Guillain-Barré Syndrome (NEUROPHYSIOLOGY 476)

Alexander M. Gosch
Aug 29, 2017 · 17 min read

Guillain-Barré syndrome is an autoimmune disease that is primarily due to the body’s immune system response to attack the myelin sheath around the axons of the neurons that make up the peripheral nervous system (PNS). Normally, the immune system only conducts such responses against foreign pathogens that would cause harm to the body if left unaltered. However, by the immune system attacking the myelin sheath of axons in the PNS, electrical signals conducted normally at very rapid rates down the axon become slower. This is due to the myelin sheath’s role in action potential conductance (NINDS, 2011). It allows for the electrical signal to essentially “jump” over the myelin sheath in order to increase current speed. Removing the myelin from an axon is the primary explanation of the symptoms of Guillain-Barré syndrome. Symptoms include muscle weakness, tingling sensations, loss of fine muscle control, and even temporary paralysis (WHO, 2016). In extreme cases, breathing can be affected and may lead to more severe complications. However, most symptoms peak at appendage weakness and tingling just three weeks after a viral or bacterial infection. The disease is very rare and has an annual incidence rate of roughly one to two cases per 100,000 individuals in the United States (Yu, Usuki, and Ariga, 2006). Morbidity from the disease is a miniscule portion of the cases per year. Typically, patients fully recover from the disease within a year.

Guillain-Barré syndrome is very interesting since it’s direct causes for the disease are still unknown. Needless to say, research is being exhaustively conducted to search for an answer to what causes the disease and triggers symptoms in some patients, but not in others that suffer from an infection or following vaccination. In a study examining fifty-four patient cases of Guillain-Barré syndrome in a course of a year period, thirty-nine of the patients were diagnosed with the disease before six weeks post-vaccination, while the fifteen rest were diagnosed after six weeks. The study concluded that thirty-one patients developed the disease following influenza vaccination and twenty patients developed it from a vaccine other than the influenza vaccine. The hepatitis vaccine was the second most associated vaccine in the study (Souayah et al., 2007). While studies support correlations between vaccination and onset of Guillain-Barré syndrome, some studies conclude no significance among the two factors. Hughes et al. examined 228 cases of the disease in the United Kingdom collected from a sample size of 1.8 million patients at general practices. Of the 228 cases, only seven were within forty-two days after vaccination. Of the seven cases, only three were post-influenza vaccination (Hughes et al., 2006). Looking at the timeline of the disease from both studies, the delay of onset of the disease also remains mysterious. Once it is diagnosed, physical therapy is needed to restore muscular function in patients. However, newer techniques are being studied in hopes to remedy the disease and its debilitating symptoms earlier, rather than manually working through them until the disease has passed. Some other methods of treatment include plasmapheresis and mechanical devices that can assist muscle fatigue and the somatic effects. The primary literature exclusively refers to new insights about the disease in etiology, physiology, and treatment methods. However, in order to reach a successful treatment method in the future, complete understanding of the disease must be achieved.

The primary literature on Guillain-Barré syndrome is devoted to many different aspects of the disease. The vast majority of clinical and case studies all around the world focus on understanding the mechanism involving the disease. It is a clinical syndrome of many pathological illnesses, such as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute axonal motor (AMAN), motor and sensory axonal neuropathy (AMSAN), acute sensory neuronopathy, acute pandysautonomia, and even Fisher syndrome (Lu and Zhu, 2010). The various subtypes of the disease lend to even trickier diagnosis techniques and variable treatment methods. A medical practitioner must accurately diagnose which form of the disease the patient has. The different subtypes can vary fairly greatly mechanistically. A study conducted on 175 cases of Guillain-Barré Syndrome showed how varying the subtypes may be. The researchers found the 46% of the cases were demyelinating, 31% axonal, and 23% were general electrophysiological complications (Shafqat et al., 2006). Demyelinating subtype means the disease is attacking and destroying the myelin sheath around the axon, ultimately slowing signal propagation in tissues where the neuron innervates and stimulates. Axonal means that the immune system is attacking the axonal tissue rather than the myelin sheath wrapped around the axon. This majorly affects signal transduction and generation in neurons. The general condition is the subtype where the neuron as a whole is being attacked, creating neurophysiological issues very similar to the prior subtypes.

As noted previously, being an autoimmune disorder, complications immediately arise due to the nature of such diseases. Autoimmune diseases are shallowly understood mechanistically. Guillain-Barré Syndrome adds an even more puzzling dynamic to the problem because the onset of the disease is very bizarre. The onset is seemingly completely random (Haber et al., 2009). In some cases, the source is determined to be surgery. In others, the source may be infection from another disease or even vaccination. First, the leading research regarding the immune function against the myelinated axons in the PNS must be discussed. Then, what triggers this reaction and the key role of different molecules within the human body to cause the symptoms will be explored. Lastly, once information giving great insight into the disease is fully understood, primary articles regarding the paths to curing the disease will be explored. The disease is highly debilitating and a cure must be sought for those suffering.

Cytokines are substances such as interleukins, interferons, or growth factors that are secreted by cells of the immune system and act on various other cells that they bind to within the body. It is thought that a whole slew of cytokines play a large role in the symptoms of Guillain-Barré Syndrome. The pathogenesis of the disease is thought by Lu and Zhu to be caused by such cytokines being secreted by immune cells such as lymphocytes and macrophages (2010). The cytokines recruit immune cells floating throughout the body regularly via inflammation and chemical signaling. The pro-inflammatory cytokines recruit immune effector cells that attack the myelin sheaths of PNS axons through release of toxic chemicals such as nitric oxide or free radicals. These compounds react negatively with Schwann cells, causing degradation of the surrounding tissue.

This degradation of the axons has a major role in the disease. However, as a result of the disintegration of axonal tissue in Guillain-Barré syndrome, researchers are looking for ways to catch this process earlier in the prognosis timeline. Often, prognosis is late in the disease and is primarily when symptoms are far more severe, which leaves little time to provide proper treatment, such as physical therapy. Petzold et al. conducted a study looking at patient’s cerebrospinal fluid for detection of axo-skeletal proteins such as neurofilaments. If axons of the PNS are being degenerated or dismantled, then the proteins and filaments connecting and securing the neurons should be apart and reside in surrounding tissue freely. The researchers found that the 118 patients had a greater average neurofilament CSF concentration than the 416 control patients. The control patients had an average neurofilament CSF concentration of 0.73 ng/ mL, whereas the experimental group was 1.00 ng/ mL (2006). This outcome shows more promise in potentially catching the disease earlier in prognosis and could allow for patients to be treated earlier, reducing risk of morbidity. The technique used before this method and still widely used is done electrophysiologically. This method is poor of showing results of the disease in early stages. However, the CSF axonal biomarker method can detect axon degeneration far earlier than electrophysiological readings of nerve firing.

Another common technique shown to be promising for diagnosing patients with Guillain-Barré syndrome is magnetic resonance imaging (MRI). Yikilmaz et al. studied forty young patients of a mean age of five years old with CSF diagnosed Guillain-Barré syndrome. The methods used MRI testing in order to compare and contrast the images to a control group of patients not diagnosed with the disease. The researchers found that an astonishing thirty-eight out of the forty patients showed similar and definitive results for proper diagnosis of the disease (2010). This included enlarged ventral and dorsal roots of the cauda equina. However, as with other methods of diagnosing the disease, the technique does not correlate or imply the physical condition or severity of the patients.

The variance in the physical severity of the disease was expressed in the study above, but was largely ignored because the research was only driven to determine significant new methods of detecting the different stages of the disease, not to imply the reasons or immunological functions involved in the severity of the disease. The study did not expressly state any reasons behind the differences in severity among patients, only that they can be shown for prognosis purposes. However, a study focusing on mannose-binding lectin and its role in the disease, shed greater light on perhaps the immunological functions causing variability in severity of the autoimmune disease. The researchers found that the complement activation in the immune response against the myelin sheath is mediated by mannose-binding lectin. This activation leads to the severity of nerve damage in the disease, which the researchers found to be determined by the MBL-2 haplotype (Geleijns et al., 2006). The complement activation pathways in immune responses are normally used to essentially “tag” a pathogen for termination by macrophages through the binding of the ligands on both the pathogen and macrophage. However, this process should not occur in regular functioning tissue the body needs, like the myelin sheath. Researching the triggering factors for the activation of the complement pathway on behalf of normally functioning cells in the body is essential to understanding the onset of the disease.

The disruption of normal axonal activity stems from the examination of the neuron’s plasma membrane, the area that plays an enormous role in action potential conductance and propagation. In the plasma membrane of nodes, there are sugar-lipid groups called gangliosides attached to the membrane that play a significant role in axon functions. Specifically, the gangliosides are composed largely of glycosphingolipids, and are expressed on motor axons. Gangliosides GM1, GM1b, GD1, and GalNAc-GM1a are thought to play a major role in antibody defense in acute axonal motor Guillain-Barré syndrome (Kuwabara, 2007). The anti-ganglioside antibodies are activated due to previous infections of lipooligosaccharides that are attached to the plasma membranes of certain bacteria. While not identical, there are some similarities, such as the extension of sugar groups. The antibodies attach and block the conduction activity of the axon plasma membrane, leading to axonal degeneration and the symptoms commonly displayed with the disease. About a third of all cases of Guillain–Barré syndrome studied are preceded by Campylobacter jejuni infection in either the gastrointestinal tract or the respiratory system (Israeli et al., 2012). The strains of the bacteria that have sampled from patients have the similar lipooligosaccharide with a GM1 modeled structure and even composition. Molecular similarities between the two saccharides in the bacteria and the peripheral nerves lead to the cause of the autoimmune disorder, as demonstrated in animal models of human-form Guillain–Barré syndrome. This information provides more detail as to why the disease oddly commonly occurs postinfection of a bacterial pathogen. The immune system initiates an immune response against the pathogen through recognition of the foreign oligosaccharides displayed on the outer membrane, then once disposed of, the antibodies remain and monitor the body for return of the bacteria. However, in some cases, the antibodies wrongly attack the sugar groups or lipid rafts of nonforeign cells, as in the case with acute axonal motor degradation.

The first thought after investigating the antibodies that attack nonforeign cells of the human body is always directed towards the next logical realization; there must be an aspect of the immune response that has failed in order to allow the antibodies to freely reign. This explanation is common among many autoimmune disorders. There are two types of lymphocytes largely responsible for many actions in the immune response, CD4+ and CD8+ cells. CD4+ cells are considered as T helper (Th) cells, while CD8+ cells are often referred to as cytotoxic T cells (Tc). As the names suggest, one subset of T cells aids in helping or monitoring the immune response, while the cytotoxic T cells are toxic to cells and destroy unwanted foreign pathogens. For Guillain-Barré syndrome, research is being conducted to measure Th cell concentrations in the suffering patient’s body. The theory stems from the idea that higher Th cell levels would mean more surveillance of the immune cells in the body, allowing for irritation and inflammatory responses and cause an autoimmune disease.

While studies indicate high Th levels are correlated with cases of Guillain-Barré syndrome, another component of T cells is shown to be lowered in patients (Wang et al., 2013). Th17 cells specifically are involved in pro-inflammatory responses. Higher traces of Th17 cells were examined in the experimental group with Guillain-Barré syndrome. On the other hand, regulatory T cells (Treg) serve as surveillance cells for the immune functions of the body. Low levels of Treg cells would allow for the opportunity of antibodies to wrongly bind and attack cells of the individual that aren’t foreign or pathological (Maddur et al., 2010). Treg cells are often referred to as suppressor T cells because they monitor and suppress effector T cells that may attack self antigens. Understanding this relationship in autoimmunity could lead to greater understanding in possible treatments for the disease or even prevention after an individual is given a vaccination or bacterial infection to avoid onset of Guillain-Barré syndrome. Finally, investigation regarding the importance and possible methods in treating or preventing the disease will be discussed.

Now that the disease is understood as far as symptoms, prognosis techniques, and mechanistically, it is important to look at possible treatment methods to cure those suffering from the disease. More importantly, the most efficient, economic, and groundbreaking techniques must be reviewed critically. First, the most used and oldest form of treatment for patients of Guillain-Barré syndrome is physical therapy and other similar physical treatments that focus on the symptoms of the disease, not the cellular components. As with many treatment techniques, it is often accompanied with side effects. Most prescription treatments for diseases focus on negative side effects, but with physical therapy, the side effects are often beneficial and a result of simply exercising.

A study conducted by Johannes B. Bussmann et al. examined the actual increase in fitness of twenty Guillain-Barré syndrome patients that underwent a twelve week physical therapy treatment. The study found that a very low percentage of patients (7%) actually significantly improved fitness change scores after the treatment. Astonishingly, far higher percentages (44%) of patients had higher changes in perceived mental functioning, as well as perceived physical functioning and actual mobility (2007). The conclusions from the study indicate that perhaps the end goal in physical therapy for axonal motor patients may be to lessen the pain and perceived suffering. Perhaps physical therapy coupled with other treatments could combine and create the most comfort moving forward. The other treatments being researched are more immunological therapies and attempt to cure the disease at a cellular level, intervening with the immune response against the axons of the peripheral nervous system.

The search for a true cure is in high gear. Many immunological studies are focusing on treatment options that could interfere with the anti-ganglioside antibodies attacking self antigens. Theoretically, there are many ways to go about performing that by knowing the way the immune system operates, especially knowing the pathology of autoimmune diseases. There can be therapies directed towards boosting regulatory T cell levels in order to form natural surveillance and control of the antibodies causing disease. There can also be investigation into immunotherapies that concentrate on administering intravenous immunoglobulin to combat the anti-ganglioside antibodies or a plasma exchange to attempt to rid the body physically of the antibodies. Many other techniques have been examined, but have failed clinically, such as amantadine treatment to help combat fatigue. The treatment showed no significance to even lessen patient fatigue in a large, double blind, placebo designed study (Garssen et al., 2006). However, the failed attempts in clinical trials are just as or more important in medicine as the successful trials. Lending its outcomes to researchers as to what not to do, or what does not work, as a building block for new methods.

An emerging and clinically significant form of treatment discussed briefly above is intravenous immunoglobulin therapy (IVIG). In a recent study of 174 patients with Guillain-Barré syndrome, the effectiveness of IVIG was determined using serum levels of IgG. IgG is an immunoglobulin subtype that is thought to cause anti-inflammatory effects in autoimmune diseases due to the IgG binding receptors on antigen presenting cells and dendritic cells that would normally cause inflammatory actions in the body. The aforementioned study showed that the IVIG therapy was most pronounced two weeks post-administration, with the highest IgG serum levels in the subjects. The subjects with the lowest serum IgG levels had taken the longest time to reach low disability scores (<2, categorized by unaided walking), whereas the higher IgG levels reached low disability ratings in a significantly shorter amount of time (Van Doorn et al., 2010). IVIG therapy is the most often used treatment for the disease and most autoimmune disorders for that matter. This is largely due to little side effects of the treatment and the benefits a patient gains from it. However, many researchers still vouch for the use of plasma exchange treatment within the first two weeks of diagnosis of the disease.

In a case study of an elder patient with the disease, a five-day course of daily IVIG at a dosage of 0.4 g/kg/day was given without any benefit. Rather the opposite, the patient decreased in fitness clinically throughout the treatment. Seven days after completion of the IVIG treatment, plasma exchange treatment was started. There was a total of five exchanges of plasma with roughly three liters every day for three days and every second day on two occasions (Buzzigoli et al., 2010). After the first exchange, slight pulmonary and respiratory improvement was recorded. After the full course of treatment, she was given independence of mechanical breathing and could walk with assistance. While this is one patient’s case, it clearly shows that plasma exchange may be a viable option in support of IVIG or separately. Medical professionals should investigate the treatment options and examine which options should be used in what order or simultaneously.

After covering nearly every aspect of the disease, including the treatment options extensively in order to lessen the effects and timeline of the disease, what is the likelihood of recovering and later contracting the disease again? Unlike most pathological diseases, having Guillain-Barré syndrome once does not protect someone from the disease again. However, in a study examining the recurrence of the disease, of the 550 subjects that were diagnosed previously with the disease and cured, only six were diagnosed with recurrence of the disease. Interestingly, of the six diagnosed, none were vaccinated within a two month period before the second diagnose (Baxter et al., 2012). This indicates that recurrence of the disease is rather low, and not significantly linked to vaccination in the event of recurrence. The study did not indicate prior infections before diagnosis, as evidence is shown that not solely vaccinations can trigger the disease.

Guillain-Barré syndrome is a very interesting disease that has defied many aspects of modern medicine. It is an autoimmune neurological disorder that is very rare around the world, yet has attracted the attention of many researchers from all around the globe. It is a rather new neurological disorder, but has been most likely observed for many years in the past due to its collective of a few disorders of similar symptoms. A few of those disorders being acute inflammatory demyelinating polyradiculoneuropathy, acute axonal motor, motor and sensory axonal neuropathy, and acute sensory neuronopathy to name a few. The most common form affecting the motor axons of the peripheral nervous system. This causes extreme discomfort, inhibited or disoriented muscle movement, and in severe cases, decreased involuntary muscle movement.

Although there is not settling evidence on the exact cause of the onset of the disease, many studies conclude correlations among prior C. jejuni infections or influenza vaccinations and resulting Guillain-Barré syndrome. However, recurrence of the disease is not shown to be significantly correlated with revaccination. There are cases of the disease with no prior immunization records, leaving holes in the theories regarding the etiology of the disease. Yet, without fully understanding the course of the disease, treatment options show promise in reducing the symptoms and time period of the disease.

As with most motor neurological disorders, physical therapy is used to regain physical ability and to increase fitness of the muscles affected. However, research indicates it has a limiting effect that is mostly perceived enhancement both physically and mentally. In contrast, methods of treatment such as intravenous immunoglobulin and plasma exchange therapies pose as a great treatment option for patients, especially if used early in the course of the disease. Also, studies indicate the patients will most likely benefit from one or the other if the first options does not work. Typically, intravenous immunoglobulin therapy is used as the first method of action, followed by plasma exchange and later physical therapy to rebuild muscle and fitness.

The research on Guillain-Barré syndrome is crucial and must be further explored. There are many questions unanswered and many unknowns still tied to the disease. While the disease is rare, the effects are usually severe and can last for periods up to a year, causing extreme discomfort and pain. Hopefully more knowledge can be gained revolving around the mechanism and action of the autoimmune disorder, in an effort to prevent or cure the disease through new treatment techniques.

Works Cited

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Alexander M. Gosch

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I spent 4 years writing this material, other people besides my professors ought to read it. Good or bad, so be it.

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