Guillain-Barré Syndrome

Guillain-Barré syndrome is a group of acute neuropathological diseases, that lead to paralysis (Dimachkie, & Barohn, 2013). In case of GBS, peripheral nerves are attacked by the immune system of a patient. Typically, development of the disease is preceded by infection or other factors leading to activation of the immune system (Willison, Jacobs, & Van Doorn, 2016). The disease has an acute start, and it ends spontaneously. Unfortunately, up to 5% people die and up to 20% remain disabled after suffering from the GBS (Yoki & Hartung, 2012), which makes it an issue of serious concern. This syndrome was described in the beginning of XX century (Guillain, Barre, & Stroh, 1916). However, still, the exact reasons for its development remain unknown. Thus, it is highly important for healthcare workers to know the main forms of Guillain-Barré syndrome, its symptoms and their biological meaning, been familiarized with description of typical case example, epidemiology, clinical pathology, diagnostic and differential tests, as well as the existing and experimental treatment options.  

Definition of the Syndrome

Guillain-Barré syndrome was described by French neurologists Guillain, Barre, and Strohl (1916). These described of two soldiers with acute paralysis and spontaneous recovery. The laboratory analysis of cerebrospinal fluid of the patients demonstrated that protein concentration was increased, while cells count was normal. Thus, the combination of acute peripheral neuropathy and the stated patterns in laboratory analysis became a Guillain-Barré syndrome. This acute neuropathy has unclear origin and usually does not repeat after the recovery (Eldar & Chapman, 2014). GBS is characterized by areflexic or hyporeflexic paralysis (Yoki & Hartung, 2012). These parameters are typical and important for the diagnosis. However, in some cases, variations in clinical manifestations might appear.

Forms of the Syndrome

Depending on the target affected by antibodies, two different types of GBS could be defined. The first type is demyelinating GBS, when immunoglobulins affect the myelin sheath and Schwann cells (Miyaji et al., 2014). The second type is axonal GBS, during which antibodies affect axonal membrane. It was stated that the demyelinating type is more frequent than the axonal one (Notturno et al., 2016). Besides, variations of syndrome could develop (Willison et al., 2016). In particular, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the most frequent case of GBS in the North America and Europe. Secondly, there is a motor axonal neuropathy (AMAN) form of the disorder, which mainly affects motor neurons. Acute motor and sensory axonal neuropathy (AMSAN), when both types of nerve fibers are affected is a relatively rare form of GBS (Eldar & Chapman, 2014). Another rare form of GBS is Miller Fisher syndrome (MFS), which includes three pathologies: ophthalmoplegia, areflexia, and ataxia (Wakerley, Uncini, & Yuki, 2014). Finally, Bickerstaff brainstem encephalitis could also be classified as a form of GBS. It starts with dysfunction of cranial nerves, followed by brainstem encephalitis and pharyngocervico-brachial patterns, if untreated (Sekiguchi et al., 2016). Therefore, GBS is a complex set of syndromes, each characterized by the specific targets, pathologies, and thus, manifestations.

Symptoms of the Disorder and Their Biological Meaning

The first symptoms of GBS appear in three days to six weeks after the infectious disease of upper respiratory or gastrointestinal tract (Yoki & Hartung, 2012). Symptoms of GBS manifest because of damage of peripheral nerves. The location of pathological changes depends on the injured nerves: cranial nerves, nerves innervating limbs, or breathing muscles (Van Den Berg et al., 2014). Clinical manifestations of the disorder also depend on a particular form of GBS and vary in different patients (Eldar & Chapman, 2014). Therefore, the disease may have a wide range of manifestations in different regions of the body, which makes proper diagnosis complicated.

In typical cases, the disease starts in the acute form. The most common symptoms include acute pain, numbness, and weakness in limbs. They appear on both sides of the body, and are relatively symmetric and progressive. The most severe weakness is commonly reached on the fourths week after the onset of disease (Eldar & Chapman, 2014). Patients usually experience reduction in the intensity of reflex reactions (Van Den Berg et al., 2014). Although hyporeflexia or areflexia is typical for GBS, approximately 10% of patients demonstrated normal level of reflective activity (Yoki & Hartung, 2012). Thus, the clinical picture is not always clear in patients with GBS.

In approximately a quarter of cases, respiratory muscles are involved in pathological process, which makes a patient dependent on artificial lung ventilation (Garg, 2017). In most cases, cranial nerves, in particular, facial, bulbar, and ocular motor nerves, are involved in the pathological process. Two thirds of patients also demonstrate signs of autonomic system dysfunction, such as cardiac arrhythmia, arterial hypertension or hypotension, malfunction of gastrointestinal tract, and abnormal sweating (Van Den Berg et al., 2014). Rarely, urinary retention and constipation develop, which occur in the end of the disease (Eldar & Chapman, 2014). These typical clinical manifestations of the disorder could be presented in the case study.

It was widely considered that GBS has a good prognosis. However, Yoki and Hartung (2012) stated that the death rate is 5%, and approximately 20% people get disability despite the applied immunotherapy. The syndrome was considered as monophasic, which means that it does not recur typically. However, in up to 7% patients, two or more episodes of GBS appeared. The average distance between episodes is seven years (Yoki & Hartung, 2012). Thus, the disease is considered poorly studied and some additional information could be identified in future.

Case Study of Guillain-Barré Syndrome

In typical cases, the development of GBS includes several stages. They are characterized by clinical manifestations, which are important for diagnostic (Willison et al., 2016). A case of Jack could be an example of typical case study of the syndrome. Jack is a man 42 years old, married, working in a bank. He arrived to clinic with neurological symptoms and reported numbness, symmetric weakness, and pain in limbs. Medical examination discovered the hyporeflexia state (Yoki & Hartung, 2012). The symptoms became worse during next 10 days, and Jack stated in clinic. Further examinations discovered that he had the areflexia (Van Den Berg et al., 2014). According to Jack’s medical history, he had previously experienced enteritis, caused by Campylobacter jejuni. Jack recovered from this disease, and 10 days after, the first neurological symptoms appeared (Yoki & Hartung, 2012). Thus, infectious disease of gastrointestinal tract became the reason for development of neurological symptoms identified in Jack.

First, the analysis of CSF was performed. It demonstrated the increase in concentration of protein and normal cells count. Based on clinical manifestations and results of CSF analysis, Guillain-Barré syndrome was diagnosed. Jack remained in clinic, because he could not walk. Regular monitoring of his heart and pulmonary functions was performed. For the treatment, the course of opioid painkillers and five procedures of plasma exchange were allocated. After two procedures of plasma exchange with a two-week delay, his state improved. The complete recover occurred in five months after the onset of the disorder.

Epidemiology of the Disease

GBS is considered a relatively rare disease (Van Den Berg et al., 2014). It has an incidence rate of 1.2-1.3 cases per year (Eldar & Chapman, 2014). Yoki and Hartung (2012) reported slightly different values, which were from 0.89 to 1.89 cases per 100,000 persons annually. At the same time, GBS is considered the most frequent cause of acute paralysis worldwide (Yoki & Hartung, 2012). Different variants of GBS are not equally distributed in the world. AIDP is the most frequent case of GBS in the North America and Europe. AMAN and AMSAN are widely spread in Asian countries (Eldar & Chapman, 2014). Thus, worldwide prevalence of different forms of the disease varies due to some factors, which are not clear yet.

In was estimated that men get the disease slightly more frequently than women. The ratio between men and women is 1.78 (Yoki & Hartung, 2012). The syndrome could develop at any age, however, the probability to get sick is higher for older persons. Besides, the prognosis becomes worse with age (Eldar & Chapman, 2014). Patients do not usually have any other autoimmune pathology or system disorders. Thus, the development of GBS is usually acute and unexpected (Eldar & Chapman, 2014). Usually, it develops after the occurrence of infection or other factors, which stimulate the immune system. In most cases, the disease occurs after the gastrointestinal or upper respiratory tracts infection. One of the possible microbial agents that can provoke GBS is the bacterium C. jejuni. Approximately 30% of GBS cases are associated with this infection. GBS develops in 0.25 to 0.65 cases per 1000 people after gastroenteritis caused by C. jejuni. Another pathogen associated with the syndrome is cytomegalovirus, which is responsible for 10% of GBS cases. The latter develops in in 0.6 to 2.2 cases per 1000 people with cytomegalovirus infection (Yoki & Hartung, 2012). Except for these two infectious agents, varivella-zoster virus, Epstein–Barr, Zika virus, and Mycoplasma pneumonia could stimulate the development of the syndrome (Eldar & Chapman, 2014). Thus, there are numerous pathogens, which can increase the risks for GBS.

Unfortunately, the exact mechanisms and links between host-pathogen interaction and later immune reaction against neurons remains unknown (Willison & Goodyear, 2013). Moreover, genetic and environmental factors, which increase the probability for the disease development are not estimated (Blum & McCombe, 2014). Thus, it is difficult to predict the possibility of the disorder and to take the preventive measures. Some authors connected the development of GBS with vaccination. For example, during mass vaccination against A/New Jersey/1976/H1N1 flu in 1976 in the United States, immunized people experienced the increased risk for developing GBS (Yoki & Hartung, 2012). However, the cause-end-effect relationship between vaccination and development of GBS is not conclusively proved (Baxter et al., 2013). In particular, no increased risk of GBS was associated with mass vaccination against influenza A (H1N1) in 2009 (Yoki & Hartung, 2012). Thus, the precise reasons for development of GBS are not known today.

Clinical Pathology

Clinical pathology of GBS includes changes in CSF. For the diagnosis of GBS, laboratory analysis of this fluid is needed. Protein concentration and cell count should be identified within liquor. Leucocytes count in CSF is typically normal: less than 10 cells per ml (Walling & Dickson, 2013). However, in some cases, it might be elevated, up to 50 cells/ml (Eldar & Chapman, 2014). At the same time, protein concentration remains normal (up to 40 mg/dL) within the first week since the symptoms appear, and increases (up to 52 mg/dL) beginning from the second week (Parra et al., 2016). Therefore, monitoring of changes in CSF composition could be used as a measure of disease progression.

Diagnostic Tests

Symptoms of GBS are typical for any neuropathology, which could develop in people with a wide range of diseases. Thus, it is highly important to differentiate GBS from such disorders and pathological states, as brain stem or spinal cord lesion, neuromuscular junction defect, muscular abnormalities, toxic neuropathy, porphyria, diphtheria, vasculitis, tick paralysis, and metabolic disturbances (Eldar & Chapman, 2014). If disease does not include sensory symptoms, GBS should be differentiated from poliomyelitis, myasthenia gravis, electrolyte imbalance (for example, hypokalemia), botulism, and myopathy (Yoki & Hartung, 2012). Thus, differential diagnosis of GBS is rather complex.

If GBS is suspected, lumbar puncture should be performed. This analysis might be useful for exclusion of other possible diagnoses, in particular, infectious diseases (Yoki & Hartung, 2012). During the first week after the symptoms appearance, the protein level might be normal. However, it will increase starting from the second week. It is important to remember that the results of laboratory investigation might be normal during the first week and thus, repetitive analysis of CSF is required (Eldar & Chapman, 2014). To exclude the pathology of spinal cord, magnetic resonance imaging should be performed (Yoki & Hartung, 2012). Neurophysiological examination and electromyography are also required. This examination helps estimate the severity of neuropathy (Yoki & Hartung, 2012. All these investigations will help to confirm the GBS diagnosis and differentiate between different forms of this syndrome.

Treatment

Current Treatment

Treatment of the disease consists of two main components, which are non-specific and immune therapy. First, the reasons for death of people with GBS include sepsis, pulmonary emboli, and cardiac arrest. Thus, it is important to prevent these complications and to examine people with GBS for their early signs, which suggests cardiac and respiratory monitoring, and blood analysis. If necessary, artificial lung ventilation is required (Van Den Berg et al., 2014). In addition, symptomatic therapy is required. Pain is a typical symptom of GBS and thus analgesics, such as opioids, gabapentin, and carbamazepine, are prescribed (Yoki & Hartung, 2012). In addition, psychotherapy might be needed to address the psychological issues related to long-term pain and temporal or permanent inability to care for oneself (Willison et al., 2016). Thus, the first component of treatment aims at the management of symptoms and complications.

Secondly, immune therapy could be applied. One of the possible approaches is plasma exchange. Such treatment allows for removal of antibodies from the patient’s blood and, correspondingly, to decrease their concentration and improve the patient’s state (Raphaël, Chevret, Hughes, & Annane, 2012). This immune therapy is usually applied for patients, who cannot walk and have the disability scale score higher than three (Willison et al., 2016). It is important to start plasma exchange procedure within a month after the development of symptoms. The procedure should be performed once in two weeks. In general, five procedures are required (Buenz, Parry, & Ranta, 2017). Another possible option under immune therapy component is immune globulin injections. They might neutralize pathological antibodies and inhibit complement activation by these antibodies. As a result, the injury of nerves decreases, as the activity of the immune system reduces. Immune globulin therapy replaces plasma exchange therapy in some clinics due to its higher availability (Hughes, Swan, & van Doorn, 2014). Thus, the second component of treatment is specific and directed against the cause of disease.

In their review, Verboon et al. (2017) recommended to start the immune therapy as soon as possible to avoid significant nerve damage. The authors also proposed to apply these approaches for patients with mild forms of the disorder. It is especially recommended for children by Verboon et al. (2017), because it is easier to perform. In case of necessity, the therapy should be repeated for all patients with GBS.

Experimental Treatment Approaches

A successful experimental treatment was applied for a patient with GBS-associated type I achalasia. Achalasia is a rare conditions characterized by dysfunction of the esophagus, which results in the absence of peristalsis. In one case of GBS-associated achalasia, peroral endoscopic myotomy was performed. Positive outcomes of treatment were immediately achieved (Shin et al., 2017). This therapy was successfully applied for treating patients with achalasia of different origin. It was considered as safe and less invasive approach (Youn, Minami, Chiu, & Park, 2016). Thus, this particular therapy might be effective for patients with GBS-associated achalasia. No other experimental approaches for GBS treatment were found in the literature.

Conclusion

Guillain-Barré syndrome is a group of neuropathological diseases, which can lead to paralysis and disability, as well as patient’s death. The disorder develops after infection or other stimulation of the immune system. Antibodies of the patient start to attack peripheral nerves, which leads to the GBS development. The main symptoms of the disorder are symmetric and progressive pain, numbness, and weakness in limbs. GBS could also affect cranial and breathing nerves. For correct diagnosis, analysis of cerebrospinal fluid should be performed. Increased level of protein with normal cell count in CSF is the indicator of GBS. Today, non-specific supportive therapy and immune therapy are applied for the treatment of the disease, and there are no alternative options widely used in clinical practice.