Guillain-Barre Syndrome

Guillain-Barré syndrome (GBS) can be described as a collection of clinical syndromes that manifests as an acute inflammatory polyradiculoneuropathy with resultant weakness and diminished reflexes. With poliomyelitis under control in developed countries, GBS is now the most important cause of acute flaccid paralysis. (See Clinical Presentation.)

Although the classic description of GBS is that of a demyelinating neuropathy with ascending weakness, many clinical variants have been well documented in the medical literature, and variants involving the cranial nerves or pure motor involvement and axonal injury are not uncommon. (See Pathophysiology.)

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the most widely recognized form of GBS in Western countries, but the variants known as acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and Miller-Fisher syndrome also are well recognized.

Based on a clinical spectrum of symptoms and findings, it is widely believed that strictly defined subgroups of GBS exist. However, these subgroups are not easily distinguished.

GBS remains a diagnosis made primarily through the assessment of clinical history and findings (see Clinical Presentation). Serum autoantibodies are not measured routinely in the workup of GBS, but results may be helpful in patients with a questionable diagnosis or a variant of GBS (see Workup).

Approximately one third of patients require admission to an intensive care unit (ICU), primarily because of respiratory failure. After medical stabilization, patients can be treated on a general medical/neurologic floor, but continued vigilance remains important in preventing respiratory, cardiovascular, and other medical complications. Treatment with intravenous immunoglobulin (IVIG) or plasma exchange may hasten recovery. After discharge, outpatient physical therapy and occupational therapy may be beneficial in helping patients with GBS to regain their baseline functional status. (See Treatment and Medication.)[5, 3, 6, 7]

Historical background

In 1859, Landry published a report on 10 patients with an ascending paralysis.[8] Subsequently, in 1916, 3 French physicians (Guillain, Barré, and Strohl) described 2 French soldiers with motor weakness, areflexia, cerebrospinal fluid (CSF) albuminocytologic dissociation, and diminished deep tendon reflexes.[1] The identified syndrome was later named Guillain-Barré syndrome. Historically, GBS was a single disorder; however, current practice acknowledges several variant forms.

GBS is a postinfectious, immune-mediated disease. Cellular and humoral immune mechanisms probably play a role in its development. Most patients report an infectious illness in the weeks prior to the onset of GBS. Many of the identified infectious agents are thought to induce production of antibodies that cross-react with specific gangliosides and glycolipids, such as GM1 and GD1b, that are distributed throughout the myelin in the peripheral nervous system.[9]

The pathophysiologic mechanism of an antecedent illness and of GBS can be typified by Campylobacter jejuni infections.[10, 11] The virulence of C jejuni is thought to be based on the presence of specific antigens in its capsule that are shared with nerves.

Immune responses directed against lipopolysaccharide antigens in the capsule of C jejuni result in antibodies that cross-react with ganglioside GM1 in myelin, resulting in immunologic damage to the peripheral nervous system. This process has been termed molecular mimicry.[12, 13]

Pathologic findings in GBS include lymphocytic infiltration of spinal roots and peripheral nerves (cranial nerves may be involved as well), followed by macrophage-mediated, multifocal stripping of myelin. This phenomenon results in defects in the propagation of electrical nerve impulses, with eventual absence or profound delay in conduction, causing flaccid paralysis. Recovery is typically associated with remyelination.

In some patients with severe disease, a secondary consequence of the severe inflammation is axonal disruption and loss. A subgroup of patients may have a primary immune attack directly against nerve axons, with sparing of myelin. The clinical presentation in these patients is similar to that of the principal type.

Subtypes of Guillain-Barré syndrome

Several variants of GBS are recognized. These disorders share similar patterns of evolution, symptom overlap, and probable immune-mediated pathogenesis. Recovery from them varies.

Acute inflammatory demyelinating polyneuropathy

The acute inflammatory demyelinating polyneuropathy (AIDP) subtype is the most commonly identified form in the United States. It is generally preceded by a bacterial or viral infection. Nearly 40% of patients with AIDP are seropositive for C jejuni. Lymphocytic infiltration and macrophage-mediated peripheral nerve demyelination is present. Symptoms generally resolve with remyelination.

Acute motor axonal neuropathy

The acute motor axonal neuropathy (AMAN) subtype is a purely motor disorder that is more prevalent in pediatric age groups.[14] AMAN is generally characterized by rapidly progressive symmetrical weakness and ensuing respiratory failure.

Nearly 70-75% of patients with AMAN are seropositive for Campylobacter, with the majority of cases of AMAN being associated with preceding C jejuni diarrhea. Patients typically have high titers of antibodies to gangliosides (ie, GM1, GD1a, GD1b). Inflammation of the spinal anterior roots may lead to disruption of the blood-CNS barrier.[12] Biopsies show wallerianlike degeneration without significant lymphocytic inflammation.

Many cases have been reported in rural areas of China, especially in children and young adults during the summer months.[15] Pure axonal cases may occur more frequently outside of Europe and North America. AMAN cases may also be different from cases of axonal GBS described in the West.

Prognosis is often quite favorable. Although recovery for many is rapid, severely disabled patients with AMAN may show improvement over a period of years.[16]

One third of patients with AMAN may actually be hyperreflexic. Although the mechanism for this hyperreflexia is unclear, dysfunction of the inhibitory system via spinal interneurons may increase motor neuron excitability. Hyperreflexia is significantly associated with the presence of anti-GM1 antibodies.[8]

Acute motor-sensory axonal neuropathy

Acute motor-sensory axonal neuropathy (AMSAN) is a severe acute illness differing from AMAN in that it also affects sensory nerves and roots.[17] Patients are typically adults. AMSAN often presents as rapid and severe motor and sensory dysfunction. Marked muscle wasting is characteristic, and recovery is poorer than it is from electrophysiologically similar cases of AMAN.

As with AMAN, AMSAN is often associated with preceding C jejuni diarrhea. Pathologic findings show severe axonal degeneration of motor and sensory nerve fibers with little demyelination.[18]

Miller-Fisher syndrome

Miller-Fisher syndrome (MFS), which is observed in about 5% of all cases of GBS, classically presents as a triad of ataxia, areflexia, and ophthalmoplegia.[19] Acute onset of external ophthalmoplegia is a cardinal feature.[12] Ataxia tends to be out of proportion to the degree of sensory loss. Patients may also have mild limb weakness, ptosis, facial palsy, or bulbar palsy. Patients have reduced or absent sensory nerve action potentials and absent tibial H reflex.[20]

Anti-GQ1b antibodies are prominent in MFS, and have a relatively high specificity and sensitivity for the disease.[21] Dense concentrations of GQ1b ganglioside are found in the oculomotor, trochlear, and abducens nerves, which may explain the relationship between anti-GQ1b antibodies and ophthalmoplegia. Patients with acute oropharyngeal palsy carry anti-GQ1b/GT1a IgG antibodies.[12] Recovery generally occurs within 1-3 months.

Acute panautonomic neuropathy

Acute panautonomic neuropathy, the rarest GBS variant, involves the sympathetic and parasympathetic nervous systems. Patients have severe postural hypotension, bowel and bladder retention, anhidrosis, decreased salivation and lacrimation, and pupillary abnormalities. Cardiovascular involvement is common, and dysrhythmias are a significant source of mortality. Significant motor or sensory involvement is lacking. Recovery is gradual and often incomplete.

Pure sensory GBS

A pure sensory variant of GBS has been described in the literature. It is typified by a rapid onset of sensory loss, sensory ataxia, and areflexia in a symmetrical and widespread pattern. Lumbar puncture studies show albuminocytologic dissociation in the CSF, and results from electromyography (EMG) show characteristic signs of a demyelinating process in the peripheral nerves.

The prognosis in pure GBS is generally good. Immunotherapies, such as plasma exchange and the administration of IVIGs, can be tried in patients with severe disease or slow recovery.

Other variants

The pharyngeal-cervical-brachial variant of GBS is distinguished by isolated facial, oropharyngeal, cervical, and upper limb weakness without lower limb involvement. There can be combinations of any of the above subtypes, and virtually any combination of nerve injury. There are likely mild cases that cause temporary symptoms, improve spontaneously, and never get definitively diagnosed.

Other unusual clinical variants with restricted patterns of weakness are observed only in rare cases.

GBS is considered to be a postinfectious, immune-mediated disease targeting peripheral nerves. Up to two thirds of patients report an antecedent bacterial or viral illness prior to the onset of neurologic symptoms.[22, 23] Respiratory infections are most frequently reported, followed by gastrointestinal infections.[24] Administration of certain vaccinations and other systemic illnesses have also been associated with GBS. Case reports exist regarding numerous medications and procedures; however, whether any causal link exists is unclear.

C jejuni

In several studies, C jejuni was the most commonly isolated pathogen in GBS. Serology studies in a Dutch GBS trial identified 32% of patients as having had a recent C jejuni infection, while studies in northern China documented infection rates as high as 60%.[15, 25, 26]

Gastrointestinal and upper respiratory tract symptoms can be observed with C jejuni infections. C jejuni infections can also have a subclinical course, resulting in patients with no reported infectious symptoms prior to the development of GBS. Patients who develop GBS following an antecedent C jejuni infection often have a more severe course, with rapid progression and a prolonged, incomplete recovery. A strong clinical association has been noted between C jejuni infections and the pure motor and axonal forms of GBS.

The virulence of C jejuni is thought to result from the presence of specific antigens in its capsule that are shared with nerves. Immune responses directed against capsular lipopolysaccharides produce antibodies that cross-react with myelin to cause demyelination.

C jejuni infections also generate anti-ganglioside antibodies—including to the gangliosides GM1, GD1a, GalNac-GD1a, and GD1b—that are commonly found in patients with AMAN and AMSAN, the axonal subtypes of GBS. (Patients with C. jejuni enteritis not complicated by GBS, however, do not produce the specific anti-ganglioside antibodies.)

Even in the subgroup of patients with GM1 antibodies, however, the clinical manifestations vary. Host susceptibility is probably one determinant in the development of GBS after infectious illness.[25, 27]

Although GM1 antibodies can also be found in patients with demyelinating GBS, they are much less common in these cases. C. jejuni infection can also generate antibodies to the ganglioside GQ1b, a component of oculomotor nerve myelin; these are associated with MFS.

CMV

Cytomegalovirus (CMV) infections are the second most commonly reported infections preceding GBS, with CMV being the most common viral trigger of GBS. The aforementioned Dutch GBS study found CMV to be present in 13% of patients.[28]

CMV infections present as upper respiratory tract infections, pneumonias, and nonspecific, flulike illnesses. GBS patients with preceding CMV infections often have prominent involvement of the sensory and cranial nerves. CMV infections are significantly associated with antibodies against the ganglioside GM2.

COVID-19

Evidence exists that coronavirus disease 2019 (COVID-19) is linked to the development of neurologic complications, including GBS. By April 20, 2020, one case of GBS in a patient with COVID-19 had been reported out of China and five such cases had been reported out of Italy. A report on the Italian cases said that GBS developed 5-10 days after COVID-19 had been diagnosed, with three of the patients having the demyelinating form of GBS, and the other two appearing to have an axonal variant.[29, 30, 31, 32]

In June 2020, the first US case report of a patient with GBS associated with COVID-19 was published. The syndrome developed soon after the individual became infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, with test results indicating that he had the demyelinating form of GBS.[33, 34]

Other infections

Other significant, although less frequently identified, infectious agents in GBS patients include Epstein-Barr virus (EBV), Mycoplasma pneumoniae, and varicella-zoster virus.[35] An association between GBS and acute human immunodeficiency virus (HIV) infection also is well recognized.[8, 36, 37, 38, 39, 40]

Infections with Haemophilus influenzae, Borrelia burgdorferi, para-influenza virus type 1, influenza A virus, influenza B virus, adenovirus, and herpes simplex virus have been demonstrated in patients with GBS, although not more frequently than they have in controls.[41]

There has been speculation that the Zika virus can cause GBS. Reported cases of the syndrome began to increase in Brazil during the Zika virus outbreak that was identified there in 2015, with hundreds of cases of GBS reported that year.[42, 43] In July 2015, for example, out of 76 patients in the state of Bahia identified with neurologic syndromes, 42 were confirmed as having GBS, with the symptom history of 26 of these confirmed cases having been consistent with Zika virus infection.[44]

Other Latin American countries to which the Zika outbreak spread, including Colombia, Venezuela, and El Salvador, also reported increases in GBS cases.[43] In El Salvador, where an average of 14 cases of GBS are reported per month, 46 cases were reported between December 1, 2015 and January 6, 2016.[44]  A literature review by Barbi et al estimated that 1.23% of Zika virus cases could develop into GBS.[45]

However, additional research will be required to resolve speculation about the Zika-GBS link. The reliability of Zika virus diagnoses outside of the United States is not known. In the United States, the only infectious disease laboratories capable of making this diagnosis are at the US Centers for Disease Control and Prevention (CDC) and a few state or local health departments. There is currently no commercially available test for Zika virus.[46]

Vaccines

Vaccinations have been linked to GBS[47] by temporal association. For example, a study reviewing GBS cases during the 1992-1993 and 1993-1994 influenza seasons found an adjusted relative risk of 1.7 cases per 1 million influenza vaccinations.[48]

In most cases, however, no definite causal relation has been established between vaccines and GBS, with the exception of rabies vaccine prepared from infected brain tissue and the 1976 swine flu vaccine.[41, 49]  (The increased risk of GBS after the swine flu vaccination, however, was just one extra case per 100,000 vaccinations.[50] )

Moreover, a review of all postvaccination cases of GBS from 1990-2005 did not reveal an increase in mortality with postvaccination cases of GBS compared with cases resulting from other causes.[47]

In addition, some studies have called the GBS/vaccine link into question, finding no evidence of an increased risk of GBS after seasonal influenza vaccine or after the 2009 H1N1 mass vaccination program.[51, 52, 53]

For example, a study by Kawai et al that monitored adverse events following administration of the 2012-13 influenza vaccines found no association between the vaccines and GBS. Results were based on 3.6 million first doses of inactivated influenza vaccine in patients aged 6 months and older and 250,000 first doses of live attenuated vaccine in patients aged 2-49 years.[54]

A study by Dieleman et al researched the association between the pandemic influenza A (H1N1) 2009 vaccine and GBS in 104 patients in 5 European countries. Adjusting for the effects of influenzalike illness/upper respiratory tract infection, seasonal influenza vaccination, and calendar time, the authors concluded that there was no increased risk of occurrence of GBS after receiving the pandemic influenza vaccine.[55]

Similarly, a study conducted by the Chinese Centers for Disease Control found no evidence of increased risk of GBS from administration of the H1N1 vaccine, following the administration of 89.6 million doses of the vaccine between September 21, 2009 and March 21, 2010.[56]

Epidemiologic studies from Finland and southern California failed to validate an earlier retrospective study from Finland that suggested a cause-effect relationship between oral polio vaccination and GBS.[57, 58] In contrast, a Brazilian study suggested that, based on a temporal association between the vaccine and the onset of GBS, the vaccine may rarely correlate with the syndrome.[59]

Results from studies into the association between GBS and other vaccines include the following:

• Data from a large-scale epidemiologic study reported a decreased GBS incidence following administration of tetanus toxoid containing vaccinations when compared with the baseline population[60]

• An epidemiologic study failed to show any conclusive epidemiologic association between GBS and the hepatitis B vaccine[61]

• A large Latin American study of more than 2000 children with GBS following a mass measles vaccination program in 1992-1993 failed to establish a statistically significant causal relationship between administration of the measles vaccine and GBS[62]

• A report from the CDC suggests that recipients of the Menactra meningococcal conjugate vaccine may be at increased risk of GBS[63]

• Case reports exist regarding group A streptococcal vaccines and the rabies vaccine; however, conclusive, statistically significant evidence is lacking

In July 2021, the US Food and Drug Administration (FDA) announced that the Janssen (Johnson & Johnson) COVID-19 vaccine may increase the risk of developing GBS, adding the warning to the vaccine’s label. This announcement arose from the approximately 100 preliminary reports of GBS in persons to whom the Johnson & Johnson vaccine had been administered that had been identified in the federal Vaccine Adverse Event Reporting System by mid-July 2021. This was out of the 12.8 million doses of the Johnson & Johnson vaccine that had been administered in the United States up to that point. The risk seems to be higher in men, particularly those aged 50 years or above. Despite the warning, however, the FDA stated that it has not yet determined whether the vaccine actually causes GBS and indicated that the benefits of the vaccine outweigh the GBS risk. The FDA announcement does not apply to the Pfizer/BioNTech and Moderna COVID-19 vaccines.[64, 65, 66]

A study by Shao et al, which included a medical record analysis and literature review, reported a rate of 1.8-53.2 cases of GBS per million doses of COVID-19 vaccine. Out of 39 cases of GBS examined in the study, the most (25) followed administration of AstraZeneca’s ChAdOx1-S vaccine, followed by the Pfizer/BioNTech, Johnson & Johnson, and Sinovac Biotech vaccines (12, 1, and 1 cases, respectively).[67]

Medications

In a case-controlled study, patients with GBS reported more frequent penicillin and antimotility drug use and less frequent oral contraceptive use. However, no definite cause-effect relationships have been established.[68]

Case reports exist in the setting of tumor necrosis factor antagonist agents used in rheumatoid arthritis.[69, 70, 71, 72] Case reports also exist regarding streptokinase, isotretinoin, danazol, captopril, gold, and heroin, among others.

A study by Ali indicated that antibiotic therapy with fluoroquinolones also is associated with the development of GBS. Using cases reported between 1997 and 2012 to the US Food and Drug Administration (FDA) Adverse Reporting System, he determined that of 539 reports of peripheral neuropathy associated with fluoroquinolone treatment, 9% were for patients with GBS.[73]

Other associations

Various events, such as surgery, trauma, and pregnancy, have been reported as possible triggers of GBS, but these associations remain mostly anecdotal.

Case reports cite associations between bariatric and other gastric surgeries, renal transplantation, and epidural anesthesia.[74]

Anecdotal associations include systemic lupus erythematosus, sarcoidosis, lymphoma, and snakebite.

Tumor necrosis factor–alpha polymorphisms with increased expression are associated with many autoimmune and inflammatory diseases, and may increase susceptibility to axonal GBS subtypes. However, the role of these polymorphisms in GBS remains unclear and warrants further investigation.[75]

Occurrence in the United States

The annual US incidence of GBS is 1.2-3 per 100,000 inhabitants, making GBS the most common cause of acute flaccid paralysis in the United States.[8, 1, 36, 76] In comparing age groups, the annual mean rate of hospitalizations in the United States related to GBS increases with age, being 1.5 cases per 100,000 population in persons aged less than 15 years and peaking at 8.6 cases per 100,000 population in persons aged 70-79 years.[77]

US military personnel are at slightly increased risk of GBS compared with the general population. An antecedent episode of infectious gastroenteritis was a significant risk factor for the development of GBS among military personnel.[24]

International occurrence

GBS has been reported throughout the world.[78, 79] Most studies show annual incidence figures similar to those in the United States, without geographical clustering. AMAN and AMSAN occur mainly in northern China, Japan, and Mexico, making up only 5-10% percent of GBS cases in the United States.[80] AIDP accounts for up to 90% of cases in Europe, North America, and the developed world.

Epidemiologic studies from Japan indicate that in this region, in comparison with North America and Europe, a greater percentage of GBS cases are associated with antecedent C jejuni infections and a lesser number are related to antecedent CMV infections. Similarly, it has been reported that 69% of GBS cases in Dhaka, Bangladesh, have clinical evidence of antecedent C jejuni infection.[37]

Race-related demographics

GBS has been reported throughout the international community; no racial preponderance exists. In North America, Western Europe, and Australia, most patients with GBS meet electrophysiologic criteria for demyelinating polyneuropathy. In northern China, up to 65% of patients with GBS have axonal pathology.[15]

Sex-related demographics

GBS has a male-to-female ratio of 1.5:1; male preponderance is especially seen in older patients. However, a Swedish epidemiologic study reported that GBS rates decrease during pregnancy and increase in the months immediately following delivery.[81]

Age-related differences in incidence

GBS has been reported in all age groups, with the syndrome occurring at any time between infancy and old age. In the United States, the syndrome's age distribution seems to be bimodal, with a first peak in young adulthood (ages 15-35 y) and a second, higher one in middle-aged and elderly persons (ages 50-75 y). Infants appear to have the lowest risk of developing GBS.[82]

Short of death, the worst-case scenario in GBS is tetraplegia within 24 hours, with incomplete recovery after 18 months or longer. The best-case scenario is mild difficulty walking, with recovery within weeks. The usual scenario, however, is peak weakness in 10-14 days, with recovery in weeks to months. Average time on a ventilator (without treatment) is 50 days. There are likely many mild cases of GBS that are never definitively diagnosed, and patients make full recovery without treatment. The spectrum of milder disease has not been well studied nor clarified.

Approximately 80% patients with GBS walk independently at 6 months, and about 60% of patients attain full recovery of motor strength by 1 year. Recovery in approximately 5-10% of patients with GBS is prolonged, with several months of ventilator dependency and a very delayed, incomplete recovery.

Mortality

A 2008 epidemiologic study reported a 2-12% mortality rate despite ICU management,[76] although the rate may be less than 5% in tertiary care centers with a team of medical professionals who are familiar with GBS management.

Causes of GBS-related death include acute respiratory distress syndrome (ARDS), sepsis, pneumonia, venous thromboembolic disease, and cardiac arrest. Most cases of mortality are due to severe autonomic instability or from the complications of prolonged intubation and paralysis.[83, 84, 85, 86] The leading cause of death in elderly patients with GBS is arrhythmia.

GBS-associated mortality rates increase markedly with age. In the United States, the case-fatality ratio ranges from 0.7% in persons younger than 15 years to 8.6% in individuals older than 65 years. Survey data has shown that in patients aged 60 years or older, the risk of death is 6-fold that of persons aged 40-59 years and is 157-fold that of patients younger than 15 years. Although the death rate increases with age in males and females, after age 40 years males have a death rate that is 1.3 times greater than that of females.

GBS-related deaths usually occur in ventilator-dependent patients, resulting from such complications as pneumonia, sepsis, acute respiratory distress syndrome, and, less frequently, autonomic dysfunction.[87] Underlying pulmonary disease and the need for mechanical ventilation increase the risk of death, especially in elderly patients.

Morbidity

A significant percentage of survivors of GBS have persistent motor sequelae. Estimates indicate that 15-20% of patients have moderate residual deficits from GBS and that 1-10% are left severely disabled. Although the exact prevalence is uncertain, up to 25,000-50,000 persons in the United States may have long-term functional deficits from GBS.

The speed of recovery varies. Recovery often takes place within a few weeks or months; however, if axonal degeneration has occurred, recovery can be expected to progress slowly over many months, because regeneration may require 6-18 months. Length of hospital stay increases with advancing age, because of disease severity and associated medical complications.

Patients may experience persistent weakness, areflexia, imbalance, or sensory loss. Approximately 7-15% of patients have permanent neurologic sequelae (although figures of as high as 40% have been estimated), including bilateral footdrop, intrinsic hand muscle wasting, sensory ataxia, and dysesthesia. Patients may also exhibit long-term differences in pain intensity, fatigability, and functional impairment compared with healthy controls.[88, 89] In extremely rare cases, patients may experience recurrent GBS.[90, 91]

Numerous papers have addressed the issue of persistent fatigue after recovery from GBS.[92, 93, 94] Studies have suggested that a large percentage of patients continue to have fatigue-related problems, subsequently limiting their function at home and at work, as well as during leisure activities. Treatment suggestions range from gentle exercise to improvement in sleep patterns to relief of pain or depression, if present.

GBS can produce long-lasting changes in the psychosocial status of patients and their families.[95, 96, 97] Changes in work and leisure activities can be observed in just over one third of these patients, and psychosocial functional health status can be impaired even years after the GBS event.

Interestingly, psychosocial performance does not seem to correlate with the severity of residual problems with physical function. Poor conditioning and easy fatigability may be contributory factors.

Rudolph et al determined that patients who have had GBS seem overall to have a reduced quality of life and physical functioning. Their findings were based on a study of 42 GBS patients who were examined after a median of 6 years post ̶ disease onset using a variety of measures, including the visual analogue scale (VAS) for pain, the disability rating index (DRI), and the Medical Outcome Study 36-item short-form health status scale (SF-36).[89]

Prognostic factors

The following factors have been associated with adverse effect on outcomes in GBS[6, 98, 99] :

• Preceding gastrointestinal infection or diarrheal illness

• Older age (57 years or older)

• Poor upper extremity muscle strength

• Acute hospital stay of longer than 11 days

• ICU requirement

• Need for mechanical ventilation

• Medical Research Council (MRC) score below 40

• Discharge to rehabilitation

A rapidly progressing onset of weakness also has been associated with less favorable outcomes in many studies, although in other reports, delayed time to peak disability has been shown to be an independent predictor of poor outcome at 1 year.

Mean compound muscle action potential (CMAP) amplitudes of less than 20% of the lower limit of normal or the presence of inexcitable nerves on initial electrophysiologic studies are other predictors of poorer functional outcomes. Later tests (>1 mo after onset) showing persistence of a low mean CMAP have an even higher sensitivity and specificity than do initial tests showing low amplitude.

A prospective, multicenter study by Petzold et al suggested that CSF levels of high ̶ molecular weight neurofilament (NfH) protein, an axonal protein, are prognostic indicators in GBS.[100] The investigators found that among patients with GBS who suffered a poor outcome (defined as an inability to walk independently), the median NfH level was 1.78 ng/mL; in patients with GBS who had a good outcome, the median level was 0.03 ng/mL.

Increased CSF levels of neuron-specific enolase and S-100b protein are also associated with longer duration of illness.[8] Serologically, a longer-lasting increase in immunoglobulin M (IgM) anti-GM1 predicts slow recovery.[8]

The presence of underlying pulmonary disease or manifestation of dysautonomia has no prognostic significance in GBS.

A cohort study by van den Berg et al indicated that in patients with GBS, an association exists between prolonged mechanical ventilation (>2 months) and poor prognosis, although a cross-sectional study by these investigators suggested that some patients who have undergone prolonged mechanical ventilation may demonstrate slow, persistent recovery that eventually allows them to walk unaided and live independently. At 6 months, in the cohort study, the ability to walk unaided had been achieved in 18% of patients treated with prolonged mechanical ventilation and in 76% of those who underwent a shorter ventilation period. However, in the cross-sectional study, which had a median follow-up period of 11 years, 58% of patients who underwent prolonged mechanical ventilation could, at maximum follow-up, walk unaided, including 31% who achieved this outcome more than a year subsequent to diagnosis.[101]

Relapse

In a small percentage (~10%) of patients, an acute relapse occurs after initial improvement or stabilization after treatment. Some patients also demonstrate treatment fluctuations during their clinical course. Recurrence of Guillain-Barré syndrome is rare but has been reported in 2-5% of patients.[90, 91]

There is no convincing evidence that IVIG treatment or plasma exchange has a significant effect on the rate of treatment failure or of acute relapse.[102] The risk of relapse does, however, appear to be higher in patients in whom there has been a later onset of treatment, a more protracted disease course, and more associated medical conditions. Additional plasma exchange or IVIG treatments often result in further improvement.[103]

Patients with GBS and their families should be educated on the illness, the disease process, and the anticipated course. GBS is a life event with a potentially long-lasting influence on patients' physical and psychosocial well-being.[95, 96, 97] Family education and training also is recommended to prevent complications during the early stages of the disease and to assist in the recovery of function during the rehabilitation stages.

For patient education information, see the Brain and Nervous System Center, as well as Guillain-Barré Syndrome.

The typical patient with Guillain-Barré syndrome (GBS), which in most cases will manifest as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), presents 2-4 weeks following a relatively benign respiratory or gastrointestinal illness with complaints of finger dysesthesias and proximal muscle weakness of the lower extremities. The weakness may progress over hours to days to involve the arms, truncal muscles, cranial nerves, and muscles of respiration. Variants of GBS may present as pure motor dysfunction or acute dysautonomia.

The mean time to the clinical function nadir is 12 days, with 98% of patients reaching a nadir by 4 weeks. A plateau phase of persistent, unchanging symptoms then ensues, followed days later by gradual symptom improvement.[3] Progression of symptoms beyond that point brings the diagnosis under question. Recovery usually begins 2-4 weeks after the progression ceases.[104] The mean time to clinical recovery is 200 days.

Some patients with atypical presentation, incomplete weakness, and some inconsistencies in their physical examination are frequently diagnosed as having a psychological reaction or hysteria, and the diagnosis is very difficult. They are frequently sent home from the emergency department and then return with persistent or progressive symptoms hours to days later.

Weakness

The classic clinical picture of weakness is ascending and symmetrical in nature. The lower limbs are usually involved before the upper limbs. Proximal muscles may be involved earlier than the more distal ones. Trunk, bulbar, and respiratory muscles can be affected as well.

Patients may be unable to stand or walk despite reasonable strength, especially when ophthalmoparesis or impaired proprioception is present. Respiratory muscle weakness with shortness of breath may be present.

Weakness develops acutely and progresses over days to weeks. Severity may range from mild weakness to complete tetraplegia with ventilatory failure.

Cranial nerve involvement

Cranial nerve involvement is observed in 45-75% of patients with GBS. Cranial nerves III-VII and IX-XII may be affected. Common complaints include the following:

• Facial droop (may mimic Bell palsy)

• Diplopias

• Dysarthria

• Dysphagia

• Ophthalmoplegia

• Pupillary disturbances

Facial and oropharyngeal weakness usually appears after the trunk and limbs are affected. The Miller-Fisher variant of GBS is unique in that this subtype begins with cranial nerve deficits.[105]

Sensory changes

Most patients complain of paresthesias, numbness, or similar sensory changes. Sensory symptoms often precede the weakness. Paresthesias generally begin in the toes and fingertips, progressing upward but generally not extending beyond the wrists or ankles. Loss of vibration, proprioception, touch, and pain distally may be present.

Sensory symptoms are usually mild. In most cases, objective findings of sensory loss tend to be minimal and variable.

Pain

In a prospective, longitudinal study of pain in patients with GBS, 89% of patients reported pain that was attributable to GBS at some time during their illness. On initial presentation, almost 50% of patients described the pain as severe and distressing. The mechanism of pain is uncertain and may be a product of several factors. Pain can result from direct nerve injury or from the paralysis and prolonged immobilization.

Pain is most severe in the shoulder girdle, back, buttocks, and thighs and may occur with even the slightest movements. The pain is often described as aching or throbbing in nature.

Dysesthetic symptoms are observed in approximately 50% of patients during the course of their illness. Dysesthesias frequently are described as burning, tingling, or shocklike sensations and are often more prevalent in the lower extremities than in the upper extremities. Dysesthesias may persist indefinitely in 5-10% of patients.

Other pain syndromes in GBS include the following:

• Myalgic complaints, with cramping and local muscle tenderness

• Visceral pain

• Pain associated with conditions of immobility (eg, pressure nerve palsies, decubitus ulcers)

The intensity of pain on admission correlates poorly with neurologic disability on admission and with the end outcome.

Autonomic changes

Autonomic nervous system involvement with dysfunction in the sympathetic and parasympathetic systems can be observed in patients with GBS.

Autonomic changes can include the following:

• Tachycardia

• Bradycardia

• Facial flushing

• Paroxysmal hypertension

• Orthostatic hypotension

• Anhidrosis and/or diaphoresis

Urinary retention due to urinary sphincter disturbances may be noted. Constipation due to bowel paresis and gastric dysmotility may be present. Bowel and bladder dysfunction are rarely early or persistent findings.

A study by Anandan et al indicated that in hospitalized patients with GBS, autonomic dysfunction most frequently manifests as diarrhea/constipation (15.5%), hyponatremia (14.9%), syndrome of inappropriate antidiuretic hormone secretion (SIADH, 4.8%), bradycardia (4.7%), and urinary retention (3.9%). The study included 2587 patients with GBS and 10,348 controls.[106]

Dysautonomia is more frequent in patients with severe weakness and respiratory failure. Autonomic changes rarely persist in a patient with GBS.

Respiratory involvement

Upon presentation, 40% of patients have respiratory or oropharyngeal weakness. Typical complaints include the following:

• Dyspnea on exertion

• Shortness of breath

• Difficulty swallowing

• Slurred speech

Ventilatory failure with required respiratory support occurs in up to one third of patients at some time during the course of their disease.

Antecedent illness

Up to two thirds of patients with GBS report an antecedent illness or event 1-3 weeks prior to the onset of weakness. Upper respiratory and gastrointestinal illnesses are the most commonly reported conditions.[22, 24] Symptoms generally have resolved by the time the patient presents for the neurologic condition.

Campylobacter jejuni is the major causative organism identified in most studies and is responsible for cases of AIDP and acute motor axonal neuropathy (AMAN). In one major study, previous diarrheal illness had occurred in 60% of patients with axonal GBS (by neurophysiologic testing).

Vaccinations, surgical procedures, and trauma have been reported to trigger the development of GBS.[47] Much of this information is anecdotal, although vaccination with the swine flu vaccine administered in 1976 was shown to increase the risk of contracting GBS to a small, but definable, degree. Rabies vaccine prepared from infected brain tissue also was found to have an association with GBS. Studies of other vaccines, however, have not shown a significant relationship between these drugs and GBS or have been inconclusive.[49, 55]

Cardiac arrhythmias, including tachycardias and bradycardias, can be observed as a result of autonomic nervous system involvement. Tachypnea may be a sign of ongoing dyspnea and progressive respiratory failure.

Blood pressure lability is another common feature, with alterations between hypertension and hypotension. Temperature may be elevated or low.

Respiratory examination may be remarkable for poor inspiratory effort or diminished breath sounds. On abdominal examination, paucity or absence of bowel sounds suggests paralytic ileus. Suprapubic tenderness or fullness may be suggestive of urinary retention.

Neurologic examination

Facial weakness (cranial nerve VII) is observed most frequently, followed by symptoms associated with cranial nerves VI, III, XII, V, IX, and X. Involvement of facial, oropharyngeal, and ocular muscles results in facial droop, dysphagia, dysarthria, and findings associated with disorders of the eye.

Ophthalmoparesis may be observed in up to 25% of patients with GBS. Limitation of eye movement most commonly results from a symmetrical palsy associated with cranial nerve VI. Ptosis from cranial nerve III (oculomotor) palsy also is often associated with limited eye movements. Pupillary abnormalities, especially those accompanying ophthalmoparesis, are relatively common as well. Papilledema secondary to elevated intracranial pressure is present in rare cases. Tonic pupils have been reported but only in severe cases.

Lower extremity weakness usually begins first and ascends symmetrically and progressively over the first several days. Upper extremity, trunk, facial, and oropharyngeal weakness is observed to a variable extent. Marked asymmetrical weakness calls the diagnosis of GBS into question.

Patients may be unable to stand or walk despite reasonable strength, especially when ophthalmoparesis or impaired proprioception is present.

Despite frequent complaints of paresthesias, objective sensory changes are minimal. A well-demarcated sensory level should not be observed in patients with GBS; such a finding calls the diagnosis of GBS into question.

Reflexes are absent or reduced early in the disease course. Hyporeflexia or areflexia of involved areas represents a major clinical finding on examination of the patient with GBS. Pathologic reflexes, such as the Babinski sign, are absent. Hypotonia can be observed with significant weakness.

Guillain-Barré syndrome (GBS) is generally diagnosed on clinical grounds. Basic laboratory studies, such as complete blood counts (CBCs) and metabolic panels, are normal and of limited value in the workup. They are often ordered, however, to exclude other diagnoses and to better assess functional status and prognosis. The ordering of specific tests should be guided by the patient's history and presentation.

Electromyography (EMG) and nerve conduction studies (NCS) can be very helpful in the diagnosis. Abnormalities in NCS that are consistent with demyelination are sensitive and represent specific findings for classic GBS. Delayed distal latencies, slowed nerve conduction velocities, temporal dispersion of waveforms, conduction block, prolonged or absent F waves, and prolonged or absent H-reflexes are all findings that support demyelination. Needle EMG may be normal in acute nerve lesions, and it may take 3-4 weeks for fibrillation to develop. In the acute phase, the only needle EMG abnormality may be abnormal motor recruitment, with decreased recruitment and rapid firing motor units in weak muscles. Unfortunately, electrodiagnostic studies can be completely normal in acute GBS and a normal study does not rule GBS.[108, 109]

Frequent evaluations of pulmonary function parameters should be performed at bedside to monitor respiratory status and the need for ventilatory assistance.

Lumbar puncture for cerebrospinal fluid (CSF) studies is recommended. During the acute phase of GBS, characteristic findings on CSF analysis include albuminocytologic dissociation, which is an elevation in CSF protein (>0.55 g/L) without an elevation in white blood cells. The increase in CSF protein is thought to reflect the widespread inflammation of the nerve roots.

Imaging studies, such as magnetic resonance imaging (MRI) and computed tomography (CT) scanning of the spine, may be more helpful in excluding other diagnoses, such as mechanical causes of myelopathy, than in assisting in the diagnosis of GBS.

A basic peripheral neuropathy workup is recommended in cases in which the diagnosis is uncertain. These studies may include the following:

• Thyroid panel

• Rheumatology profiles

• Vitamin B-12

• Folic acid

• Hemoglobin A1C

• Erythrocyte sedimentation rate (ESR)

• Rapid protein reagent

• Immunoelectrophoresis of serum protein

• Tests for heavy metals

Biochemical screening includes the following studies:

• Electrolyte levels

• Liver function tests (LFTs)

• Creatine phosphokinase (CPK) level

• ESR

The following should be considered:

• LFT results are elevated in as many as one third of patients

• CPK and ESR may be elevated with myopathies or systemic inflammatory conditions

• A stool culture for C jejuni and a pregnancy test are also indicated

• The syndrome of inappropriate antidiuretic hormone (SIADH) may occur

Serologic studies are of limited value in the diagnosis of GBS. Assays for antibodies to the following infectious agents may be considered:

• C jejuni

• Cytomegalovirus (CMV)

• Epstein-Barr virus (EBV)

• Herpes simplex virus (HSV)

• HIV

• Mycoplasma pneumoniae

An increase in titers for infectious agents, such as CMV, EBV, or Mycoplasma, may help in establishing etiology for epidemiologic purposes. HIV has been reported to precede GBS, and serology should be tested in high-risk patients to establish possible infection with this agent.

Serum autoantibodies

Serum autoantibodies are not measured routinely in the workup of GBS, but results may be helpful in patients with a questionable diagnosis or a variant of GBS. Antibodies to glycolipids are observed in the sera of 60-70% of patients with GBS during the acute phase, with gangliosides being the major target antigens.[110]

Specific antibodies found in association with GBS include the following:

• Antibodies to GM1: Frequently found in the sera of patients with the acute motor axonal neuropathy (AMAN) or acute demyelinating polyradiculoneuropathy (AIDP) variants of GBS

• Anti-GM1 antibodies: Elevated titers are closely associated antecedent C jejuni infections

• Anti-GQ1b antibodies: Found in patients with GBS with ophthalmoplegia, including patients with the Miller-Fisher variant

Other antibodies to different major and minor gangliosides also have been found in GBS patients.

Nerve conduction studies (NCS) can be very helpful in the diagnostic workup and prognostic evaluation of patients with suspected GBS. Abnormalities in NCS that are consistent with demyelination are sensitive and represent specific findings for classic GBS.[108]

Signs of demyelination can include the following:

• Nerve conduction slowing

• Prolongation of the distal latencies

• Prolongation or absence of the F-waves[1, 2]

• Conduction block or dispersion of responses: Evidence frequently demonstrated at sites of natural nerve compression.

Changes on NCS should be present in at least 2 nerves in regions that are not typical for those associated with compressive mononeuropathies (preferentially in anatomically distinct areas, such as an arm and a leg or a limb and the face).

Although NCS results classically show a picture of demyelinating neuropathy in most patients, axonal neuropathy and inexcitable results are found in certain subgroups. The inexcitable studies may represent either axonopathy or severe demyelination with distal conduction block.

Other characteristics of GBS include the following:

• Nerve motor action potentials: May be decreased, but this is technically difficult to determine until the abnormality is severe; the extent of decreased action potentials correlates with prognosis

• Compound muscle action potential (CMAP): Amplitude may be decreased

• Sensory abnormalities: Exhibited by most patients, but these findings are much less marked than they are in motor nerves; sural sparing is a common finding in patients with clinical sensory deficits

• Abnormal (delayed, small, or absent) H-reflex: May be noted

The needle examination is of limited value in GBS. Reduced motor unit recruitment and absent denervation help to support the suggestion of a demyelinating mechanism, although the same changes can be observed in early axonal damage with pending wallerian degeneration. In severe cases, denervation changes may be observed later in the disease course.

In the axonal variant of the disease, absent or markedly reduced distal CMAP is observed on NCS. On needle examination, profuse and early denervation potentials (fibrillations) also support the conclusion that there has been axonal injury.

In some cases, neurophysiologic testing is normal in patients with GBS, especially in the first 1-2 weeks of the disease. This is believed to be due to the location of demyelinating lesions in proximal sites not amenable to study.[109]  For example, a retrospective, single-center study by Luigetti et al found that in 37% of patients with GBS who underwent an early nerve conduction study (ie, 4 days or less after disease onset), neurophysiologic results were normal. As a result, the investigators, whose study involved 71 patients with GBS, suggested that extensive neurophysiologic assessment should be performed in patients who are in the early phases of GBS.[111]

Maximal inspiratory pressures and vital capacities are measurements of neuromuscular respiratory function and predict diaphragmatic strength. Maximal expiratory pressures also reflect abdominal muscle strength. Frequent evaluations of these parameters should be performed at bedside to monitor respiratory status and the need for ventilatory assistance.

Forced vital capacity (FVC) is very helpful in guiding disposition and therapy.[86] Patients with an FVC of less than 15-20 mL/kg, maximum inspiratory pressure of less than 30 cm water, or a maximum expiratory pressure of less than 40 cm water generally progress to require prophylactic intubation and mechanical ventilation. Respiratory assistance should also be considered when there is a decrease in oxygen saturation (arterial partial pressure of oxygen [PO2] < 70 mm Hg).

Negative inspiratory force (NIF) is a relatively easy bedside test to measure respiratory muscle function and can easily be performed every half hour to hour in difficult cases. Normal is usually greater than 60 cm water. If the NIF is dropping or nears 20 cm water, respiratory support needs to be available.

Most, but not all, patients with GBS have an elevated CSF protein level (>400 mg/L), with normal CSF cell counts. Elevated or rising protein levels on serial lumbar punctures and 10 or fewer mononuclear cells/mm3 strongly support the diagnosis.

A normal CSF protein level does not rule out GBS, however, as the level may remain normal in 10% of patients. CSF protein may not rise until 1-2 weeks after the onset of weakness.

Normal CSF cell counts may not be a feature of GBS in HIV-infected patients. CSF pleocytosis is well recognized in HIV-associated GBS.

MRI is sensitive, but nonspecific, for diagnosis. However, it can reveal nerve root enhancement and may be an effective diagnostic adjunct.[112, 113]

Spinal nerve root enhancement with gadolinium is a nonspecific feature seen in inflammatory conditions and is caused by disruption of the blood-nerve barrier. Selective anterior nerve root enhancement appears to be strongly suggestive of GBS,[114] with the cauda equina nerve roots being enhanced in 83% of patients.

Muscle biopsy may help to distinguish GBS from a primary myopathy in unclear cases. Many different abnormalities may be seen on electrocardiography, including second- and third-degree atrioventricular (AV) block, T-wave abnormalities, ST depression, QRS widening, and various rhythm disturbances.

Lymphocyte and macrophage infiltration is observed on microscopic examination of peripheral nerves, with macrophage influx believed to be responsible for the multifocal demyelination seen in GBS. A variable degree of wallerian degeneration also can be observed with severe inflammatory changes.

Cellular infiltrates are scattered throughout the cranial nerves, nerve roots, dorsal root ganglions, and peripheral nerves.

Patients who are diagnosed with GBS should be admitted to a hospital for close monitoring until it has been determined that the course of the disease has reached a plateau or undergone reversal. Although the weakness may initially be mild and nondisabling, symptoms can progress rapidly over just a few days. Continued progression may result in a neuromuscular emergency with profound paralysis, respiratory insufficiency, and/or autonomic dysfunction with cardiovascular complications.

Approximately one third of patients require admission to an ICU, primarily because of respiratory failure. After medical stabilization, patients can be treated on a general medical/neurologic floor, but continued vigilance remains important in preventing respiratory, cardiovascular, and other medical complications. Patients with persistent functional impairments may need to be transferred to an inpatient rehabilitation unit.

Continued care also is needed to minimize problems related to immobility, neurogenic bowel and bladder, and pain. Early involvement of allied health staff is recommended.

Early recognition and treatment of GBS also may be important in the long-term prognosis, especially in the patient with poor clinical prognostic signs, such as older age, a rapidly progressing course, and antecedent diarrhea.[115]

Immunomodulatory treatment has been used to hasten recovery. Intravenous immunoglobulin (IVIG) and plasma exchange have proved equally effective.

Corticosteroids (oral and intravenous) have not been found to have a clinical benefit in GBS.[116] Consequently, this class of drugs is not currently employed in treatment of the syndrome.

A few studies have investigated other medications to treat GBS; however, the trials have been small and the evidence weak,[117] highlighting the need for further investigation of potential treatment options.

Prehospital care of patients with Guillain-Barré syndrome (GBS) requires careful attention to airway, breathing, and circulation (ABCs). Administration of oxygen and assisted ventilation may be indicated, along with establishment of intravenous access. Emergency medical services personnel should monitor for cardiac arrhythmias and transport expeditiously.

In the emergency department (ED), continuation of ABCs, intravenous treatment, oxygen, and assisted ventilation may be indicated.[118] Intubation should be performed on patients who develop any degree of respiratory failure. Clinical indicators for intubation in the ED include the following:

• Hypoxia

• Rapidly declining respiratory function

• Poor or weak cough

• Suspected aspiration

Typically, intubation is indicated when the forced vital capacity (FVC) is less than 15 mL/kg.[119] Declining NIF to -30 cm water should cause concern and very close monitoring.[120]

Patients should be monitored closely for changes in blood pressure, heart rate, and arrhythmias. Treatment is rarely needed for tachycardia. Atropine is recommended for symptomatic bradycardia.

Because of the lability of dysautonomia, hypertension is best treated with short-acting agents, such as a short-acting beta blocker or nitroprusside. Hypotension from dysautonomia usually responds to intravenous fluids and supine positioning. Temporary pacing may be required for patients with second- and third-degree heart block.

Consult a neurologist if any uncertainty exists as to the diagnosis. Consult the ICU team for evaluation of need for admission to the unit.

Good supportive care is critical in the treatment of patients with GBS.[92] Admission to the ICU should be considered for all patients with labile dysautonomia, a forced vital capacity of less than 20 mL/kg, or severe bulbar palsy.[3, 4] Any patients exhibiting clinical signs of respiratory compromise to any degree also should be admitted to an ICU.[3]

Because most deaths related to GBS are associated with complications of ventilatory failure and autonomic dysfunction, many patients need to be monitored closely in ICUs by physicians experienced in acute neuromuscular paralysis and its accompanying complications.

Competent intensive care includes the following features:

• Respiratory therapy

• Cardiac monitoring

• Safe nutritional supplementation

• Monitoring for infectious complications (eg, pneumonia, urinary tract infections, septicemia)

Respiratory therapy

Approximately one third of patients with GBS require ventilatory support. Monitoring for respiratory failure, bulbar weakness, and difficulties with swallowing help to anticipate complications. Proper positioning of the patient to optimize lung expansion and secretion management for airway clearance is required to minimize respiratory complications.

Serial assessment of ventilatory status is needed, including measurements of vital capacity and pulse oximetric monitoring. Respiratory assistance should be considered when the expiratory vital capacity decreases to less than 18 mL/kg or when a decrease in oxygen saturation is noted (arterial PO2< 70 mm Hg). Tracheotomy may be required in a patient with prolonged respiratory failure, especially if mechanical ventilation is required for more than 2 weeks.

Cardiac monitoring

Close monitoring of heart rate, blood pressure, and cardiac arrhythmias allows early detection of life-threatening situations. Critically ill patients require continuous telemetry and close medical supervision in an ICU setting.[3] Antihypertensives and vasoactive drugs should be used with caution in patients with autonomic instability. Hemodynamic changes related to autonomic dysfunction are usually transitory, and patients rarely require long-term medications to treat blood pressure or cardiac problems.

Nutrition

Enteral or parenteral feedings are required for patients on mechanical ventilation to ensure that adequate caloric needs are met when the metabolic demand is high. Even patients who are off the ventilator may require nutritional support if dysphagia is severe. Precautions against dysphagia and dietary manipulations should be used to prevent aspiration and subsequent pneumonias in patients at risk.

Prevention of infection

The risk of sepsis and infection can be decreased by the use of minimal sedation, frequent physiotherapy, and mechanical ventilation with positive end-expiratory pressure where appropriate.[3] Transfer may be appropriate if a facility does not have the proper resources to care for patients who require prolonged intubation or prolonged intensive care.

Prevention of thromboses, pressure sores, and contractures

Prevention of secondary complications of immobility is also required. Subcutaneous unfractionated or low ̶ molecular-weight heparin (LMWH) and thromboguards are often used in the treatment of immobile patients to prevent lower-extremity deep venous thrombosis (DVT) and consequent pulmonary embolism (PE).

Prevention of pressure sores and contractures entails careful positioning, frequent postural changes, and daily range-of-motion (ROM) exercises.

Bowel and bladder management

Although bowel and bladder dysfunction is generally transitory, management of these functions is needed to prevent other complications. Initial management should be directed toward safe evacuation and the prevention of overdistention. Monitoring for secondary infections, such as urinary tract infection, also is an area of concern. Nephropathy has been reported in pediatric patients.[121]

Mental status management

Hospitalized patients with GBS may experience mental status changes, including hallucinations, delusions, vivid dreams, and sleep abnormalities.[122] These occurrences are thought to be associated with autonomic dysfunction and are more frequent in patients with severe symptoms. Such problems resolve as the patient recovers. Psychiatric and psychological problems such as depression and anxiety are likely to occur. Education, counseling, and medications are necessary to manage these problems and help the patient adjust and improve from their profound disability.

Estimates suggest that approximately 40% of patients who are hospitalized with GBS require inpatient rehabilitation. Unfortunately, no long-term rehabilitation outcome studies have been conducted, and treatment is often based on experiences with other neurologic conditions. The goals of the therapy programs are to reduce functional deficits and to target impairments and disabilities resulting from GBS.

Early in the acute phase of GBS, patients may not be able to fully participate in an active therapy program. At that stage, patients benefit from daily ROM exercises and proper positioning to prevent muscle shortening and joint contractures. Addressing upright tolerance and endurance also may be a significant issue during the early part of rehabilitation.

Active muscle strengthening can then be slowly introduced and may include isometric, isotonic, isokinetic, or progressive resistive exercises. Mobility skills, such as bed mobility, transfers, and ambulation, are targeted functions. Patients should be monitored for hemodynamic instability and cardiac arrhythmias, especially upon initiation of the rehabilitation program. The intensity of the exercise program also should be monitored, because overworking the muscles may, paradoxically, lead to increased weakness.

In a study by Gupta et al in 35 patients (27 with classic GBS and 8 with acute motor axonal neuropathy [AMAN]), GBS-related deficits included neuropathic pain requiring medication therapy (28 patients), foot drop necessitating ankle-foot orthosis (AFO) use (21 patients), and locomotion difficulties requiring assistive devices (30 patients). At 1-year follow-up, the authors found continued foot drop in 12 of the AFO patients. However, significant overall functional recovery had occurred within the general cohort.[123]

Occupational therapy professionals should be involved early in the rehabilitation program to promote upper body strengthening, ROM, and activities that aid functional self care. Restorative and compensatory strategies can be used to promote functional improvements. Energy conservation techniques and work simplification also may be helpful, especially if the patient demonstrates poor strength and endurance.

Participation in recreational therapy assists in the patient's adjustment to disability and improves integration into the community. Recreational activities, either new or adapted, can be used to promote the growth, development, and independence of a long-term hospital patient.

Speech therapy is aimed at promoting speech and safe swallowing skills for patients who have significant oropharyngeal weakness with resultant dysphagia and dysarthria. In ventilator-dependent patients, alternative communication strategies also may need to be implemented.

Once weaned from the ventilator, patients with tracheostomies can learn voicing strategies and can eventually be weaned from the tracheostomy tube. Cognitive screening also can be performed conjointly with neuropsychology to assess for deficits, since cognitive problems have been reported in some patients with GBS, especially those who have had an extended ICU stay.

Plasma exchange carried out over a 10-day period may aid in removing autoantibodies, immune complexes, and cytotoxic constituents from serum and has been shown to decrease recovery time by 50%. A review of 6 randomized, controlled trials involving 649 participants found that plasma exchange helped speed recovery from GBS without causing harm, apart from being followed by a slightly increased risk of relapse.[124]

In well-controlled clinical trials, the efficacy of IVIGs in GBS patients has been shown to equal that of plasma exchange.[125, 126, 127, 128, 129, 130, 131, 132, 133]

IVIG treatment is easier to implement and potentially safer than plasma exchange, and the use of IVIGs versus plasma exchange may be a choice of availability and convenience.[129, 134, 135]

Additionally, IVIG is the preferential treatment in hemodynamically unstable patients and in those unable to ambulate independently.[136, 137] Some evidence suggests that in select patients who do not respond initially to IVIG, a second dose may be beneficial.[138] However, this is not currently standard therapy and warrants further investigation.

Combining plasma and IVIG has not been found to improve outcomes or shorten illness duration in GBS.[136] However, some clinicians prefer to try plasma exchange first, and if this does not provide patient improvement then they go to IVIG. Theoretically, if IVIG is given first, then the plasma exchange will be removing the IVIG, which was just given days earlier. There are no randomized controlled trials that allow one to decide on the best plan.

Immunotherapy for children with GBS has not been rigorously studied with randomized, well-controlled studies, but it is a standard aspect of treatment in this age group.[136, 139] Immunotherapy for pregnant women has not been studied, and safety for use during pregnancy has not been established.

Other possible treatments modulating the immune system include complement inhibitors such as eculizumab. This has been shown to be effective in animal models of Miller-Fisher syndrome[140, 141] and to be safe in humans.[142, 143, 144]  The Japanese Eculizumab Trial for GBS (JET-GBS), a prospective, multicenter, placebo-controlled, double-blind, randomized phase 2 study, reported eculizumab to be safe in severe cases of GBS. The investigators also found that at 24 weeks, 91.6% of patients on eculizumab could walk independently and 74% could run, compared with 71.9% and 18%, respectively, for those on placebo. Nonetheless, the report noted that "[t]he primary outcome measure did not reach the predefined response rate." Moreover, the study, which was designed to evaluate safety, was considered underpowered with regard to showing efficacy.[143, 144]

Corticosteroids are ineffective as monotherapy.[1, 17, 145] According to moderate-quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome.[145] According to low-quality evidence, oral corticosteroids delay recovery.[131, 145] Diabetes requiring insulin was significantly more common and hypertension less common with corticosteroids.

Methylprednisolone

Substantial evidence shows that intravenous methylprednisolone alone produces neither significant benefit nor harm.[145] In combination with IVIG, intravenous methylprednisolone may hasten recovery but does not significantly affect long-term outcome.[131, 146]

Pain medications may be required in inpatient and outpatient settings. A tiered pharmacologic approach that starts with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, with narcotic agents added as needed, is usually recommended.

Narcotics should be used judiciously because patients may already be at risk for ileus.[3] Most patients do not require narcotic analgesics after the first couple of months of illness.

Adjunct medications for pain, such as tricyclic antidepressants and certain anticonvulsants, may be beneficial for dysesthetic-type pains.[3, 147] Single small, randomized, controlled trials support the use of gabapentin or carbamazepine in the ICU for management during the acute phase of GBS.

Nonpharmacologic pain relief therapies include frequent passive limb movements, gentle massage, and frequent position changes. Desensitization techniques can be used to improve the patient's tolerance for activities. Modalities such as transcutaneous electrical nerve stimulation (TENS) and heat may prove beneficial in the management of myalgia. Education and psychological counseling can decrease the amount of suffering associated with this pain and disability.

Immune adsorption is an alternative treatment for Guillain-Barré syndrome that is still in the early stages of investigation. A small, prospective study reported no difference in outcome between patients treated with immunoadsorption and those treated with plasma exchange.[148]

In critically ill patients, a small German study reported that treatment with selective immune adsorption (SIA) seemed to be safe and effective. In comparison with treatment with SIA only, sequential therapy with IVIG was not more effective.[149]

Venous thromboembolism is one of the major sequelae of extremity paralysis. Time to development of DVT or pulmonary embolism varies from 4-67 days following symptom onset.[3] Prophylaxis with gradient compression hose and subcutaneous LMWH may dramatically reduce the incidence of venous thromboembolism.[3]

True gradient compression stockings (30-40 mm Hg or higher) are highly elastic and provide compression along a gradient that is highest at the toes and gradually decreases to the level of the thigh. This reduces capacity venous volume by approximately 70% and increases the measured velocity of blood flow in the deep veins by a factor of 5 or more.

The ubiquitous white stockings known as antiembolic stockings or thromboembolic disease (TED) hose produce a maximum compression of 18 mm Hg and rarely are fitted in such a way as to provide adequate gradient compression. They have not been shown to be effective as prophylaxis against thromboembolism.

Consultation with a neurologist can be helpful in the initial diagnosis, workup, and treatment of patients admitted to the medical floor with GBS.

Critical care specialists may be required for patients in the ICU to help manage respiratory failure and multiple medical complications.

Consultation with a pulmonologist may be needed to perform workup and to manage respiratory issues, such as acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure.

Consultation with a cardiologist may be required if significant cardiovascular complications, such as labile blood pressure and cardiac arrhythmias, arise from the associated autonomic dysfunction.

Consultation with a surgeon may be required for the placement of tracheostomies, enteral feeding tubes, and central lines.

Physical medicine and rehabilitation specialists (physiatrists) should evaluate patients for impairments and disabilities arising from GBS and should help to determine the most appropriate setting for and intensity of rehabilitation care and assist with their rehabilitation and return to function.

Although follow-up studies generally have assessed patients 6-12 months after onset of GBS, some studies have reported continued improvements in strength even beyond 2 years. With prolonged recovery possible, GBS patients with continued neurologic deficits may benefit from ongoing physical therapy and conditioning programs.

As previously mentioned, numerous papers have addressed the issue of persistent fatigue after recovery from GBS.[92, 93, 94] Studies have suggested that a large percentage of patients continue to have fatigue-related problems, subsequently limiting their function at home and at work, as well as during leisure activities. Treatment suggestions range from gentle exercise to improvement in sleep patterns to relief of pain or depression, if present.

GBS can produce long-lasting changes in the psychosocial status of patients and their families.[95, 96, 97] Changes in work and leisure activities can be observed in just over one third of these patients, and psychosocial functional health status can be impaired even years after the GBS event.

Interestingly, psychosocial performance does not seem to correlate with the severity of residual problems with physical function. Poor conditioning and easy fatigability may be contributory factors. Therefore, providing long-term attention and support for this population group is important.

Immunomodulatory therapy, such as plasmapheresis or the administration of intravenous immunoglobulins (IVIGs), is frequently used in patients with Guillain-Barré syndrome (GBS).[150] The efficacy of plasmapheresis and IVIGs appears to be about equal in shortening the average duration of disease.[125, 126, 127, 128, 151] Combined treatment has not been shown to produce a further, statistically significant reduction in disability.

A study by Lin et al indicated that the pretreatment severity score has the strongest association with therapeutic outcome in patients with GBS who undergo double-filtration plasmapheresis, with a higher score being linked to a poorer outcome. The study involved 60 GBS patients who underwent first-line therapy with the procedure.[152]

The decision to use immunomodulatory therapy is based on the disease's severity and rate of progression, as well as on the length of time between the condition's first symptom and its presentation. Risks, such as thrombotic events associated with IVIG, should be taken into consideration.[153, 154] Patients with severe, rapidly progressive disease are most likely to benefit from treatment, with faster functional recovery.[155]

Class Summary

These medications are used to improve the clinical and immunologic aspects of GBS. They may decrease autoantibody production and increase the solubilization and removal of immune complexes.

Intravenous immunoglobulin (Bivigam, Carimune NF, Gammagard S/D, Gamunex-C, Hizentra, Octagam, Privigen)

IVIG is derived from fractionated, purified human plasma collected from a large pool of multiple donors. The product is treated with solvents and detergents to inactivate any blood-borne virus. IVIG may work via several mechanisms, including the blockage of macrophage receptors, the inhibition of antibody production, the inhibition of complement binding, and the neutralization of pathologic antibodies.

Class Summary

Low ̶ molecular-weight heparin (LMWH) is used in the prophylaxis of deep venous thrombosis (DVT). The first LMWH to become available in the United States was enoxaparin (Lovenox). LMWH has been used widely in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as unfractionated heparin.

Reversible elevation of hepatic transaminase levels occurs occasionally. Heparin-associated thrombocytopenia has been observed with LMWH.

Enoxaparin (Lovenox)

Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. It also slightly affects thrombin and clotting time and preferentially increases the inhibition of factor Xa.

This agent has a wide therapeutic window; the prophylactic dose is not adjusted based on the patient's weight. Enoxaparin is safer and more effective than unfractionated heparin for prophylaxis of venous thromboembolism. The average duration of treatment is 7-14 days.

Dalteparin (Fragmin)

Dalteparin is an LMWH with antithrombotic properties. It enhances the inhibition of Factor Xa and thrombin by increasing antithrombin. It has a minimal effect on activated partial thromboplastin time (aPTT).

Tinzaparin

Tinzaparin is an LMWH with antithrombotic properties. It enhances the inhibition of Factor Xa and thrombin by increasing antithrombin. It has a minimal effect on aPTT.

Class Summary

Pain medications may be required in inpatient and outpatient settings. A tiered pharmacologic approach that starts with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, with narcotic agents added as needed, is usually recommended.

Acetaminophen (Tylenol, AspirinFree Anacin, Cetafen, Feverall, Mapap Extra Strength)

Acetaminophen is the drug of choice for the treatment of pain in patients with documented hypersensitivity to aspirin or NSAIDs, as well as in those with upper GI disease or who are taking oral anticoagulants.

Ibuprofen (Motrin, Advil, Neoprofen, Provil)

Ibuprofen inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. It is used to provide relief of cervical myofascial pain.

Indomethacin (Indocin)

Indomethacin is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)

Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Diclofenac (Voltaren-XR, Cataflam, Zipsor, Cambia)

Diclofenac inhibits prostaglandin synthesis by decreasing COX enzyme activity, which, in turn, decreases formation of prostaglandin precursors.

Ketoprofen

Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are indicated initially in small patients, elderly patients, and patients with renal or liver disease. Doses higher than 75 mg do not increase the therapeutic effects. Administer high doses with caution, and closely observe the patient's response.

Celecoxib (Celebrex)

Celecoxib primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, GI toxicity may be decreased. Seek the lowest dose of celecoxib for each patient. It is extensively metabolized in liver primarily via cytochrome P450 2C9.

Although increased cost can be a negative factor, the incidence of costly and potentially fatal GI bleeds is clearly less with COX-2 inhibitors than with traditional NSAIDs. Ongoing analysis of cost avoidance of GI bleeds will further define the populations that will find COX-2 inhibitors the most beneficial.

Class Summary

Anticonvulsants may be used to alleviate painful dysesthesias, which frequently accompany peripheral neuropathies. Although they have many different mechanisms of action, their use for alleviating neuropathic pain probably depends on their general tendency to reduce neuronal excitability.

Gabapentin (Gralise, Neurontin)

Gabapentin is a membrane stabilizer, a structural analogue of the inhibitory neurotransmitter gamma-amino butyric acid (GABA), which paradoxically is thought not to exert an effect on GABA receptors. Gabapentin appears to exert action via the alpha(2)delta1 and alpha(2)delta2 auxiliary subunits of voltage-gaited calcium channels

It is used to manage pain and provide sedation in neuropathic pain.

Carbamazepine (Carbatrol, Equetro, Epitol, Tegretol, Tegretol-XR)

Carbamazepine is a sodium channel blocker that typically provides substantial or complete relief of pain in 80% of individuals with some forms of painful paresthesia. It reduces sustained, high-frequency, repetitive neural firing and is a potent enzyme inducer that can induce its own metabolism. Due to potentially serious blood dyscrasias, undertake benefit-to-risk evaluation before the drug is instituted.

Class Summary

Tricyclic antidepressants are effective in painful paresthesias. Whereas the drugs in this category are administered in similar dosages, their sedative properties vary. Amitriptyline may be given if the patient suffers from insomnia, whereas nortriptyline and desipramine are better choices when sedation becomes a problem.

Amitriptyline

Amitriptyline is an analgesic for certain chronic and neuropathic pain. It blocks the reuptake of norepinephrine and serotonin, which increases their concentration in the CNS. Amitriptyline decreases pain by inhibiting spinal neurons involved in pain perception. It is highly anticholinergic. The drug is often discontinued because of somnolence and dry mouth.

Cardiac arrhythmia, especially in overdose, has been described; monitoring the QTc interval after reaching the target level is advised. Up to 1 month may be needed to obtain clinical effects.

Nortriptyline (Pamelor)

Nortriptyline has demonstrated effectiveness in the treatment of chronic pain.

By inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the CNS.

Pharmacodynamic effects such as the desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors also appear to play a role in its mechanisms of action.

Desipramine (Norpramin)

This is the original TCA used for depression. These agents have been suggested to act by inhibiting reuptake of noradrenaline at synapses in central descending pain-modulating pathways located in the brainstem and spinal cord.