Level A) | Plasmapheresis should be used within 4 weeks from the disease onset (Level A, Class II) |
IVIg has fewer side effects than plasma exchange (PE), which would favor IVIG over PE treatment (Level B) | PE is recommended for ambulant patients within 2 weeks of the onset of neuropathic symptoms (Level B, Class II) |
IVIg treatment after PE, as a standard combination, does not produce significant extra benefit and cannot be recommended (Level B) | If PE started within 2 weeks of onset, the effects of PE and IVIg in patients requiring walking aids are equal (Level B, Class I) |
Combining high-dose intravenous methylprednisolone with IVIg may have a minor short-term benefit (Level C) | IVIg is recommended for non-ambulant patients within 4 weeks of the onset of neuropathic symptoms (Level B, Class II) |
Patients who improve after IVIg and then relapse should preferentially be retreated with a second course of IVIg (good practice point) | If started within 2 weeks of onset, IVIg has comparable efficacy to PE in patients requiring walking aids (Level B, Class I) |
In patients who seem to be unresponsive to the first course of IVIg, a second course may be tried, but evidence supporting such a strategy is lacking (good practice point) | IVIg is recommended for non-ambulant patients within 2 weeks of onset of neuropathic symptoms (Level A, Class II) |
No recommendations can be given as to whether mildly affected GBS patients or patients with Miller Fisher syndrome should be treated with IVIg | Sequential treatment with PE followed by IVIg does not have a greater effect than either treatment given alone (Level A, Class I) |
Management of patients who worsen or fail to improve after being treated with IVIg or PE is unknown. It is common practice to retreat patients with IVIg (2 g/kg in 2–5 days) or PE. There is some indication that relapses occurring after 9 weeks may indicate that the patient had acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP) [73–75].
Despite a great variety of clinical forms of GBS, the qualitative and quantitative characteristics of recovery after the use of either of two modern methods of treatment of this disease—plasmapheresis or immune therapy—are similar. In some cases, in 8 weeks after initial improvement as a result of plasmapheresis sessions or immune therapy, the patient’s condition may deteriorate again. This phenomenon can be explained by continuous production of abnormal antibodies and can easily be eliminated with a repeated treatment course. This repeated course may improve the patient’s condition again, although no data on randomized clinical studies are available so far [20, 44, 73, 75].
Corticosteroids: the results obtained over the past years have demonstrated no response to therapy with corticosteroids in patients with GBS. A special study (meta-analysis), which summarized the results of six randomized trials of corticosteroids, has put a final point in this issue [76, 77]. Its major conclusion was as follows: recovery by the end of the first month of the disease was similar in patients treated with corticosteroids or placebo; however, it was worse in patients treated with hormones by the end of the first year.
Plasmapheresis is used in patients demonstrating increase in the severity of neurological symptoms in patients who need mechanical ventilation, those who cannot walk more than 5 m with support or assistance, or those who can get out of bed and slowly walk more than meters on their own. The optimal volume of plasmapheresis is not known. In most cases, five sessions of plasma exchange are applied using at least 2–3 L of plasma depending on body weight per session for 2 weeks. This therapy should be initiated within the first 4 weeks from the disease onset [78].
The number of complications associated with plasma exchange is higher than that of immunoglobulin use. This fact, along with convenient route of administration and high availability of the product in developed countries, has made the immunoglobulin a more preferable type of treatment in many centers. One of the restrictions of this therapy is its high cost, so in a number of clinics (especially in low-income countries), plasma exchange is still used [20, 44, 76–86].
Summary
- 1.
Treatment of GBS must be started as soon as possible.
- 2.
Treatment with plasma exchange or intravenous immunoglobulin hastens recovery from GBS.
- 3.
Plasmapheresis and intravenous immunoglobulin are equally effective in patients with advanced GBS symptoms.
- 4.
Plasmapheresis may carry a higher risk of side effects and is more difficult to administer.
- 5.
Combining the two treatments is not recommended.
- 6.
Corticosteroid treatment is not recommended.
4.9 Supportive Care
Despite progress in immunotherapy, GBS remains a severe pathology with an unpredictable outcome. This statement is based on statistical data. The mortality rate ranges between 4% and 15%, and some 20% patients have residual disability [87–90]. Complications of infection and sepsis are the major causes of mortality. Cardiac arrhythmia is the cause of 20%–30% of deaths in patients with GBS. Lethal outcomes predominantly develop in patients who need mechanical ventilation (MV), which is a considerable risk factor of morbidity and mortality. Nearly 20%–30% of patients with GBS have respiratory insufficiency (RI) and require MV [48, 62, 89, 91, 92], and 78% of these patients need ventilation longer than 3 weeks.
Time from onset to admission of less than 1 week, bulbar paresis, facial and neck weakness, and Medical Research Council sum score are strong risk factors associated with respiratory failure [22, 57, 59]. Lack of foot flexion ability at the end of immune therapy is a strong predictor of prolonged MV and tracheostomy [60]. Muscle weakness, dysphagia, and pneumonia are possible causes of RI. In some cases only one of these causal factors is present, but other patients might have all these causes of RI simultaneously. The major problem in evaluating the respiratory function of a patient with GBS is that the standard approach assesses almost predominantly muscle weakness. The “20/30/40 rule” is a classic assessment tool for making a decision on trachea intubation and the commencement of MV [48]. According to the rule, the patient should be intubated if forced vital capacity is less than 20 ml/kg body weight, maximum inspiratory pressure is less than −30 cm H2O, and maximum expiratory pressure is less than 40 cm H2O. This approach does not consider the severity of dysphagia and pneumonia. The Burdenko respiratory insufficiency scale might support objective decision-making in difficult clinical situations (Chap. 8, Table 4.2).
Noninvasive MV should be avoided in patients with GBS, because it does not improve outcomes and can be dangerous. Trachea intubation is the method of choice for airway management. The timing of tracheostomy is still a controversial issue. The generally accepted timing for tracheostomy is 14 days of MV. That is a quite reasonable tactic, which makes it possible to avoid unnecessary operations and probable complications, including life-threatening sequels. However, on the other hand, such an approach leads to patient discomfort, increases sedation load and the risk of laryngeal injury, and impedes oral hygiene and upper airway suction. Depth of experience makes percutaneous dilation tracheostomy a safe operation [93]. In recent years there has been a clear trend toward early tracheostomy in many groups of critically ill patients, even in those who usually have a shorter duration of MV among GBS patients [94–96].
Severity of muscular weakness and RI are strongly correlated with autonomic disturbances. Cardiac arrhythmias and extreme hypertension or hypotension occur in approximately 20% of patients with GBS [97, 98]. Bradycardia can be extremely severe, which might require a cardiac pacemaker [3, 99]. Endotracheal suction can provoke these changes. A reduction in variation in heart rate predicted subsequent dysautonomia. A dynamic ileus and dysfunction of bronchial mucosa are other important autonomic disturbances in GBS [2, 100, 101].
Different types of sensory disturbances occur in the majority of cases of GBS. Pain develops in one-third to two-thirds of patients and should be managed adequately and in a timely manner. Acetaminophen and nonsteroid anti-inflammatory drugs are the medications of first choice; however, patients with GBS frequently need opioids. Other drugs, such as gabapentin, carbamazepine, and tricyclic antidepressants, may also be required. Excessive use of opioids is associated with bowel hypomotility, which exacerbates ileus [5, 102].
Prolonged immobilization, muscle weakness, and complications of infection are strong risk factors for the development of deep vein thrombosis (DVT) [7]. All patients should be given subcutaneous fractionated or unfractionated heparin and stockings [5, 102].
4.10 Conclusion
The prognosis of GBS is generally considered favorable. The outcome of GBS has varied widely in published series, with mortality rates ranging between 1 and 18% [103]. Mortality in ventilated patients is usually higher and ranges from 20 to 38.3% in a number of studies [104, 105]. Factors that affect mortality are age (>40 or >50 years), rate of progression, sensory disorders, need for ventilation, bulbar dysfunction, dysautonomia, sepsis, and pulmonary complications [106–109].
In general, the mortality rate of even well-treated patients is about 4%, up to 20% of patients can walk unaided after 4 weeks, and only 60% regain full motor strength after 1 year; 14% of patients still have severe disability after a year. The presence of positive antibodies to gangliosides may indicate a poor recovery and be a predictive factor [106–109].
Key Points
Guillain-Barré syndrome (GBS), also called acute inflammatory demyelinating polyradiculoneuropathy (AIDP), is an inflammatory disorder affecting the peripheral nervous system that is characterized by acute or subacute onset and typically monophasic course of the disease. The most common manifestation of GBS is bilateral muscle weakness.
The disease generally starts in the lower limbs and is ascending. Reflexes may be decreased or normal at the beginning of the disease, and they disappear afterward.
The phenomenon of combined normal cell count and increased protein concentration is known as cytoalbuminologic dissociation and is typical for patients with Guillain-Barré syndrome.
Electrodiagnostic testing and CSF analysis are often used for diagnosis, but inconclusive in the early stages of the disease.
Clinical variants of GBS are typical clinical GBS, acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), Miller Fisher syndrome (MFS), pharyngeal-cervical-brachial variant, acute pandysautonomia, pure sensory GBS, and others.
Plasma exchange and intravenous immunoglobulin and IVIg are equally effective in patients with advanced GBS symptoms.