Guillain–Barré syndrome (GBS) is a rapid-onsetmuscle weakness caused by theimmune system damaging theperipheral nervous system.[4] Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often in the back along with muscle weakness, beginning in the feet and hands, often spreading to the arms and upper body.[4] The symptoms may develop over hours to a few weeks.[4] During the acute phase, the disorder can be life-threatening, with about 15% of people developingrespiratory muscle weakness requiringmechanical ventilation.[1] Some are affected bychanges in the function of theautonomic nervous system, which can lead to dangerous abnormalities inheart rate andblood pressure.[4]
Although the cause is unknown, the underlying mechanism involves anautoimmune disorder in which the body's immune system mistakenly attacks the peripheral nerves and damages theirmyelin insulation.[4] Sometimes this immune dysfunction is triggered by an infection or, less commonly, by surgery, and byvaccination.[1][4] The diagnosis is usually based on the signs and symptoms through the exclusion of alternative causes and supported by tests such asnerve conduction studies and examination of thecerebrospinal fluid.[4] There are several subtypes based on the areas of weakness, results of nerve conduction studies, and the presence ofcertain antibodies.[6] It is classified as an acutepolyneuropathy.[1]
In those with severe weakness, prompt treatment withintravenous immunoglobulins orplasmapheresis, together with supportive care, lead to good recovery in the majority of cases.[4] Recovery may take weeks to years, with about a third having some permanent weakness.[4] Globally, death occurs in approximately 7.5% of patients.[1] Guillain–Barré syndrome is rare, at 1 or 2 cases per 100,000 people every year.[4][5]
The first symptoms of Guillain–Barré syndrome are numbness, tingling, and pain, alone or in combination. This is followed by weakness of the legs and arms that affects both sides equally and worsens over time.[9][10] The weakness can take half a day to over two weeks to reach maximum severity, and then becomes steady.[10] In one in five people, the weakness continues to progress for as long as four weeks.[6] The muscles of the neck may also be affected, and about half experience involvement of thecranial nerves that supply the head and face; this may lead toweakness of the muscles of the face,swallowing difficulties and sometimesweakness of the eye muscles.[6] In 8%, the weaknessaffects only the legs (paraplegia or paraparesis).[6] Involvement of the muscles that control the bladder and anus is unusual.[10] In total, about a third of people with Guillain–Barré syndrome continue to be able to walk.[6] Once the weakness has stopped progressing, it persists at a stable level ("plateau phase") before improvement occurs. The plateau phase can take between two days and six months, but the most common duration is a week.[6] Pain-related symptoms affect more than half, and includeback pain,parasthesia,muscle pain, and pain in the head and neck relating to irritation of the lining of the brain.[6]
Many people with Guillain–Barré syndrome have experienced the signs and symptoms of an infection in the 3–6 weeks before the onset of the neurological symptoms. The infection typically affects theupper respiratory tract (rhinitis, sore throat, cough) orgastrointestinal tract (diarrhea, abdominal pain, bloating).[10]
Various patterns of manifestation of Guillain–Barré syndrome
In children, particularly those younger than six years old, the diagnosis can be difficult and the condition is often initially mistaken (sometimes for up to two weeks) for other causes of pains and difficulty walking, such as viral infections,[6] or bone and joint problems.[11]
Two-thirds of people with Guillain–Barré syndrome have experienced an infection before the onset of the condition. Most commonly, these are episodes ofgastroenteritis or arespiratory tract infection. In many cases, the exact nature of the infection can be confirmed.[6] Approximately 30% of cases are provoked byCampylobacter jejuni bacteria, which cause diarrhea. A further 10% are attributable tocytomegalovirus (CMV, HHV-5). Despite this, only very few people withCampylobacter or CMV infections develop Guillain–Barré syndrome (0.25–0.65 per 1000 and 0.6–2.2 per 1000 episodes, respectively).[10] The strain ofCampylobacter involved may determine the risk of GBS; different forms of the bacteria have differentlipopolysaccharides on their surface, and some may induce illness (see below) while others will not.[6]
Links between other infections and GBS are less certain. Two other herpes viruses (Epstein–Barr virus/HHV-4 andvaricella zoster virus/HHV-3) and the bacteriumMycoplasma pneumoniae have been associated with GBS.[10] GBS is known to occur after influenza and influenza vaccination has been demonstrated to be associated with a reduced risk.[14] The tropical flaviviral infectionsdengue fever andZika virus have also been associated with episodes of GBS.[15][16] Previoushepatitis E virus infection is more common in people with GBS.[6][8]
An increased incidence of Guillain–Barré syndrome followed influenza immunization that followed the1976 swine flu outbreak (H1N1 A/NJ/76); 8.8 cases per million (0.0088 per 1000) recipients developed it as a complication.[17] GBS cases occurred in 362 patients during the 6 weeks after influenza vaccination of 45 million persons, an 8.8-fold increase over normal rates.[18] The 1976 swine flu vaccination-induced GBS was an outlier; small increases in incidence have been observed in subsequent vaccination campaigns, but not to the same extent.[17] The2009 flu pandemic vaccine againstpandemic swine flu virus H1N1/PDM09 did not cause a significant increase in cases. In fact, "studies found a small increase of approximately 1 case per million vaccines above the baseline rate, which is similar to that observed after administration of seasonal influenza vaccines over the past several years."[10] Natural influenza infection is a stronger risk factor for the development of GBS than is influenza vaccination and the vaccination reduced the risk of GBS overall by lowering the risk of catching influenza.[19]
In the United States, GBS after seasonal influenza vaccination is listed on the federal government'svaccine injury table.[20] On March 24, 2021, after reviewing several post-marketing observational studies, where an increased risk of Guillain–Barré syndrome was observed after 42 days following vaccination with theZoster vaccine Shingrix, theFDA required safety label changes from the manufacturerGlaxoSmithKline to include warnings for risk of Guillain–Barré syndrome.[21]
GBS has been reported in association withCOVID-19, and may be a potential neurological complication of the disease.[22][23][24][25] GBS has been reported as a very rare side effect of theJanssen andOxford–AstraZeneca COVID-19 vaccines[26] and theEuropean Medicines Agency issued a warning to the patients and healthcare providers.[27] The incidence of GBS following the vaccination with the Oxford–AstraZeneca vaccine was originally reported as being lower than the incidence of GBS following a COVID-19 infection.[28] More recent studies, however, found no measurable link between COVID-19 infection and GBS, while correlations with a first dose of AstraZeneca or Janssen vaccines were still positive.[29]
COVID-19 has been reported as causing peripheral neuropathy and more recently some evidence of aggravation of autoimmune disorders including GBS.[30]
Zimelidine, an antidepressant, had a very favorable safety profile but as a result of rare case reports of Guillain–Barré syndrome was withdrawn from the market.[31][32][33]
The nerve dysfunction in Guillain–Barré syndrome is caused by an immune attack on the nerve cells of the peripheral nervous system and their support structures. The nerve cells have their body (the soma) in thespinal cord and a long projection (theaxon) that carrieselectrical nerve impulses to theneuromuscular junction, where the impulse is transferred to the muscle. Axons are wrapped in a sheath ofSchwann cells that containmyelin. Between Schwann cells are gaps (nodes of Ranvier) where the axon is exposed.[10] Different types of Guillain–Barré syndrome feature different types of immune attacks. The demyelinating variant (AIDP, see below) features damage to the myelin sheath bywhite blood cells (T lymphocytes andmacrophages); this process is preceded by activation of a group of blood proteins known ascomplement. In contrast, the axonal variant is mediated byIgG antibodies and complement against thecell membrane covering the axon without direct lymphocyte involvement.[10]
Various antibodies directed at nerve cells have been reported in Guillain–Barré syndrome. In the axonal subtype, these antibodies have been shown to bind togangliosides, a group of substances found in peripheral nerves. A ganglioside is a molecule consisting ofceramide bound to a small group ofhexose-type sugars and containing various numbers ofN-acetylneuraminic acid groups. The key four gangliosidesagainst which antibodies have been described areGM1, GD1a, GT1a, and GQ1b, with different antiganglioside antibodies being associated with particular features; for instance, GQ1b antibodies have been linked with Miller Fisher variant GBS and related forms including Bickerstaff encephalitis.[10] The production of these antibodies after an infection probably is the result ofmolecular mimicry, where the immune system is reacting to microbial substances, but the resultant antibodies also react with substances occurring naturally in the body.[10][34] After aCampylobacter infection, the body produces antibodies of theIgA class; only a small proportion of people also produce IgG antibodies against bacterial substance cell wall substances (e.g. lipooligosaccharides) that cross-react with human nerve cell gangliosides. It is not currently known how this process escapescentral tolerance to gangliosides, which is meant to suppress the production of antibodies against the body's own substances.[35] Not allantiganglioside antibodies cause disease, and it has recently been suggested that some antibodies bind to more than one type ofepitope simultaneously (heterodimeric binding) and that this determines the response. Furthermore, the development of pathogenic antibodies may depend on the presence of other strains of bacteria in the bowel.[35]
It has been suggested that a poor injection technique may also cause a direct injury to the axillary nerves adjacent to the injection site in the deltoid muscle which may lead to peripheral neuropathy. The consequent vaccine transfection and translation in the nerves may spur an immune response against nerve cells potentially causing an autoimmune nerve damage, leading to conditions like Guillain–Barré syndrome.[36]
The diagnosis of Guillain–Barré syndrome depends on findings such as rapid development of muscle paralysis, absent reflexes, absence of fever, and absence of a likely cause. Cerebrospinal fluid analysis (through alumbar spinal puncture) andnerve conduction studies are supportive investigations commonly performed in the diagnosis of GBS.[6][8][10] Testing for antiganglioside antibodies is often performed, but their contribution to diagnosis is usually limited.[6] Blood tests are generally performed to exclude the possibility of another cause for weakness, such as alow level of potassium in the blood.[10] Anabnormally low level of sodium in the blood is often encountered in Guillain–Barré syndrome. This has been attributed to theinappropriate secretion of antidiuretic hormone, leading to relative retention of water.[37]
In many cases,magnetic resonance imaging of the spinal cord is performed to distinguish between Guillain–Barré syndrome and other conditions causing limb weakness, such asspinal cord compression.[6][10] If an MRI scan shows enhancement of thenerve roots, this may be indicative of GBS.[6] In children, this feature is present in 95% of scans, but it is not specific to Guillain–Barré syndrome, so other confirmation is also needed.[11]
Cerebrospinal fluid envelops the brain and the spine, and a lumbar puncture or spinal tap is the removal of a small amount of fluid using a needle inserted between thelumbar vertebrae. Characteristic findings in Guillain–Barré syndrome are an elevated protein level, usually greater than 0.55 g/L, and fewer than 10 white blood cells per cubic millimeter of fluid ("albuminocytological dissociation").[38] This pattern distinguishes Guillain–Barré syndrome from other conditions (such aslymphoma andpoliomyelitis) in which both the protein and thecell count are elevated. Elevated CSF protein levels are found in approximately 50% of patients in the first 3 days after onset of weakness, which increases to 80% after the first week.[6]
Repeating the lumbar puncture during the disease course is not recommended. The protein levels may rise after treatment has been administered.[6]
Directly assessingnerve conduction of electrical impulses can exclude other causes of acute muscle weakness, as well as distinguish the different types of Guillain–Barré syndrome. Needleelectromyography (EMG) and nerve conduction studies may be performed. In the first two weeks, these investigations may not show any abnormality.[6][39] Neurophysiology studies are not required for the diagnosis.[10]
Formal criteria exist for each of the main subtypes of Guillain–Barré syndrome (AIDP and AMAN/AMSAN, see below), but these may misclassify some cases (particularly where there is reversible conduction failure), and therefore changes to these criteria have been proposed.[40] Sometimes, repeated testing may be helpful.[40]
Several subtypes of Guillain–Barré syndrome are recognized.[6][40] Despite this, many people have overlapping symptoms that can make the classification difficult in individual cases.[7][41] All types have partial forms. For instance, some people experience only isolated eye movement or coordination problems; these are thought to be a subtype ofMiller Fisher syndrome and have similar antiganglioside antibody patterns.[12][41]
Isolated muscle weakness without sensory symptoms in less than 10%; cranial nerve involvement uncommon
Rare in Europe and North America, a substantial proportion (30–65%) in Asia and Central and South America; sometimes called "Chinese paralytic syndrome"
Axonal polyneuropathy, normal sensory action potential
GM1a/b, GD1a & GalNac-GD1a
Acute motor and sensory axonal neuropathy (AMSAN)
Severe muscle weakness similar to AMAN but with sensory loss
—
Axonal polyneuropathy, reduced or absent sensory action potential
GM1, GD1a
Pharyngeal-cervical-brachial variant
Weakness particularly of the throat muscles, and face, neck, and shoulder muscles
—
Generally normal, sometimes axonal neuropathy in arms
Mostly GT1a, occasionally GQ1b, rarely GD1a
Miller Fisher syndrome
Ataxia, eye muscle weakness, areflexia but usually no limb weakness
This variant occurs more commonly in men than in women (2:1 ratio). Cases typically occur in the spring and the average age of occurrence is 43 years old.[42]
Generally normal, sometimes discrete changes in sensory conduction orH-reflex detected
GQ1b, GT1a
Other diagnostic entities are often included in the spectrum of Guillain–Barré syndrome.Bickerstaff's brainstem encephalitis (BBE), for instance, is part of the group of conditions now regarded as forms of Miller Fisher syndrome (anti-GQ1b antibody syndrome),[12] as well as a related condition labelled "acute ataxic hypersomnolence"[43] where coordination problems and drowsiness are present but no muscle weakness can be detected.[41] BBE is characterized by the rapid onset of ophthalmoplegia, ataxia, and disturbance of consciousness, and may be associated with absent or decreased tendon reflexes and as well asBabinski's sign.[41] The course of the disease is usually monophasic, but recurrent episodes have been reported. MRI abnormalities in the brainstem have been reported in 11%.[12]
Whether isolated acute sensory loss can be regarded as a form of Guillain–Barré syndrome is a matter of dispute; this is a rare occurrence compared to GBS with muscle weakness but no sensory symptoms.[39]
Plasmapheresis andintravenous immunoglobulins (IVIG) are the two main immunotherapy treatments for GBS. Plasmapheresis attempts to reduce the body's attack on the nervous system by filtering antibodies out of the bloodstream.[44] Similarly, administration of IVIG neutralizes harmful antibodies and inflammation. These two treatments are equally effective, but a combination of the two is not significantly better than either alone.[45] Plasmapheresis speeds recovery when used within four weeks of the onset of symptoms.[46] IVIG works as well as plasmapheresis when started within two weeks of the onset of symptoms, and has fewer complications.[46] IVIG is usually used first because of its ease of administration and safety; the risks include occasionally causingliver inflammation, or in rare cases, kidney failure.[47]Glucocorticoids alone are not effective in speeding recovery and could potentially delay recovery.[48]
While pain is common in people with Guillain–Barré syndrome, studies comparing different types ofpain medication are insufficient to make a recommendation as to which should be used.[50]
Physiotherapy interventions include strength, endurance, and gait training with graduated increases in mobility, maintenance of posture and alignment as well as joint function. Occupational therapy aims to improve everyday function with domestic and community tasks as well as driving and work. Home modifications, gait aids,orthotics, and splints may be provided.[51]Speech-language pathology input may be required in those with speech and swallowing problems, as well as to support communication in those who require ongoing breathing support (often through atracheostomy). Nutritional support may be provided by the team and bydietitians. Psychologists may provide counselling and support. Psychological interventions may also be required for anxiety, fear, and depression.[51]
Ongoing specialist community support, information, advice, and guidance is available from a range ofCharities,Non-Government Organisations (NGOs), and Patient Advisory Groups around the world. In theUnited Kingdom this is provided by Inflammatory Neuropathies UK,[53] in theUSA it is provided by GBS/CIDP Foundation International,[54] and inThe European Union by a range of organisations under the umbrella of EPODIN (European Patient Organization for Dysimmune & Inflammatory Neuropathies).[55]
Guillain–Barré syndrome can lead to death as a result of many complications: severe infections, blood clots, and cardiac arrest likely due to autonomic neuropathy. Despite optimum care, this occurs in about 5% of cases.[10]
There is a variation in the rate and extent of recovery.[10] The prognosis of Guillain–Barré syndrome is determined mainly by age (those over 40 may have a poorer outcome), and by the severity of symptoms after two weeks. Furthermore, those who experienced diarrhea before the onset of the disease have a worse prognosis.[13] In the nerve conduction study, the presence of conduction block predicts poorer outcomes at six months.[13] In those who have received intravenous immunoglobulins, a smaller increase in IgG in the blood two weeks after administration is associated with poorer mobility outcomes at six months than those whose IgG level increased substantially.[13] If the disease continues to progress beyond four weeks, or there are multiple fluctuations in the severity (more than two in eight weeks), the diagnosis may bechronic inflammatory demyelinating polyneuropathy, which is treated differently.[6]
In research studies, the outcome from an episode of Guillain–Barré syndrome is recorded on a scale from 0 to 6, where 0 denotes completely healthy:
Thehealth-related quality of life (HRQL) after an attack of Guillain–Barré syndrome can be significantly impaired. About a fifth are unable to walk unaided after six months, and many experiencechronic pain,fatigue, and difficulty with work, education, hobbies, and social activities.[57] HRQL improves significantly in the first year.[57]
In Western countries, the number of new episodes per year has been estimated to be between 0.89 and 1.89 cases per 100,000 people. Children and young adults are less likely to be affected than the elderly: the relative risk increases by 20% for every decade of life.[5] Men are more likely to develop Guillain–Barré syndrome than women; therelative risk for men is 1.78 compared to women.[5][10]
The distribution of subtypes varies between countries. In Europe and the United States, 60–80% of people with Guillain–Barré syndrome have the demyelinating subtype (AIDP), and AMAN affects only a small number (6–7%). In Asia and Central and South America, that proportion is significantly higher (30–65%). This may be related to the exposure to different kinds of infection, but also the genetic characteristics of that population.[6] The Miller Fisher variant is thought to be more common in Southeast Asia.[10][12]
Georges Guillain, together with Barré and Strohl, described two cases of self-limiting acute paralysis with peculiar changes in the cerebrospinal fluid. He succeeded his teacherPierre Marie as professor of neurology at theSalpêtrière hospital in Paris in 1925.[58]
C. Miller Fisher described the variant that bears his name in 1956.[12][61] British neurologistEdwin Bickerstaff described theencephalitis type in 1951 and made further contributions with another paper in 1957.[12][62][63] Guillain had reported on some of these features before their full description in 1938.[12] Further subtypes have been described since then, such as the form featuring pure ataxia and the type causing pharyngeal-cervical-brachial weakness.[12] The axonal subtype was first described in 1986.[64]
Diagnostic criteria were developed in the late 1970s after the series of cases associated withswine flu vaccination. These were refined in 1990.[6][65] The case definition was revised by theBrighton Collaboration for vaccine safety in 2009,[66] but is mainly intended for research.[6] Plasma exchange was first used in 1978, and its benefit was confirmed in larger studies in 1985.[67] Intravenous immunoglobulins were introduced in 1988, and studies in the early 1990s demonstrated that they were no less effective than plasma exchange.[67]
The understanding of the disease mechanism of Guillain–Barré syndrome has evolved in recent years.[39] Development of new treatments has been limited since immunotherapy was introduced in the 1980s and 1990s.[39][67] Current research is aimed at demonstrating whether some people who have received IVIg might benefit from a second course if the antibody levels measured in blood after treatment have shown only a small increase.[13][67] Studies of the immunosuppressive drugsmycophenolate mofetil,brain-derived neurotrophic factor andinterferon beta (IFN-β) have not demonstrated benefit to support their widespread use.[67]
An animal model (experimental autoimmune neuritis in rats) is often used for studies, and some agents have shown promise:glatiramer acetate,quinupramine,fasudil (an inhibitor of theRho-kinase enzyme),[39] and the heart drugflecainide.[67] An antibody targeted against the anti-GD3 antiganglioside antibody has shown benefit in laboratory research.[39] Given the role of the complement system in GBS, it has been suggested that complement inhibitors (such as the drugeculizumab) may be effective.[67]
In animals, it is called acute polyradiculoneuritis or "coonhound paralysis", and may onset in thecoonhound 7 to 10 days after transmission fromraccoons. If the coonhound has not been around raccoons, the disease is called acute idiopathic polyradiculoneuritis.[68][69]
^abcUncini A, Kuwabara S (August 2012). "Electrodiagnostic criteria for Guillain-Barrè syndrome: a critical revision and the need for an update".Clinical Neurophysiology.123 (8):1487–95.doi:10.1016/j.clinph.2012.01.025.PMID22480600.S2CID33276521.
^Mori M, Kuwabara S, Yuki N (January 2012). "Fisher syndrome: clinical features, immunopathogenesis and management".Expert Review of Neurotherapeutics.12 (1):39–51.doi:10.1586/ern.11.182.PMID22149656.S2CID5597853.
^Wakerley, BR; Soon, D; Yuki, N (2013). "Atypical Bickerstaff brainstem encephalitis: ataxic hypersomnolence without ophthalmoplegia".J Neurol Neurosurg Psychiatry.84 (11):1206–7.doi:10.1136/jnnp-2013-304993.PMID23564757.S2CID22756453.
^Fisher M (July 1956). "An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia)".The New England Journal of Medicine.255 (2):57–65.doi:10.1056/NEJM195607122550201.PMID13334797.
Steinberg GJ, Parry JS (2006).Guillain–Barré syndrome: from diagnosis to recovery. New York: Demos; ANN Press (American Academy of Neurology).ISBN978-1-932603-56-9.
