Guillain–Barré Syndrome (GBS)
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Introduction
Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. It starts with changes in sensation or pain, followed by muscle weakness beginning in the feet & hands. The symptoms develop a period of half a day to two weeks.
During the acute phase, the disorder can be life-threatening with about a quarter developing weakness of the breathing muscles & requiring mechanical ventilation. Some are affected by changes in the function of the autonomic nervous system, which can lead to dangerous abnormalities in heart rate & blood pressure.
This autoimmune disease is caused by the body's immune system mistakenly attacking the peripheral nerves & damaging their myelin insulation. This immune dysfunction can be triggered by an infection. The diagnosis is usually made based on the signs & symptoms, through the exclusion of alternative causes, and supported by tests such as nerve conduction studies and examination of the cerebrospinal fluid. Various classifications exist, depending on the areas of weakness, results of nerve conduction studies, and the presence of antiganglioside antibodies. It is classified as an acute polyneuropathy.
In those with severe weakness, prompt treatment with intravenous immunoglobulins or plasmapheresis, together with supportive care, will lead to good recovery in the majority. Some may experience ongoing difficulty with walking, painful symptoms, and some require long-term breathing support. Guillain–Barré syndrome is rare, at one to two cases per 100,000 people every year.
Signs and symptoms
The first symptoms of Guillain–Barré syndrome are:
- numbness
- tingling
- pain
These occur alone or in combination.
Followed by weakness of the legs & arms that affects both sides equally & worsens over time. This can take half a day to over two weeks to reach maximum severity, then becomes steady.
One in five people, experience this weakness for as long as four weeks. The muscles of the neck may also be affected, & about half experience involvement of the cranial nerves which supply the head & face. This may lead to weakness of the muscles of the face, difficulties in swallowing & sometimes weakness of the eye muscles. In 8%, the weakness affects only the legs & the muscles that control the bladder & anus. In total, about a third of people with Guillain–Barré syndrome continue to be able to walk.
Once the weakness has stopped progressing, it persists at a stable level before improvement occurs. This is known as the plateau phase & usually takes a week, but can take between two days & six months. Pain-related symptoms affect more than half, & include back pain, painful tingling, muscle pain & pain in the head, neck. This is due to irritation of the lining of the brain.
Many people with Guillain–Barré syndrome have experienced the signs and symptoms of an infection in the 3–6 weeks prior to the onset of the neurological symptoms. This may consist of upper respiratory tract infection or diarrhea.
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, or bone and joint problems.
On neurological examination, characteristic features are the reduced power and reduced or absent tendon reflexes (hypo- or areflexia, respectively). However, a small proportion has normal reflexes in affected limbs before developing areflexia, and some may have exaggerated reflexes. In the "Miller Fisher variant" subtype of Guillain–Barré syndrome, weakness of the eye muscles (ophthalmoplegia) is more pronounced and may occur together with abnormalities in coordination (ataxia). The level of consciousness is normally unaffected in Guillain–Barré syndrome, but the Bickerstaff brainstem encephalitis subtype may feature drowsiness, sleepiness, or coma.
Respiratory failure
A quarter of all people with Guillain–Barré syndrome develop weakness of the breathing muscles leading to respiratory failure, the inability to breathe adequately to maintain healthy levels of oxygen and/or carbon dioxide in the blood. This life-threatening scenario is complicated by other medical problems such as pneumonia, severe infections, blood clots in the lungs and bleeding in the digestive tract in 60% of those who require artificial ventilation.
Autonomic dysfunction
The autonomic or involuntary nervous system, which is involved in the control of body functions such as heart rate and blood pressure, is affected in two thirds of people with Guillain–Barré syndrome, but the impact is variable. Twenty percent may experience severe blood-pressure fluctuations and irregularities in the heart beat, sometimes to the point that the heart beat stops and requiring pacemaker-based treatment. Other associated problems are abnormalities in perspiration and changes in the reactivity of the pupils. Autonomic nervous system involvement can affect even those who do not have severe muscle weakness.
Causes
Two thirds of people with Guillain–Barré syndrome have experienced an infection before the onset of the condition. Most commonly these are episodes of gastroenteritis or a respiratory tract infection. In many cases, the exact nature of the infection can be confirmed. Approximately 30% of cases are provoked by Campylobacter jejuni bacteria, which cause diarrhea. A further 10% are attributable to cytomegalovirus (CMV, HHV-5). Despite this, only very few people with Campylobacter or CMV infections develop Guillain–Barré syndrome (0.25–0.65 per 1000 and 0.6–2.2 per 1000 episodes, respectively). The strain of Campylobacter involved may determine the risk of GBS; different forms of the bacteria have different lipopolysaccharides on their surface, and some may induce illness (see below) while others will not.
Links between other infections and GBS are less certain. Two other herpesviruses (Epstein–Barr virus/HHV-4 and varicella zoster virus/HHV-3) and the bacterium Mycoplasma pneumoniae have been associated with GBS. The tropical viral infection dengue fever has been associated with episodes of GBS. Previous hepatitis E virus infection has been found to be more common in people with Guillain–Barré syndrome. Zika virus has been linked to Guillain–Barré syndrome.
Some cases may be triggered by the influenza virus and potentially influenza vaccine. An increased incidence of Guillain–Barré syndrome followed influenza immunization that followed the 1976 swine flu outbreak (H1N1 A/NJ/76); 8.8 cases per million recipients developed the complication. Since then, close monitoring of cases attributable to vaccination has demonstrated that influenza itself can induce GBS. The benefits from vaccination to prevent influenza outweigh the small risks of GBS after vaccination. Even those who have previously experienced Guillain–Barré syndrome are considered safe to receive the vaccine in the future. Other vaccines, such as those against poliomyelitis, tetanus or measles, have not been associated with a risk of GBS.
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.[1] Different types of Guillain–Barré syndrome feature different types of immune attack. 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.[1]
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 anti-ganglioside antibodies being associated with particular features; for instance, GQ1b antibodies have been linked with Miller Fisher variant GBS and related forms including Bickerstaff encephalitis. The production of these antibodies after an infection is probably 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. 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 crossreact 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. 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 ofter strains of bacteria in the bowel.
Diagnosis
The diagnosis of Guillain–Barré syndrome depends on findings such as rapid development of muscle paralysis, absent reflexes, absence of fever, and 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. Testing for antiganglioside antibodies is often performed, but their contribution to diagnosis is usually limited. Blood tests are generally performed to exclude the possibility of another cause for weakness, such as a low level of potassium in the blood. 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.
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. If an MRI scan shows enhancement of the nerve roots, this may be indicative of GBS. 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.
Spinal fluid
Cerebrospinal fluid envelops the brain and the spine, and lumbar puncture or spinal tap is the removal of a small amount of fluid using a needle inserted between the lumbar 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"). This combination distinguishes Guillain–Barré syndrome from other conditions (such as lymphoma and poliomyelitis) in which both the protein and the cell count are elevated. Despite this, the CSF is unremarkable in 50% of people with Guillain–Barré syndrome in the first few days of symptoms, and 80% after the first week; therefore, normal results do not exclude the condition.
Repeating the lumbar puncture during the disease course is not recommended. The protein levels may rise after treatment has been administered.
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. Formal criteria exist for each of the main subtypes of Guillain–Barré syndrome (AIDP and AMAN/AMSAN), but these may misclassify some cases (particularly where there is reversible conduction failure) and therefore changes to these criteria have been proposed. Sometimes, repeat testing may be helpful.
Clinical subtypes
A number of subtypes of Guillain–Barré syndrome are recognized. Despite this, many people have overlapping symptoms that can make the classification difficult in individual cases. 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.
Other diagnostic entities are often included in the spectrum of Guillain–Barré syndrome. Bickerstaff's brainstem encephalitis, for instance, is part of the group of conditions now regarded as forms of Miller Fisher syndrome (anti-GQ1b antibody syndrome), as well as a related condition labelled "acute ataxic hypersomnolence" where coordination problems and drowsiness are present but no muscle weakness can be detected. 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 as Babinski's sign. The course of the disease is usually monophasic, but recurrent episodes have been reported. MRI abnormalities in the brainstem have been reported in 11%.
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.
Treatment
Immunotherapy
Plasmapheresis and intravenous 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. Similarly, administration of IVIg neutralizes harmful antibodies and inflammation. These two treatments are equally effective and a combination of the two is not significantly better than either alone. Plasmapheresis speeds recovery when used within four weeks of the onset of symptoms. IVIg works as well as plasmapheresis when started within two weeks of the onset of symptoms, and has fewer complications. IVIg is usually used first because of its ease of administration and safety. Its use is not without risk; occasionally it causes liver inflammation, or in rare cases, kidney failure. Glucocorticoids alone have not been found to be effective in speeding recovery and could potentially delay recovery.
Respiratory failure
Respiratory failure may require intubation of the windpipe and breathing support through mechanical ventilation, generally on an intensive care unit. The need for ventilatory support can be anticipated by measurement of two spirometry-based breathing tests: the forced vital capacity (FVC) and the negative inspiratory force (NIF). An FVC of less than 15 ml per kilogram body weight or an NIF of less than 60 cmH2O are considered markers of severe respiratory failure.
Pain
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.
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). Studies into the subject have been limited, but it is likely that intensive rehabilitation improves long-term symptoms. Teams may include physical therapists, occupational therapists, 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.
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. Psychologists may provide counseling and support. Home modifications, gait aids, orthotics and splints may be provided. 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 a tracheostomy). Nutritional support may be provided by the team and by dietitians. Psychological interventions may be required for anxiety, fear and depression.
Prognosis
Guillain–Barré syndrome can lead to death as a result of a number of complications: severe infections, blood clots, and cardiac arrest likely due to autonomic neuropathy. Despite optimum care this occurs in about 5% of cases.
There is a variation in the rate and extent of recovery. 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 disease have a worse prognosis. On the nerve conduction study, the presence of conduction block predicts poorer outcome at 6 months. 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. 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.
In research studies, the outcome from an episode of Guillain–Barré syndrome is recorded on a scale from 0–6, 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.
The health-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 experience chronic pain, fatigue and difficulty with work, education, hobbies and social activities. HRQL improves significantly in the first year.
Epidemiology
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 risk increases by 20% for every decade of life. Men are more likely to develop Guillain–Barré syndrome than women; the relative risk for men is 1.78 compared to women.
References
