Guillain-Barre Syndrome (GBS): Physiology, Variants and Treatments

Abstract

Guillain-Barre Syndrome (GBS) is a disease which causes damage in the peripheral nervous system. Guillain-Barre Syndrome refers to a group of disorders, including several variants such as acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor-sensory axonal neuropathy, as well as, Miller Fischer Syndrome.  The cause of Guillain-Barre syndrome is unknown; bacterial or viral infections can lead to the development of Guillain-Barre Syndrome. Due to molecular mimicry, the immune system attacks healthy cells instead of the infection and ultimately destroys the myelin sheath or axon. In the early stages, the Schwann cells make new myelin, but overtime this slows the impulses traveling down the axon. This demyelination or axonal damage in the peripheral nervous system leads to paresthesia, muscle weakness, impaired reflexes, speech and vision difficulties, orthostatic hypertension, and in some cases death. In order to diagnose Guillain-Barre Syndrome, a lumbar puncture is performed. Additionally, a Nerve Conduction Study (NCS) or electromyography (EMG) may be conducted. Treatment for Guillain-Barre Syndrome includes intravenous immunoglobins (IVIg) or plasmapheresis.

Keywords: Guillain-Barre Syndrome, demyelination, immune system

Guillain-Barre Syndrome

Guillain-Barre Syndrome (GBS) is an autoimmune disease with annual incidence rates of one or two out of 100,000 (Craig, 2019). Guillain-Barre Syndrome (GBS) was first identified in 1859, when five patients presented with contemporary GBS symptomology (Donofrio, 2017). Since the eradication of Polio, GBS has become the number one cause of acute loss of muscle tone, weakness, and loss of reflexes worldwide (Donofrio, 2017). Overall, GBS is a rare disease, however it is one of the more common types of neuropathy. Guillain-Barre Syndrome has an average onset of forty years old and affects more males than females (Dimachkie & Barohn, 2013). Two-thirds of all cases are linked to a preceding infection (Dimachkie & Barohn, 2013). Additionally, the exact cause is unknown, but Guillain-Barre syndrome is most frequently preceded by exposure to an infection (Mayo Clinic, 2018). Overall, the risk of developing GBS within one’s lifetime is less than one in 1,000 (Donofrio, 2017).

Individuals with Guillain-Barre Syndrome experience symmetrical numbness and weakness in their lower limbs in the earlier stages. Additionally, individuals experience loss of reflexes and sensory abnormalities (Craig, 2019). The progression of symptoms varies from one individual to another, but in some cases the onset of weakness can be rapid resulting in quadriplegia within a few days (Donofrio, 2017). In most cases, the weakness begins distally and spreads proximally. In rare instances, the weakness is localized to the legs (Donofrio, 2017). Roughly half of all individuals with GBS experience facial weakness, and cranial nerve dysfunction (Wijdicks & Klein, 2017). When Guillain-Barre was first discovered, it was believed to be a single disorder. Over the last century of work, it is better understood as a group of disorders including the following: acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), or acute motor-sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS) variant. The classic presentation of GBS is acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (Wijdicks & Klein, 2017).

Physiology of Guillain-Barre Syndrome

Causes of Guillain-Barre Syndrome

GBS is categorized as an acute polyradiculoneuropathy, which means its onset and progression is rapid and it affects the peripheral nerves. The diseases most associated with onset are Epstein-Barre Virus, Mycoplasma pneumoniae, Cytomegalovirus, and Campylobacter jejuni, among others (Dimachkie & Bahrohn, 2013). Campylobacter jejuni is a gastrointestinal infection, whereas, Epstein-Barre Virus, Mycoplasma pneumoniae, and Cytomeglavirus are respiratory infections. The introduction of an infection into the body results in an immune response which specifically targets the peripheral nerves (Willison, Jacobs, & Doorn, 2016). Within ten to fourteen days after a respiratory illness or gastroenteritis, GBS can occur (Donofrio, 2017).  Among all infections, Campylobacter is the most commonly identified. Antibodies aimed at attacking the Campylobacter antigen are among those most commonly found in cases of GBS (Donofrio, 2017). Aside from infections, there is controversy regarding other succeeding health concerns and GBS onset including Zika virus, surgery, pregnancy, and vaccinations (Donofrio, 2017). In a retrospective study on thirty-six adult patients with GBS, seventeen of them had symptoms of infection and four of them underwent surgery or trauma within six weeks prior to GBS diagnosis (Yang, Lian, Liu, Wu, & Duan, 2016). Overall, the researchers determined that GBS axonal type occurs more often post-surgery, as opposed to non-surgical or non-trauma patients (Yang et al., 2016).

The disease worsens due to what is known as molecular mimicry. The antigens from bacterial or viral infections appear similar to the lipids found in the myelin sheath, resulting in the immune system attacking those cells and ultimately destroying the myelin sheath. In the early stages, Schwann cells make new myelin, but overtime this slows the impulses traveling down the axon (Liu, Dong, & Ubogu, 2018). The succeeding events of this are largely unknown at this time (Willison, Jacobs, & Doorn, 2016). Additionally, the source of impairment, whether it be the myelin or axon is a marked difference among variants of the disease. Destruction of the myelin or axon leads to the clinical presentation of Guillain-Barre. This demyelination or axonal impairment in the peripheral nervous system leads to paresthesia, muscle weakness, impaired reflexes, speech and vision difficulties, orthostatic hypertension, gastrointestinal symptoms, and in some cases death (Willison, Jacobs, & Doorn, 2016). During the first two weeks, the disease progresses rapidly, and limb weakness becomes progressively worse. This worsening of symptoms also involves the sensory and cranial nerves. The facial nerve is involved in up to seventy percent of cases (Dimachkie & Barohn, 2013).

Guillain-Barre Syndrome variants

Acute inflammatory demyelinating polyradiculoneuropathy

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is a type of Guillain-Barre and is the most common form within the U.S. This demyelinating type is characterized by muscle weakness in the lower limbs which spreads proximally (Mayo Clinic, 2018). In AIDP type, both the motor and sensory nerves are affected. Additionally, the myelin is predominately affected and minimal axonal damage occurs (Craig, 2019). The antigens involved are associated with demyelination due to macrophage cleanup (Wijdicks & Klein, 2017). Overall, there is a high likelihood of regaining functioning if patients have proper medical care (Willison, Jacobs, & Doorn, 2016).

Physiology. In the acute inflammatory demyelinating polyradiculoneuropathy variant of GBS, otherwise known as demyelinating type, there is damage to the myelin sheath which surround the axons near white blood cells (Kloos, 2016; Kegelmeyer, Buford, & Heathcock, 2016). The complement system is activated. This is a part of the immune system most related to antibodies and phagocyte cells. The purpose of the complement system is the clear away debris and fight off infection by attacking the infection’s plasma membrane. T-cells are activated by this system which also activate macrophages which damage the myelin (Liu, Dong, & Ubogu, 2018). However, in AIDP, the disease mimics the normal anatomical makeup of peripheral nerves. This is known as molecular mimicry (Liu, Dong, & Ubogu, 2018). The disease tricks the immune system into attacking the myelin, when in fact the immune response is intended to attack the disease. As a result of this mimicry, the myelin sheath is destroyed, signal conduction is impaired, and normal functioning of the periphery is halted (Dimachkie & Barohn, 2013; Kloos et al., 2016).

Clinical Presentation. For individuals with AIDP, their symptoms progress rapidly. Feelings of weakness occur on both the right and left side, in a symmetric fashion, and begin distally and progress proximally. In the majority of AIDP cases, roughly ninety percent experience muscle weakness which begins in the legs and progresses proximally. This weakness in the extremities is the result of demyelination of the axons. Electrical signals are unable to send properly. More specifically, these electrical signals, or action potentials, have a harder time traveling further distances. Hence, the weakness in the distal areas of the limbs in the earlier stages (Donofrio, 2017). This weakness continues to spread, eventually affecting the respiratory muscles. This progression of the disease is better explained by continued demyelination, and which further impairs the ability of signals to adequately send. Consequently, respiratory issues including respiratory failure can occur which is due to the rapid progression of symptoms and the impairment traveling from distal to proximal areas. This weakness extends to reflexes, specifically a general loss of reflexes in patients. Guillain-Barre Syndrome can also affect the autonomic nervous system which is linked to symptoms such as urinary retention or orthostatic hypertension (Willison, Jacobs, & Doorn, 2016). Over the duration of one to three weeks the disability progresses. The ability to walk independently is typically lost at the time of peak impairment (Fokke et al., 2014).

Acute motor axonal neuropathy and Acute motor-sensory axonal neuropathy

Acute motor axonal neuropathy (AMAN) and Acute motor-sensory axonal neuropathy (AMSAN), also known as the axonal type, are most associated with infections such as Campylobacter Jejuni, and more controversially, the Zika virus (Dimachkie & Barohn, 2013; Wijdicks & Klein, 2017). In the axonal form, patients are subject to more rapid deterioration and prolonged duration of paralysis as well as respiratory issues. These respiratory issues can escalate to respiratory failure over the course of a few days (Dimachkie & Bahrohn, 2013). Although the axonal type is less common within the U.S., this form is marked by immunoglobulins which target gangliosides (Mayo Clinic, 2018). Antigens of the bacterial and viral infections are subject to molecular mimicry which causes destruction of the myelin (Liu, Dong, & Ubogu, 2018).

Physiology. In the axonal type, immunoglobulin G (IgG) antibodies and complement act directly against the cell membrane. Therefore, the damage is mediated by IgG antibodies in addition to the complement system (Dash et al., 2014). When an infection such as enters the system, its antigens mimic the normal anatomy of peripheral neurons, specifically the gangliosides. There are four key gangliosides, GM1, GD1a, GT1a, and GQ1b, each with different anti-ganglioside antibodies (Dash et al., 2014; Wijdicks & Klein, 2017). The immune system recognizes a foreign substance but instead of attacking the infection, the antibodies attack the gangliosides which are located within peripheral axons. Most commonly in the case of GBS, Campylobacter infection might enter the body which leads to a production of IgG antibodies against the bacterial cell wall substances. This cross reacts with nerve cell gangliosides. This attack on the axons leads to degradation and impairment (Dash et al., 2014).

Miller Fisher syndrome (MFS)

Miller Fisher Syndrome was the first variant of GBS. In this type of Guillain-Barre syndrome, paralysis begins behind the eyes as opposed to in the lower limbs (Mayo Clinic, 2018). Furthermore, MFS is associated with ataxia, loss of reflexes, ophthalmoplegia, among other abnormalities (Craig, 2019). This type is associated with alterations in consciousness. MFS is less common within the U.S. population. Generally, patients with MFS have two features of GBS along with elevated cerebrospinal fluid protein along and associated antibodies which informs diagnosis of GBS (Dimachkie & Barohn, 2013). In the Miller Fischer variant, the antibodies which attack normally occurring gangliosides are GQ1b and GT1a (Wijdicks & Klein, 2017). In this variant, the oculomotor nerves are affected which leads to paralysis or weakness in the eye area (Wijdicks & Klein, 2017) As with other type of GBS, molecular mimicry is responsible for this attack response which impairs the peripheral nervous system  (Liu, Dong, & Ubogu, 2018). It is possible for MFS to progress to GBS (Dimachkie & Barohn, 2013).

Treatment

Diagnosis

The best contributor to positive treatment outcomes is early detection. In addition to medical testing, patients presenting with Guillain-Barre syndrome are likely to display progressive weakness in all four limbs, specifically the arms and legs, including a loss of reflexes (Craig, 2019). Individuals presenting with such complaints are screened for a variety of disorders including GBS. In order to diagnose Guillain-Barre syndrome, a lumbar puncture, nerve conduction test, or electromyography is performed depending on the duration of symptoms and progression of the disease. Nerve conduction studies determine the subtype of GBS. If abnormalities are detected in motor neurons this is indicative of demyelinating type, whereas sensory neuron abnormalities are indicative of axonal type (Dash et al., 2014). Nerve conduction studies (NCS). In NCS, the nerves outside of the brain and spinal cord are stimulated through the use of electrodes placed on the skin. Both muscle and sensory nerve action potentials are recorded (Dash et al., 2014). This helps to identify the type of GBS, for example, axonal or demyelinating, while also providing information about the overall current functioning of the axons. In addition to NCS, electromyography tests muscles in response to stimulation. These studies generally show less muscle recruitment (Dash et al., 2014). Lumbar puncture is the standard procedure used to diagnose GBS, specifically, the prevalence of cytoalbuminologic dissociation, or increased levels of cerebrospinal fluid protein within the cerebrospinal fluid (Willison, Jacobs, & Doorn, 2016; Fokke, Berg, Drenthen, Walgaard, Doorn, Jacobs, 2014). This increase occurs because of the inflammation. Generally, individuals with GBS will have greater than 0.55 g/L of protein (Willison, Jacobs, & Doorn, 2016; Fokke et al., 2014). In addition, symmetrical weakness which travels distal to proximal, and progression of symptoms resulting in loss of reflexes are key factors for diagnosis as GBS symptoms can be similar to that of other disorders.

Challenges with Diagnosis

The symptoms of GBS overlap with a wide array of other medical disorders. Making early detection challenging, as other diagnosis may be suspected and screened for early on. For example, the symptoms of GBS can be similar to myasthenia gravis, stoke, or encephalitis, among others (Dash et al., 2014). Doctors are not likely to encounter GBS frequently throughout their career. This coupled with the various presentations can be diagnosis challenging, let alone early detection. The onset of GBS occurs overtime and as a result, serum analysis may not reveal CSF protein levels synonymous with GBS until several days after onset. Making diagnosis a challenging process (Dash et al., 2014).

Treatment Options

Treatment for GBS includes intravenous immunoglobins or plasmapheresis. The mechanism of action is not yet fully understood for these interventions (Liu, Dong, & Ubogu, 2018). Plasma exchange or intravenous immunoglobin speeds the recovery process, however, combination immunotherapy is not more effective (Wijdicks & Klein, 2017). Plasma exchange works by removing the specific inflammatory substances mediating the disease (Dimachkie & Barohn, 2013). Plasma exchange, or plasmapheresis, removes antibodies which contribute to the destruction of peripheral nerves  (Liu, Dong, & Ubogu, 2018). Intravenous Immunoglobulin (IVIg) acts to halt degradation of the peripheral nerves. IVIg introduces an anti-inflammatory effect throughout the periphery (Dimachkie & Barohn, 2013). Immunoglobulins aim to clear damaging substances from circulating in the peripheral nervous system (Liu, Dong, & Ubogu, 2018).

Future Directions

Since Guillain-Barre Syndrome was first identified, over a century of work in this area has led to a better understanding of the pathology of this disorder. In order to improve patient outcomes moving forward, research aimed at identifying biomarkers for disease severity are needed (Esposito & Longo, 2017). With proper treatment patients are able to have a full recovery, however a small percentage of patients still experience weakness three years later (Willison, Jacobs, & Doorn, 2016). A small proportion of patients experience weakness or tingling several years later.

References

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