key: cord-269347-oc2pb00b authors: Ahmad, I.; Rathore, F. A. title: Guillain Barr e syndrome in COVID-19:A scoping review date: 2020-06-16 journal: nan DOI: 10.1101/2020.06.13.20130062 sha: doc_id: 269347 cord_uid: oc2pb00b Introduction The novel coronavirus (COVID19) can result in several neurological complications. Guillain-Barre Syndrome (GBS) is one of them and has been reported from different parts of the world in this pandemic. It is an acute post-infectious polyneuropathy. The review aims to summarize the demographic features, clinical presentation, diagnostics workup, and management strategies of COVID-19 associated GBS reported in the literature. Material and method We searched Medline, PubMed Central, SCOPUS, and Google Scholar using pre-defined keywords, with no time limits and in the English language only. We aimed to include all kinds of manuscripts. The last search was done on 18th May 2020. Demographics, clinical features, diagnostic workup, management, and outcomes were documented in the datasheet. Results We identified 24 cases of COVID-19 associated GBS. Most of the cases were reported from Italy followed by the USA. The majority were males (18 /24) The age ranged from 23 -84 years. The clinical presentation was typical sensory-motor GBS in most. Nine patients had facial palsy of which five had bilateral involvement. Two patients had bilateral abducent nerve palsy while two presented as paraparetic GBS variant with autonomic dysfunction. Electrodiagnostics was performed in 17 patients only and 12 had typical features of acute inflammatory demyelinating polyneuropathy. Intravenous immunoglobulins were the preferred mode of treatment in most of the patient. There was one death, and most were discharged to rehabilitation or home. Conclusion GBS is a frequent neurological complication associated with COVID-19. There is no clear causative relationship between GBS, and COVID-19 at present, and more data are needed to establish the casualty. However, most cases have a post-infectious onset with male preponderance. Most of the cases have a typical presentation but some may present in an atypical way. Prognosis is generally good. The novel coronavirus (COVID19) infection originated from Huanan seafood market in Wuhan city China in December 2019. It rapidly spread to more than 200 countries of the world with 7 million confirmed cases and more than 400,000 fatalities as of 10 st June 2020. 1 COVID-19 primarily affects the respiratory tract and the lungs. However, involvement of cardiovascular, renal system and neurological system has also been reported. The reported neurological manifestations and complications of COVID-19 include anosmia, headaches, dizziness, delirium, stroke, epilepsy, encephalitis, encephalopathy, myalgias and Guillain-Barr é syndrome (GBS) 2 , 3, 4 At present, there are no reviews, full length research article or reports discussing a specific neurological complications in detail. The objective of this review is to summarize the important demographic features, clinical presentation, diagnostics, and management strategies of COVID-19 associated GBS reported in literature so far. We aim to inform the readers about this important neurological manifestation of COVID-19 in order to formulate better diagnostic and management strategies. The mysterious link between infections followed by paralysis has intrigued physicians for centuries. 5 Although this relationship was mentioned by the famous Muslim physician Avicenna centuries ago and many other authors published their cases too, but the detailed description of the disease, including nerve conductions studies and cerebrospinal fluid analysis with albuminocytological disproportions was first documented by three French physicians Georges Guillain, Jean Alexandre Barr´, and Andr´e Strohl, who were working together at the Neurological Center of All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint 5 the French 6th Army during first world war. They treated and published data on two soldiers, who developed typical features of GBS with complete recovery. The disease was named Guillain-Barr é syndrome after them. 6 GBS is acute onset immune mediated disorder characterized by rapidly progressive limbs and bulbar weakness which can lead to respiratory failure. 7 Many triggers for GBS have been identified including bacterial and viral infections, surgery, and pregnancy. The link of GBS with vaccination is controversial. Campylobacter Jejuni is capable of inducing antibodies that cross react with glycans present on nerve gangliosides. 8 The exact trigger to mount this misdirected immune response is still not known. There is no specific genetic predisposition as only 1% of all campylobacter infections will result in GBS. GBS has also been reported after viral infections for example Cytomegalovirus, Ebstein-Barr virus, Influenza, Zika, and Chikungunya virus . 12 ,8 The clinical hallmark is hyporeflexia or areflexia. The course of the disease is monophasic. Recommended treatment for GBS includes plasmapheresis (PLEX) and immunoglobulins (IVIG) infusion. 9 GBS was initially described only as a All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 10 . These include, cranial, autonomic, ataxic, paraparetic and mixed variety. The GBS reported from North America and Europe is predominantly demyelinating type while in Asian countries the axonal type of GBS constitutes 30-50 % of the reported cases. 11,12,13 ,14 The mortality of GBS reported from European and North American studies ranges from 3-7%, and is mainly due to respiratory failure, deep vein thrombosis and autonomic dysfunction. The axonal variants of GBS mostly reported in the Chinese and Asians populations have a poor prognosis. 15 The poor prognosis is because peripheral nerve remyelination is a natural and active process. Whereas in case of axonal variant of GBS, once the axonal integrity is damaged, it does not be regenerate actively and completely. 2 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 16 . These are enveloped, single-stranded RNA viruses with a diameter of approximately 60-140 nm. The viral envelope has four structural proteins known as S (spike), E (envelope), M (membrane), and N (nucleocapsid). It is the interaction with the spike protein and host cell receptor which is essential for virulence and infectivity. 17 Coronaviruses are not primarily neurotropic viruses and their primary target is respiratory and cardiovascular systems. It is through the Angiotensin-converting enzyme 2 (ACE-2) receptors the virus is attached to host cells leading to internalization and subsequent viral replication. This receptor is also found in glial cells in the Central Nervous System (CNS) and spinal neurons. Very rarely the virus can invade peripheral nerves and lead to retrograde transfer via synapse mediated route to CNS. Another proposed route of entry is through the olfactory nerves. 18 , 19 Past experience with Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory syndrome (MERS) related cases has also provided insights into the neuro invasive potential of Coronaviruses. 20 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint COVID-19 does not directly invade peripheral nerves , nerve roots, or anterior horn cells leading to inflammation and death of motor neurons as seen in polio virus or West Nile virus. Even the Cerebrospinal fluid (CSF) Polymerase chain reaction (PCR) for coronavirus in multiple reported cases of COVID-19 related GBS has been negative. 22 It is likely a post infectious or may be a para-infectious complication resulting from an aberrant immune response. During the inflammatory phase numerous mediators of inflammation are released from activated leukocytes including Interleukin-6 (IL-6) ,named as Cytokine storm. This can result in major organ damage, rapid deterioration of the patient and ultimately death. 23 However, due to lack of experimental data It is difficult to deduct if IL-6 is also responsible for the c is also causing neurological damage 37 After the acute phase of the infection, an immune response is generated by the host and may lead to a misdirected response against host epitopes. It can result in an autoimmune, response directed against peripheral nerves and nerve roots in susceptible individuals. This may be either demyelinating or axonal degeneration type. This results in a typical GBS like presentation in the peripheral nerves and spinal roots. However, due to lack of clear data, there is still not enough evidence available to conclude if antibodies to any specific ganglioside antigen are present in these cases or not. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint We searched Medline, PubMed Central, SCOPUS and Google Scholar using keywords " COVID-19", "Coronavirus", " Coronavirus Infections", "Coronaviridae", "2019 nCoV ". "pandemic", "SARS-COV-2", "neurology", "neurological", "complications", "manifestations" , "Guillain-Barr é syndrome" , "GBS", "acute inflammatory demyelinating polyneuropathy"," Demyelinating Polyradiculoneuropathy", "polyneuropathy", and "Miller Fisher syndrome". Different combinations of Boolean logic (AND, OR and NOT) were used to identify relevant articles. Search was limited only to English language manuscripts with no time limit. It is important to note that new data is being shared regularly and so far, it consists mostly of pre-prints, letters to editor, single case reports, small case series, and part of an article describing clinical features of COVID-19. Most of the data on COVID-19 at present is published from countries most severely affected, including China, Italy, Spain, and USA. The last literature search was done on 18 th May 2020. At that time there was no specific research article, systematic or narrative review describing COVID-19 associated GBS. However, we identified two systematic reviews protocols on this topic registered in the International prospective register of systematic reviews. 24 , 25 Both authors independently performed the literature search and compared the results for any major discrepancies. The information was extracted on a predesigned data sheet. The items of interest were the demographic data, presenting features, clinical examination, laboratory and radiological investigations, treatment protocol and outcomes. Due to the limited number of cases and nature of the review, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint a quantitative analysis was not done, and we have only provided a qualitative review of the retrieved information. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint After removing the duplicates, non-English manuscripts, and unrelated articles, we identified 24 cases of GBS in COVID-19, published in the English biomedical literature till 18 th May 2020. These were published as letter to editor, case reports or case series. The results are summarized in the Tables 1 and 2. Most of the cases (8) 42 Majority of the patients were males (18 /75%). The age ranged from 23-84 years and mean age is 60 years. Most of the patients (17/24) had typical presenting features of GBS with sensory paresthesia followed by ascending paralysis. Three patients had Miller Fisher variant presenting as ataxia, ophthalmoplegia and areflexia. Total of nine patient developed facial palsy out of which six had bilateral facial palsy. One case had only bilateral facial palsy without any peripheral manifestations and was labeled as facial diplegic variant of GBS. Two patients developed bilateral six nerve palsy. One patient among above who initially presented with bilateral facial and hypoglossal palsy and progressed to a locked in syndrome like condition. One case each from the US 31 and Switzerland 41 initially presented with paraparesis and bladder and bowel All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint dysfunction. Spinal cord imaging was normal in both these cases and these were labeled as paraparetic variant with autonomic dysfunction. An important peripheral nervous manifestation i.e. hyposmia and hypogeusia was reported in Five patients. One of them had complete reversal of hyposmia at the time of discharge. The predominant clinical presentation in majority of the cases was post-infectious. However, in three cases the onset of symptoms suggested a parainfectious course of disease. Nasopharyngeal swab samples of all cases were PCR positive for COVID-19, except one case. That patient repeatedly tested negative but, later his serology tested positive for COVID-19. CSF PCR for COVID-19 was tested in twelve patients and it was negative in all. Ganglioside antibody was tested in twelve cases. It was positive in two case only. One of them was the Miller Fisher Variant. CSF analysis performed in 20 cases. Four patients had a normal CSF analysis while in 16 cases it showed albuminocytological disproportion of GBS. An important finding was that revealed COVID-19 associated lung changes on High-Resolution Chest Tomography (HRCT) chest in fourteen cases. X-ray chest was normal in six cases and revealed pneumonia in one case. Chest imaging was not reported in two cases. This can potentially guide the clinicians. During this pandemic, in a GBS patient HRCT chest should be ordered in case of any doubt to detect possible COVID-19 associated pneumonia as both can be contribute towards respiratory failure. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Three cases were ambulatory with minimum motor deficit and were not offered any treatment for GBS. One of them was a Miller Fisher variant. Nineteen patients were given IVIG. Among these two cases had repeat sessions of IVIG and two cases had PLEX after IVIG due to initial inadequate response. Two case had PLEX sessions as primary treatment one among them had IVIG after PLEX also. One case expired due to complications. Nine patients were either discharged to nursing homes or shifted to rehabilitation for exercise. Complete recovery was reported in eight patients. At the time of publication of cases, three patients were on mechanical ventilation, one was critically ill, and no improvement was reported in one case. Outcome and discharge status were not mentioned for three cases. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . This review suggests that in COVID-19 associated GBS, AIDP variant is more common followed by AMAN and AMSAN variants. However, Umapathi has recently suggested that Covid-19 GBS might be axonal due to paranodal pathologies and follow up EDX might help in reaching to a conclusion. 43 Three patients presented All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. The experience with Zika virus related GBS suggests that the patient present with typical symptoms including facial palsy on presentation, male predominance, and AIDP on EDX. A similar pattern was documented in this review. In a review from Puerto Rico facial weakness was seen in 62% cases of Zika Virus associated GBS as compared with 10% in non-Zika related GBS 44 . In this review 37.5 % of the cases had facial weakness with 5 having bilateral facial paralysis. The incidence of dysphagia in Zika Virus associated GBS has been reported to be 53.5% while it is very low in COVID-19 associated GBS (5/24 (20%). Two patients had paraparesis at presentation followed by urinary retention and were later diagnoses as GBS. 31,41 This paraparetic pattern is seen more commonly in Zika Virus associated GBS cases. We do not know the exact mechanism of this phenomenon. In 5 cases hyposmia and hypogeusia were either the presenting or co-existing features. 29,35 These were likely due to the COVID-19 infection and not because of GBS. This is an important finding and can be used as a clinical indicator of COVID-19 infections in suspected GBS cases. Seropositivity of GBS for ganglioside antibody is reported to be around 30% with the cases of MFS having 95% GQ1b positivity. In this review only one case was positive GD 1b ganglioside antibody. However, this data is too small to make a conclusion Most of the cases in this review were treated with 5 sessions of IVIG. In two cases, IVIG was repeated while in two cases PLEX was also done after giving IVIG. PLEX All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint has been used in two cases as initially and in one it was followed by IVIG due to inadequate response. One of the possible reasons for use of frequent use of IVIG in all these cases is that all of them were in high income countries with adequate resources and easy access to IVIG. We would like to suggest that in resource constrained areas and the developing world PLEX might prove to be equally beneficial as this is the preferred mode of treatment in cytokine storm syndrome due to COVID-19. Most of the patients had a good outcome and were either discharged to home with complete recovery or were referred to rehabilitation for management of residual weakness and motor deficits. There was one death and four patients were reported to be on mechanical ventilation at the time of publication of the case reports. However, due to the limited data, it is difficult to comment if COVID-19 associated GBS increases severity of illness, length of Intensive care Unit (ICU) admission and prolongs ventilatory support. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint The published data regarding neurological complication and manifestations associated with MERS is limited. 45 , Error! Bookmark not defined. ,47 In addition, MERS was an epidemic limited to one geographic area and GBS associated with MERS was rarely reported so it is not possible to make a detailed comparison between this and COVID-19 associated GBS due to paucity of data. There is one case report of a critical illness neuropathy due to prolong intensive care unit stay reported from Saudi Arabia. 46 which is a global health care crisis affecting millions. However, the common feature among both is the craniobulbar involvement in both. 47 See Table 3 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint The comparison of COVID-19 associated GBS with Zika Virus associated is presented in Table 3 . In Zika Virus-GBS the median time from symptoms to disease onset was seven days consistent with para infectious GBS whereas in this review the median time was 11 days (3-28) days. In Zika Virus GBS the disease was more aggressive with frequent ICU admission and need for ventilatory support. Our data reports a similar pattern with a total of nine patients needing respiratory support. Seven were placed on mechanical ventilation and two were on noninvasive ventilation. On EDX evaluation demyelinating type is the most finding both with =Zika Virus and COVID-19 associated GBS. Cranial involvement is another feature common to both types of GBS. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint Despite a rigorous search methodology for this review, we were not able to perform literature search all the major English bio-medical literature search databases due to lack of resources and access. There is a possibility that we might have missed some cases which we hope will be identified in the systematic reviews registered in the International prospective register of systematic reviews. The total number of confirmed cases of COVID-19 globally is now more than 7 million but we were able to document only 24 cases of GBS reported in the English biomedical literature so far. This is a very small number of cases to make a causal relationship or a definitive conclusion regarding COVID-19 associated GBS. Due to the wide spread of the disease and wide variations in the documentation and reporting of data from different parts of the world, there are chances that mild cases of GBS or cases with limited involvement might be missed or do not report to hospitals. Moreover, neurological services are not widely available in many developing countries and there is a possibility that some COVID-19 associated GBS cases remain undiagnosed due to lack of expertise in neurology. In addition, mortality in COVID-19 cases due to rapidly progressive respiratory failure is usually attributed to the COVID-19 itself. There is a possibility of co-existing GBS which may contribute to the worsening of the condition. We hope that as more data from different parts of the world is shared, things will become clearer in future and provide further insights into the COVID-19 associated GBS.. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint The primary presentation of COVID-19 is respiratory but neurological manifestations and complications are increasingly being reported in the literature. GBS is one of the frequent neurological complication associated with COVID-19. There is no clear causative relationship between GBS, and COVID-19 at present and more data are needed to establish the casualty. However, from the available data we conclude that most of the cases present as a post-infectious disease with male preponderance. The EDX reveal a demyelinating type of polyneuropathy in most of the cases with few being AMAN and AMSAN variants. IVIG is the preferred mode of treatment and prognosis is generally good with most of the patients responding to treatment and rehabilitation plan. There is a need for large scale data collection on GBS and other related neurological manifestations and complications of COVID-19 to formulate better care plans in future. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint World Health Organization. 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The copyright holder for this preprint this version posted Acute polyradiculoneuritis with locked-in syndrome in a patient with Covid-19 Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? COVID-19 may induce Guillain-Barr ´e syndrome Guillain-Barré syndrome as a complication of SARS-CoV-2 infection Covid-19 and Guillain-Barr ´e syndrome: More than a coincidence! Does COVID-19 cause axonal GBS? Clinical features of Guillain-Barré syndrome with vs without Zika virus infection Neurological complications during treatment of Middle East respiratory syndrome No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV) Neurological component in coronaviruses induced disease: systematic review of SARS-COV Guillain-Barré syndrome associated with Zika virus infection in Martinique in 2016: a prospective study All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.13.20130062 doi: medRxiv preprint