Guillain–Barré syndrome

Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system.^[3] 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.^[3] The symptoms may develop over hours to a few weeks.^[3] During the acute phase, the disorder can be life-threatening, with about 15% of people developing weakness of the breathing muscles and, therefore, requiring mechanical ventilation.^[1] Some are affected by changes in the function of the autonomic nervous system, which can lead to dangerous abnormalities in heart rate and blood pressure.^[3]

Although the cause is unknown, the underlying mechanism involves an

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.[8]^[9] The weakness can take half a day to over two weeks to reach maximum severity, and then becomes steady.^[9] In one in five people, the weakness continues to progress for as long as four weeks.^[5] The muscles of the neck may also be affected, and about half experience involvement of the cranial nerves that supply the head and face; this may lead to weakness of the muscles of the face, swallowing difficulties and sometimes weakness of the eye muscles.^[5] In 8%, the weakness affects only the legs (paraplegia or paraparesis).^[5] Involvement of the muscles that control the bladder and anus is unusual.^[9] In total, about a third of people with Guillain–Barré syndrome continue to be able to walk.^[5] 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.^[5] Pain-related symptoms affect more than half, and include back pain, painful tingling, muscle pain, and pain in the head and neck relating to irritation of the lining of the brain.^[5]

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. This may consist of upper respiratory tract infection (rhinitis, sore throat), or diarrhea.^[9]

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,^[5] or bone and joint problems.^[10]

On

Two-thirds of people with Guillain–Barré syndrome have experienced an infection before the onset of the condition. Most commonly, these are episodes of

An increased incidence of Guillain–Barré syndrome followed influenza immunization that followed the

GBS has been reported in association with COVID-19, and may be a potential neurological complication of the disease.^{[21][22][23][24]} GBS has been reported as a very rare side effect of the Janssen and the Oxford–AstraZeneca COVID-19 vaccine for COVID-19^[25] and European Medicines Agency (EMA) had issued warning to the patients and healthcare providers.^[26] 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.^[27] 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.^[28]

COVID-19 has been reported as causing peripheral neuropathy and more recently some evidence of aggravation of autoimmune disorders including GBS.^[29]

Drug induced

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.^[30][31][32]

Pathophysiology

Dendrite

Soma

Axon

Nucleus

Node of
Ranvier

Axon terminal

Schwann cell

Myelin sheath

Structure of a typical neuron

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 the spinal cord and a long projection (the axon) that carries electrical nerve impulses to the neuromuscular junction, where the impulse is transferred to the muscle. Axons are wrapped in a sheath of Schwann cells that contain myelin. Between Schwann cells are gaps (nodes of Ranvier) where the axon is exposed.^[9] Different types of Guillain–Barré syndrome feature different types of immune attacks. The demyelinating variant (AIDP, see below) features damage to the myelin sheath by white blood cells (T lymphocytes and macrophages); this process is preceded by activation of a group of blood proteins known as complement. In contrast, the axonal variant is mediated by IgG antibodies and complement against the cell membrane covering the axon without direct lymphocyte involvement.^[9]

Various antibodies directed at nerve cells have been reported in Guillain–Barré syndrome. In the axonal subtype, these antibodies have been shown to bind to gangliosides, a group of substances found in peripheral nerves. A ganglioside is a molecule consisting of ceramide bound to a small group of hexose-type sugars and containing various numbers of N-acetylneuraminic acid groups. The key four gangliosides against which antibodies have been described are GM1, 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.^[9] The production of these antibodies after an infection probably is the result of molecular mimicry, where the immune system is reacting to microbial substances, but the resultant antibodies also react with substances occurring naturally in the body.^[9][33] After a Campylobacter infection, the body produces antibodies of the IgA 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 escapes central tolerance to gangliosides, which is meant to suppress the production of antibodies against the body's own substances.^[34] Not all antiganglioside antibodies cause disease, and it has recently been suggested that some antibodies bind to more than one type of epitope 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.^[34]

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 deltoid muscle that 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.^[35]

Diagnosis

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 a lumbar spinal puncture) and nerve conduction studies are supportive investigations commonly performed in the diagnosis of GBS.^[5][7][9] Testing for antiganglioside antibodies is often performed, but their contribution to diagnosis is usually limited.^[5] Blood tests are generally performed to exclude the possibility of another cause for weakness, such as a low level of potassium in the blood.^[9] An abnormally low level of sodium in the blood is often encountered in Guillain–Barré syndrome. This has been attributed to the inappropriate secretion of antidiuretic hormone, leading to relative retention of water.^[36]

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 as spinal cord compression.^[5][9] If an MRI scan shows enhancement of the nerve roots, this may be indicative of GBS.^[5] 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.^[10]

Spinal fluid

Repeating the lumbar puncture during the disease course is not recommended. The protein levels may rise after treatment has been administered.[5]

Neurophysiology

Directly assessing nerve conduction of electrical impulses can exclude other causes of acute muscle weakness, as well as distinguish the different types of Guillain–Barré syndrome. Needle electromyography (EMG) and nerve conduction studies may be performed. In the first two weeks, these investigations may not show any abnormality.^[5][38] Neurophysiology studies are not required for the diagnosis.^[9]

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.^[39] Sometimes, repeated testing may be helpful.^[39]

Clinical subtypes

A number of subtypes of Guillain–Barré syndrome are recognized.^[5][39] Despite this, many people have overlapping symptoms that can make the classification difficult in individual cases.^[6][40] All types have partial forms. For instance, some people experience only isolated eye-movement or coordination problems; these are thought to be a subtype of Miller Fisher syndrome and have similar antiganglioside antibody patterns.^[11][40]

Other diagnostic entities are often included in the spectrum of Guillain–Barré syndrome.

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.[38]

Treatment

Immunotherapy

While pain is common in people with Guillain–Barré syndrome, studies comparing different types of pain medication are insufficient to make a recommendation as to which should be used.^[49]

Rehabilitation

Following the acute phase, around 40% of people require intensive rehabilitation with the help of a multidisciplinary team to focus on improving activities of daily living (ADLs).^[50] Studies into the subject have been limited, but it is likely that intensive rehabilitation improves long-term symptoms.^[51] Teams may include physical therapists, occupational therapists, speech language pathologists, social workers, psychologists, other allied health professionals and nurses. The team usually works under the supervision of a neurologist or rehabilitation physician directing treatment goals.^[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,

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.[9]

There is a variation in the rate and extent of recovery.^[9] 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.^[12] On the nerve conduction study, the presence of conduction block predicts poorer outcome at 6 months.^[12] 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.^[12] 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 be chronic inflammatory demyelinating polyneuropathy, which is treated differently.^[5]

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; 1 very minor symptoms but able to run; 2 able to walk but not to run; 3 requiring a stick or other support; 4 confined to bed or chair; 5 requiring long-term respiratory support; 6 death.^[52]

The

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.^[4] Men are more likely to develop Guillain–Barré syndrome than women; the relative risk for men is 1.78 compared to women.^[4][9]

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.^[5] Miller Fisher variant is thought to be more common in Southeast Asia.^[9][11]

History

Jean-Baptiste Octave Landry first described the disorder in 1859.^[55] In 1916, Georges Guillain, Jean Alexandre Barré, and André Strohl diagnosed two soldiers with the illness and described the key diagnostic abnormality—albuminocytological dissociation—of increased spinal fluid protein concentration but a normal cell count.^[6][7][56]

Diagnostic criteria were developed in the late 1970s after the series of cases associated with swine flu vaccination. These were refined in 1990.^[5][61] The case definition was revised by the Brighton Collaboration for vaccine safety in 2009,^[62] but is mainly intended for research.^[5] Plasma exchange was first used in 1978, and its benefit was confirmed in larger studies in 1985.^[63] Intravenous immunoglobulins were introduced in 1988, and studies in the early 1990s demonstrated that they were no less effective than plasma exchange.^[63]

Research directions

The understanding of the disease mechanism of Guillain–Barré syndrome has evolved in recent years.^[38] Development of new treatments has been limited since immunotherapy was introduced in the 1980s and 1990s.^[38][63] 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.^[12][63] Studies of the immunosuppressive drugs mycophenolate mofetil, brain-derived neurotrophic factor and interferon beta (IFN-β) have not demonstrated benefit to support their widespread use.^[63]

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 the Rho-kinase enzyme),^[38] and the heart drug flecainide.^[63] An antibody targeted against the anti-GD3 antiganglioside antibody has shown benefit in laboratory research.^[38] Given the role of the complement system in GBS, it has been suggested that complement inhibitors (such as the drug eculizumab) may be effective.^[63]

In animals it is called acute polyradiculoneuritis or "coonhound paralysis", and may onset in the