key: cord-0924251-pzaaturw authors: Whittaker, Abigail; Anson, Matthew; Harky, Amer title: Neurological Manifestations of COVID‐19: A systematic review and current update date: 2020-06-02 journal: Acta Neurol Scand DOI: 10.1111/ane.13266 sha: 9e4606ff22f416e410ba0c4896fb9e7126259b42 doc_id: 924251 cord_uid: pzaaturw The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), was first identified in December of 2019 in the city of Wuhan, China. Since the outbreak, various reports detail its symptoms and outcomes, primarily focusing on respiratory complications. However, reports are emerging of the virus’ effects systemically, including that of the nervous system. A review of all current published literature was conducted, and we report that headache and anosmia were common neurological manifestations of SARS‐CoV‐2. Less common symptoms include seizure, stroke and isolated cases of Guillain‐Barre syndrome. Further research is now warranted to precisely determine the relationship between those patients developing neurological sequelae, their clinical state and any subsequent morbidity and mortality. virus, which has consequently sparked a global pandemic, has also been widely reported to display a range of respiratory manifestations. Milder, and most commonly, symptoms include fever, fatigue and cough; however, more severe cases of the disease can induce respiratory distress, renal and cardiac failure and eventually death. 1 In addition to respiratory symptoms, reports are emerging of neurological manifestations of SARS-CoV-2, which range from milder presentations such as headache to severe complications such as seizures and strokes. We provide a comprehensive review of the neurological manifestations of SARS-CoV-2 and its outcomes on mortality and propose the implications this has on clinical practice now and in the future. A comprehensive electronic literature search was done on PubMed, SCOPUS, Embase, Cochrane database, Google Scholar and Ovid in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines to identify the articles that discussed the neurological presentations and relation with COVID- 19 . Keywords used were "Neurology" "COVID-19" "SARS-CoV2" "Neurological manifestations" "Nervous system" "Guillain-Barre syndrome" "Neuropathy" "Outcomes" "Stroke" "Nerve" "Critical care". The search terms were used as keywords and in combination as MeSH terms to maximize the output from literature findings. A staged literature search was done, whereby a separate literature search was performed for each section within this article and all the relevant studies were identified and summarized separately. If a paper is reporting on many aspects of COVID-19 and neurology aspect, then the results have been shared between different parts of this review. The relevant articles are cited and referenced within each section separately. No limit placed on publication time or language of the article. All the relevant articles were identified and screened by three authors; the results are summarized in narrative manner in each relevant section within the text of this review. A summary table of each section is provided where appropriate. Studies were included if they have reported outcomes on any aspects of neurology in relation to COVID-19; the main exclusion criteria were editorials, commentary, narrative reviews with no reports on case outcomes or proposed treatment method. All the studies and data collection were done by two authors (AW and MA), and disagreements were resolved by consensus and involvement of senior author (AH). PRISMA flow chart is reported as in Figure 1 . A total of 339 articles were found; after removal of duplicates and non-original research papers, a total of 38 articles were used for full-text screening; and finally, only 31 studies met the final inclusion criteria and were included in our study. They are summarized in Table 1 . Among those studies, there were 13 case reports, 2 observation studies of between 8-382 case-cohort size, 13 retrospective, 2 prospective and 1 cross-sectional study. Among the 31 studies, 7 reported on Guillain-Barre syndrome, 11 reported on headache, 5 reported on olfactory dysfunction, and 5 reported on acute cerebrovascular accidents. The respiratory manifestations of SARS-CoV-2 are well documented and known. There is an increasing body of significant anecdotal evidence suggesting anosmia as being a symptom of SARS-CoV-2, giving rise to the possibility that there may be a degree of neurological involvement with the infection. It has been proposed that SARS-CoV-2 gains entry to the CNS by one of two ways: firstly, by systemic vascular dissemination and, secondly, more locally across the cribriform plate of the ethmoid bone, which may or may not have implications regarding the much-reported anosmia that patients with SARS-CoV-2 experience. 2 there is an increasing awareness that its neurological manifestations are something to be recognized alongside its more well-understood respiratory presentation. After having conducted a review of all the literature on PubMed pertaining to the neurological manifestation of SARS-CoV-2 using key terms such as "Covid AND neurology"; "Covid AND nervous system", we summarize the findings of 31 such papers that were available to review at the time in Table 1 . Key symptoms reported were headache and dysfunction of olfaction and gustatory sensation. However, it is important to note that no papers as of yet have sought to determine whether neurological involvement is a predictor of poor outcomes in patients with SARS-CoV-2, something which we feel may be worthwhile. It is worth mentioning that all studies in this area to date limit chemistry is yet to be fully understood, most likely however, is it a combination of both. Worryingly, Oxley et al 10 reported five cases of large vessel stroke in patients younger than 50 who had a diagnosis of SARS-CoV-2. The youngest two patients, aged 33 and 37, had no previous medical history. Two further studies detailing the rate of thromboembolic complications in patients with SARS-CoV-2 noted the incidence of ischaemic stroke to be 1.6% 11 and 2.5%, 12 respectively. Both authors recognized that the incidence of thrombotic complications was remarkably high for their particular institutions. There are clearly additional risk factors predisposing patients with SARS-CoV-2 to develop thromboembolic stroke beyond the traditional cardiovascular and metabolic co-morbidities and those pertinent to a protracted stay within intensive care settings. The thrombo-inflammatory nature that SARS-Cov-2 predisposes patients to, was described by Connor and colleagues who reported the coagulative parameters in 16 critically ill patients. 13 They found that fibrinogen (94%), platelet (62%) and D-dimer (100%) levels were increased, as well as interleukin-6 (IL-6) (100%). They propose a correlation between inflammation and subsequent coagulopathy, by IL-6 and fibrinogen, respectively. 13 Upon damage to the alveoli, an inflammatory state is generated, and as a result, the production of inflammatory cytokines is released, including IL-6. The downstream effects are broadly categorized into two sequelae: firstly, the production of pro-coagulative factors and, secondly, damage to capillary endothelium resulting in dysregulation of its anti-thrombotic properties. Both of which result in the formation of microvascular thrombosis, that in turn have the potential to embolize systemically. 13 The pathophysiology of pro-thrombotic states following viral infection has been extensively documented and mirrors the proposed mechanism by Connor et al However, we must also consider the possibility that the predisposition to coagulopathy and thrombotic events may well be explained by the long stays in ITU and consequent immobility. There have also been eleven confirmed case reports and another po- The long-stay admissions that some patients are currently experiencing may also pose another issue, that of post-intensive care syndrome (PICS), in particular critical illness polyneuropathy and myopathy (CIPNM). Case reports from SARS-CoV detail patients who experienced CIPNM following infection with the virus. 26 The underlying mechanism, though not fully understood, is thought to be due to systemic inflammatory response syndrome (SIRS) that results. 27 This mediates the release of pro-inflammatory cytokines and free radicals, which affect the microcirculation of both the central and peripheral nervous system by reducing oxygen and nutrient delivery. 27 It is also important to note that risk factors for PICS have F I G U R E 2 Illustration of reported neurological manifestations of SARS-CoV-2 been identified and include long durations of mechanical ventilation, hypoxia and sepsis, features that are common to severe SARS-CoV-2 cases. 27 Yet, no reports detail such symptoms in SARS-CoV-2 patients thus far; however, due to the similarity of the sister viruses, this may be a potential long-term complication. Current published studies have suggested that neurological involvement in the pathogenesis of SARS-CoV-2 does seem to be associated with a more "severe" infection and subsequent mortality. However currently, no direct cause and effect has been attributed to neurological deterioration in patients with SARS-CoV-2 and this relationship could just as plausibly be explained by association with other multi-organ system failures. The direct effect on mortality and morbidity in such "neurological involving" patients is yet to be elucidated. Interestingly, peripheral nervous system involvement by way of anosmia has been shown to be the initial presentation of SARS-CoV-2 in 36% of patients a recent Spanish case-control study. These so-called smell and taste disorders (STD) were found to be significantly more prevalent in SARS-CoV-2 patients than in influenza patients. 28 Whilst respiratory symptoms of SARS-CoV-2 are well recognized and subsequently protocols are in place to screen for and manage these, scope remains for this to be broadened to cover neurological symptoms of the disease. As referenced to previously, the first paper to describe neurological involvement in SARS-CoV-2 patients concluded that symptoms were much more common in patients with "severe" forms of the disease, defined by respiratory symptoms. 7 They also reported that typical symptoms, such as cough and lethargy, are less pronounced in severely unwell patients. 7 The implications this has on current clinical practice are therefore twofold. Firstly, that all patients, but especially those with "severe" SARS-CoV-2, must be monitored for the progression of neurological symptoms, as this may indicate a worsening of their condition. This should also include coagulation parameters, as suggested by Connor's et al due to the predisposition of thrombosis the virus conveys. Secondly, that patients presenting with new-onset focal neurology, with or without the presence of coryzal symptoms, should be reviewed and treated with suspicion of SARS-CoV-2 infection. This will allow the early detection of the disease and therefore prevention of deterioration or transmission. To fully understanding the impact of SARS-CoV-2 on the nervous system, it is essential that documentation of all neurological symptoms is collected for patients infected with the disease, so that further analysis can be performed into neurological manifestations. An aspect of SARS-CoV-2, not yet fully understood, is the long-term sequelae the virus may have on different systems of the body [47] [48] [49] [50] . Again, detailed documentation and long-term follow-up of recovered SARS-CoV-2 patients will allow conclusions to be drawn on this area. More data are required to establish the prevalence and, importantly, the implications of neurological manifestations in SARS-CoV-2 patients, both short-and long-term, including mortality rates. As more case reports become available, we hope a stronger correlation can be established between the two. Diligent documentation of all neurological symptoms is recommended to help achieve this. The mechanism underlying the neuroinvolvement of SARS-CoV-2 is also yet to be fully understood and remains an area of interest. Identifying modes of transmission is essential in possibly reducing spread and establishing novel therapeutics, to target the virus. The underlying pathophysiology of neurological manifestations in SARS-CoV-2 remains to be fully determined. Increasing numbers of papers are reporting neurological involvement in patients, but more data are required to adequately correlate the two and the impact this has clinically. 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