Guillain-Barre syndrome: An autoimmune disorder post-COVID-19 vaccination?

SARS-CoV-2 causes Coronavirus Disease 2019 (COVID-19), an infectious condition that can present none or one or more of these symptoms: fever, cough, headache, sore throat, loss of taste and smell, aches, fatigue and musculoskeletal pain. For the prevention of COVID-19, there are vaccines available including those developed by Pfizer, Moderna, Sinovac, Janssen, and AstraZeneca. Recent evidence has shown that some COVID-19-vaccinated individuals can occasionally develop as a potential side effect Guillain-Barre syndrome (GBS), a severe neurological autoimmune condition in which the immune response against the peripheral nerve system (PNS) can result in significant morbidity. GBS had been linked previously to several viral or bacterial infections, and the finding of GBS after vaccination with certain COVID-19, while rare, should alert medical practitioners for an early diagnosis and targeted treatment. Here we review five cases of GBS that developed in different countries after COVID-19 vaccination.


Introduction
Coronaviruses (CoV), a superfamily of viruses, are the causal agents for COVID-19 and other deadly infectious diseases such as Severe Acute Respiratory Syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) [1] . Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by SARS-CoV-2 that can readily spread from infected to healthy individuals [ 2 , 3 ].
COVID-19 patients have a wide range of symptoms that may include, concomitantly or not, chest pain, cough, high temperature, breathing difficulties, fatigue, and loss of taste and smell [4][5][6][7] . Those symptoms develop from 1 to 14 days after the encounter with the virus [8] and can vary from person to person. Older or immune-compromised individuals face harsher and more severe consequences such as respiratory failures, crucial organ failure, or death [ 9 , 10 ]. However, some infected individuals may carry the virus without developing any noticeable symptoms [11] . Others individuals, may continue to have a wide range of symp- Table 1 Illustration of vaccine types, manufacturers and its efficiency.  [51] weakness in the leg muscles that worsen over time, difficulty in chewing, talking, or swallowing food, and urinary incontinence [ 21 , 22 ]. In extreme cases, acute flaccid paralysis can develop [23] .

Coronavirus disease 2019 (COVID-19)
COVID-19 is caused by the single-stranded RNA virus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [ 1 , 2 ]. SARS-Cov-2 is genetically highly similar to the SARS coronavirus that caused the outbreaks in 2002 [24] . Coronavirus is a large virus family that affects humans and causes disease in other animals such as cats, bats, and camels. It primarily affects the upper respiratory tract and has been linked to the common cold [25] . Middle East Respiratory Syndrome (MARS) and SARS (Severe Acute Respiratory Syndrome Coronavirus) are two examples of coronaviruses that have evolved from animal to human infection.
The epicenter of COVID-19 Wuhan discovered the first case in December of 2019 [26] . The doctor initially misidentified the COVID-19 as an extreme instance of pneumonia due to a lack of pre-information. Scientists identified the primary cause of this unique pneumonia as "new coronavirus (n-CoV) " [27] in the first month of 2020. Similar cases had begun to emerge in other parts of the world, including the United States, Pakistan, India, and several European and African countries. On January 29, 2020, the World Health Organization (WHO) acted and proclaimed the current SARS-CoV-2 outbreak a global emergency [28] . COVID-19 spreads quickly to the outer reaches of the globe in March 2020, resulting in hundreds of thousands of deaths and being labeled a global pandemic by the WHO [29] .
Initially, there was some inaccurate information about COVID-19 transmission modes, but this issue has now been resolved. The most common way of transmission is by coming into close touch with an infected person, and a healthy person can readily contract COVID-19. Other modes of transmission include contaminated droplets in the air, contaminated surfaces touched by infected people, and virus-carrying airborne particles [ 30 , 31 ]. Some typical preventive measures to avoid infection include daily hand washing for at least 20 s, covering the nose and mouth with a piece of cloth while sneezing and coughing, and wearing a facemask while going to crowded places [ 32 , 33 ].
Since the emergence of COVID-19, the efforts to combat this disease have resulted in the development, production and distribution of multiple vaccines to combat this global pandemic at its source. Here we attempted to discuss a few vaccines.

Pfizer
BioNTech (German Biotechnology Company) created the first COVID-19 vaccine, which was allowed and approved by a stringent regulatory authority and the Food and Drug Administration Authority (USA) [34] .
It is a nucleoside modified messenger RNA vaccine that targets the Corona Virus's S protein [35] . This vaccination aids the immune system in the production of antibodies that fight the virus's S protein. It is worth noting that S protein aids coronavirus entry into type 2 alveolar cells via the ACE2 receptor [36] .

Moderna
Spikevax [37] is developed and manufactured by Moderna, a firm based in the United States. It is a messenger RNA-based vaccination encased in a lipid nanoparticle that encodes the SARS-CoV-2 spike protein [38] . Spike glycoprotein aids virus attachment and penetration into cells, making it a prime target for vaccine development [39] . It also activates the CD4 + T -cell and CD8 + cytotoxic T-cell responses, allowing the virus to be removed from the body. The entire immunization regimen consists of two doses injected into the body's deltoid muscle [40] . This vaccine may be stored in the refrigerator rather than the freezer, making a delivery to developing nations easier [41] .

AstraZeneca/Oxford
The vaccine's code name is AZD1222, and it is sold under the brand names Vaxzevria and Covishield. It was created and prepared in partnership with Astra Zeneca (a British-Swedish company) by the University of Oxford (United Kingdom) [42] . It is a viral vector-based vaccine that is administered intramuscularly [43] . It can be kept in the refrigerator without the need for a freezer. After the injection, a person may suffer mild side effects such as site discomfort, headache, and nausea, which disappear on their own in one to two days [44] .

Janssen vaccine
Janssen Pharmaceuticals, a Johnson & Johnson subsidiary (American company), manufactured and developed this vaccine. The gene responsible for generating the SARS-CoV-2 spike protein has been inserted into human adenovirus [45] . It targets the S protein coronavirus to start the antibody response against COVID-19 [46] . Antibodies directed against the S protein impede virus entrance into the alveolar type 2 cell of the lungs.
The vaccine is the most effective strategy to combat and control this virus, although it has had major side effects on many people. Guillain- Fig. 1. Schematic presentation of the pathogenesis of COVID-19-associated GBS. The angiotensin-converting enzyme 2 (ACE2) receptor [2] , which is found on the central nervous system's nasal and oral mucosa, neurons, glia cells, and blood vessels, has a high affinity for SARS-COV-2. SARS-COV-2 binds to this receptor and is endocytosed during an infection. Because the peptide sequences or epitopes of SARS-Cov-2 and gangliosides are similar (molecular mimicry), antibodies generated against the virus may bind the gangliosides found on peripheral neurons via T cell-B cell interactions. This could trigger an immunological reaction, causing myelin and/or axons to be destroyed.
Barre syndrome is one of these side effects; which is of high concern for neurologists.

Pathophysiology of Guillain Barré syndrome
Guillain-Barré Syndrome (GBS) is an autoimmune disorder of the peripheral nervous system (PNS) [16] . The mechanism of GBS is quite complicated; its explanation depends on what factors and agents trigger the disease ( Fig. 1 ). Till now, four different kinds of GBS have been reported [52] . Furthermore, every kind has its mechanism, but one thing is fairly consistent in every case: the attack of the immune cell on nerve cells of PNS and their supporting structure that leads to its dysfunctionality [53] .
The first variant of GBS is acute inflammatory Demyelinating Polyneuropathy (AIDP), the most common kind of GBS. In this kind, T cell and antibody start to attack Schwann cell and myelin epitopes in peripheral nerve roots that slow down the electrophysiological conduction, and extreme muscle weakness is inevitable [54] .
Acute Motor Sensory Axonal Neuropathy (AMSAN) is the second type of GBS, the most severe of the other variants. In this type, Inflammation and degeneration of axons in the motor and Sensory occur [55] .
The victim of Miller Fisher Syndrome (MFS), the third kind of GBS, typically experienced a problem with the movement of an eye muscle, ataxia, and areflexia [56] . Most of the patients' bodies have antibodies against GQ1b (a ganglioside component of the nerve) [57] . A gan-glioside is a molecule with ceramide attached to a group of hexosetype sugars and contains several N-acetylneuraminic acid groups [58] . The production of anti-ganglioside antibodies after the infection or postvaccination mostly results from molecular mimicry, where the immune system produces antibodies against the microbial antigen. However, sometimes the resultant antibodies cross-react with epitope present in the peripheral nerve, leading to the destruction of that nerve cell [59] .
AMAN (Acute Motor Axonal Neuropathy) is the fourth variant of GBS characterized by the loss of reflexes and acute paralysis. Pathologically, in this condition, the antibodies start to attack the axon of the motor nerve and the nodes of Ranvier (space between the two Schwann cells) [60] .

Correlation between COVID-19 vaccine and GBS
The correlation between GBS and COVID-19 vaccine is presented by many cases reported in several counties across the world.

Case 1
The first case of GBS was a 20-year-old man from England who had a past medical history of ulcerative colitis [61] . One day after receiving his first dose of Astra Zeneca, he complained of an occipital headache without any symptoms of photophobia or stiffness in the neck. One day later, his distal lower limb developed dysesthesia. He developed facial diplegia in the coming three days, which became severe in less than 24 h.

Case 2
The second case of GBS was reported Caucasian male (57-year-old) after receiving the COVID-19 vaccine [61] . This particular man had Asthma and osteoarthritis in his past medical history. He used to take loratadine, tamsulosin, omeprazole, steroid, and salbutamol inhalers as regular medication. A couple of days after receiving his first dose of Astra Zeneca, the man noted a mild back pain that slowly spread into his flanks. . Four days later, he showed facial weakness and dysarthria. The facial weakness reached its peak within 48 h. The patient also experienced weakness and severe dysesthesia in his distal that continued to progress until admission.

Case 3
A 55 years-old Caucasian male with past history of hypertension treated with Lisinopril and amlodipine received the Astra-Zeneca vaccine [61] . He was hospitalized within 29 days after taking his first dose. Seven days prior to admission, he experienced bilateral thigh paresthesias. One day later, he noted numbness in the lambral and sacral regions. Two days before the presentation, he noticed facial diplegia, which reached a nadir within less than 96 h.

Case 4
The first case of Guillain Barré Syndrome in Latin America was reported in 2021 in a 73-year-old man from Colombia [62] . He received a dose of the Chinese vaccine Sinovac and was admitted to the National reference University hospital within four days in March 2021. His-symptoms were upper limb paresis, dyspnea, and inability to walk. It should be remembered that the person had a history of GBS, but with the proper treatment, he had then recovered from it.

Case 5
In Malta, a doctor reported a case of GBS after a first dose of Astra Zeneca vaccine in a 48 years-old male with a history of dyslipidemia [63] . In 10 days, he presented to the hospital after taking the first dose of the COVID-19 vaccine. He developed a motor neuron weakness on the left side of the face. Bell's palsy was also diagnosed in a patient treated with prednisolone, eye drops, and physiotherapy. Severe mid-thoracic back pain was also noticed in the patient, which was unresponsive to a simple painkiller. The facial weakness progressed from left side to right side within 24 h. His-cognitive function, voice tone, and cranial nerve examination, excluding facial weakness, were normal.

Conclusion
GBS is a rare complication associated with COVID-19 vaccination, and neurologists should be aware of it. Diagnosis of GBS can be difficult and time-consuming, particularly in asymptomatic COVID-19 patients or those with a mild respiratory illness that might have been present only weeks earlier. However, an early detection of GBS can allow a better treatment and improve clinical outcomes. Although many case reports or case series make up the literature about GBS, it needed more extensive studies to determine the causal connection between COVID-19 and GBS.

Funding
None.

Ethical approval
None.