key: cord-333805-xmqs2ax7 authors: Romoli, Michele; Jelcic, Ilijas; Bernard‐Valnet, Raphaël; García Azorín, David; Mancinelli, Luca; Akhvlediani, Tamar; Monaco, Salvatore; Taba, Pille; Sellner, Johann title: A systematic review of neurological manifestations of SARS‐CoV‐2 infection: the devil is hidden in the details date: 2020-06-05 journal: Eur J Neurol DOI: 10.1111/ene.14382 sha: doc_id: 333805 cord_uid: xmqs2ax7 BACKGROUND: We systematically reviewed available evidence for reports of neurological signs and symptoms in Coronavirus disease (COVID)‐19 patients to identify cases with severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection or immune‐mediated reaction in the nervous system. METHODS: We followed PRISMA guidelines and used the MEDLINE, EMBASE, Google Scholar, MedRxiv and ChinaXiv databases to search for papers on COVID‐19 and nervous system involvement which were published from January 1(st) to April 24(th) 2020. Data on design, sample size, neurologic assessment and related work‐up were extracted. Biases were assessed with the Newcastle‐Ottawa scale. RESULTS: We analysed 27 publications on potential neuroinvasive or parainfectious neurological complications of COVID‐19. The reports focused on smell and taste (n=5) and evaluation of neurological symptoms and signs in cohorts (n=5). There were cases of Guillain‐Barré syndrome/Miller‐Fisher syndrome/cranial neuropathy (7 cases), meningitis/encephalitis (9 cases) and various other conditions (5 cases). Patients with cerebrospinal fluid (CSF) examination and in particular SARS‐CoV‐2 PCR was negligible. Amongst, two had a positive SARS‐CoV‐2 PCR exam of CSF specimen. The study of potential parenchymal involvement with magnetic resonance imaging was rare. Only 4 reports received a rating for the highest quality standards. CONCLUSION: This systematic review failed to establish comprehensive insights to nervous system manifestations of COVID‐19 beyond immune‐mediated complications as aftermath of respiratory symptoms. The authors therefore provide guidance for more careful clinical, diagnostic and epidemiological studies to characterize the manifestations and burden of neurological disease caused by SARS‐CoV‐2 on behalf of the Infectious Disease Panel of the European Academy of Neurology. The clinical spectrum of SARS-CoV-2 infection is wide, and encompasses asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and sometimes death. From a neurobiological and translational viewpoint, neurological manifestations can be expected in COVID- 19 . This is substantiated on the one hand by a few cases with neurologic signs and symptoms and detectable virus load in cerebrospinal fluid (CSF) during the SARS-CoV-1 epidemic in 2003 [1] . SARS-CoV-1 and SARS-CoV-2 share genetic sequences but SARS-CoV-2 has a 10-20 times higher binding affinity to ACE2 [2] . On the other hand, angiotensin converting enzyme-2 (ACE-2), the functional receptor utilized by SARS-CoV-1 and -2 for cell entry, is not only expressed in the lungs but also in the central nervous system (CNS) [3, 4] . Expression of ACE-2 is found in neurons and non-neuronal cells, the latter include astrocytes, oligodendrocytes and olfactory support cells [5, 6] . Moreover, infection of neurons with SARS-CoV-1 has been proven in transgenic mice and several presumed routes of CNS entry were described in preclinical models [7] . In a report from Wuhan, China more than a third of the hospitalized COVID-19 patients had some sort of nervous system-related clinical signs or symptoms [8] . These included on the one hand more specific conditions such as loss of sense of smell or taste, myopathy, and stroke. There were non-specific symptoms such as headache, impaired level of consciousness, dizziness, or seizure on the other hand. From a neuroinfectiologic viewpoint, the relevance of these findings is limited; these conditions can be coincidental, secondary to systemic complications or a side-effect of therapy. Only further diagnostic details such as focused neuroimaging, evaluation cardiovascular risk factor and comorbidities, assessment of prothrombotic or systemic hyperinflammatory states, presence of intrathecal inflammation and systematic exclusion of differentials would enable a placement within the spectrum of complications. This study therefore aimed to identify clinical cases of confirmed nervous system invasion or postinfectious neurological disease in the available COVID-19 literature on the basis of a systematic review. Hereupon, members of the Infectious Disease Panel of the European Academy of Neurology (EAN) compiled guidance for the diagnostic approach, which emphasizes the need for precise case definitions and standards for reporting. A systematic review was carried out to study all cases reporting nervous system involvement in patients with proven SARS-CoV2 infection. The protocol followed the PRISMA guidance for reporting of systematic reviews. MEDLINE, EMBASE, Google Scholar, MedRxiv and ChinaXiv database were searched for papers Accepted Article published from 1 st January 2020 to April 24 th 2020 regarding the nervous system and COVID-19. The search strings for PubMed were as follows: (("COVID"[All Fields] OR "coronavirus"[All Fields] OR "SARS-Cov-2"[All Fields]) AND (("neurology"[MeSH Terms] OR "neurolog*"[All Fields]) OR ("brain" [MeSH Terms] OR "brain"[All Fields]) OR ("neuro"[All Fields]) OR ("nervous system"[MeSH Terms] OR "nervous system"[All Fields])) AND ("2020/01/01"[PDAT] : "2020/04/24"[PDAT])). We also hand-searched reference lists of all articles identified in the electronic search using common search engines (e.g. google, bing). The search selected studies reporting neurological features of patients with SARS-CoV-2 infection. Studies were identified after search and data were extracted regarding: study design, sample size, neurological assessment and diagnostic workup including brain imaging and CSF analysis. Biases were assessed with Newcastle-Ottawa scale [9] . The systematic search yielded 102 papers, of which 30 were eligible for full-text assessment ( Figure 1 for PRISMA flow-chart). Four were excluded; these were commentaries, response letters and review articles proposing on SARS-CoV-2 nervous system invasion but did not comprise clinical findings. Twenty-six publications reporting neurological disturbances in patients with SARS-CoV-2 infection were evaluated, the major readouts are shown in Table 1 . Bias assessment revealed low to fair quality more than half of the studies (14/27, 52%), as shown in Figure 2 . This was mainly due to selection and reporting bias, as well as on the basis of uncertain exposure and lack of testing for SARS-CoV-2 with PCR in CSF. Only 4 reports reached a rating for high quality; one study evaluated neurological diagnoses of deceased patients with COVID-19 [10] , another studied neurological signs and symptoms in a cohort of hospitalized COVID-19 patients [8] , and a case series of peripheral nervous system dysfunction with in-depth phenotyping and diagnostic workup [11] . The fourth study described the clinical characteristics, laboratory features, treatment, and outcomes of cerebrovascular disease complicating SARS-CoV-2 infection [12] . Among the consecutively admitted 221 patients with COVID-19, 11 (5%) had acute ischemic stroke, 1 (0.5%) cerebral venous sinus thrombosis (CVST), and 1 (0.5%) cerebral hemorrhage. Five observational studies evaluated smell and taste dysfunction. The first study used an internet-based platform in adults who underwent testing for COVID-19 and found a higher rate of smell and taste impairment in SARS-CoV-2 positive patients [13] . The second report was a European multicenter study of mild-to-moderate COVID-19 patients which used standardized questionnaires [14] . They found olfactory Accepted Article and gustatory dysfunction in 85.6% and 88.0%, respectively. The third study used an online checklist inquired for self-reported anosmia/hyposmia [15] . In that cohort, 48% had hyposmia or anosmia and the onset was reported as sudden in 76%. The fourth report was a case-control study of smell and taste disorders among patients positive for SARS-CoV-2 on nasopharyngeal swab examination and also included SARS-CoV-2 negative patients as controls [16] . They found that COVID-19 patients were significantly younger (81%) and a high rate of smell (45%) and taste disorders (90.%). The fifth study smell dysfunction in 98% of the SARS-CoV-2 nasopharyngeal swab PCR positive patients and reported that this was evident for all 40 odorants studied [17] . The study also had a age-and sex-matched control group. None of these five studies provided data CSF analysis or brain imaging. Five studies examined neurological disorders in cohorts. In the first study, hypoxic encephalopathy was the cause of death in 20% of patient who died from COVID-19 [10] . The second report assessed neurologic manifestations in a cohort hospitalized at three dedicated COVID-19 inpatient centers [8] . They found that 36.4% had various neurologic manifestations that involved the CNS, peripheral nervous system (PNS), and skeletal muscles. Brain imaging, CSF analysis and further workup were reported in neither of the studies. The third study reported neurologic features in 90.6% of consecutive patients admitted because of acute respiratory distress syndrome (ARDS) due to COVID-19 and treated at the ICU [18] . Confusion, agitation, pyramidal signs and dysexecutive syndrome were the most common clinical manifestations. Cerebral magnetic resonance imaging (MRI) was performed in 13/58 (22%), there was evidence for leptomeningeal enhancement in 62% and ischemic stroke in 23%. EEG (8/58, 14%) and CSF examinations were performed in some patients (7/58, 12%). None of the patients had a pleocytosis in CSF. A multicentre retrospective study evaluated the occurrence of seizures in COVID-19 patients [19] . There was not a single case of symptomatic seizures or status epilepsy among this cohort in which patients with epilepsy were excluded a priori. The fifth study has been already covered above and concerned the rate of acute cerebrovascular events (6%) in a cohort of COVID-19 patients [12] . The average of time from symptoms of SARS-CoV-2 infection to clinical manifestation of cerebrovascular disease was 10 days (interquartile range 1-29). The patients with cerebrovascular disease were significantly older, more likely to suffer from severe respiratory disease and more likely to have cardiovascular risk factors and medical history of cerebrovascular disease. They were also more likely to have an increased inflammatory response and hypercoagulable state. Four publications reported eight cases of Guillain-Barre syndrome (GBS) in patients with confirmed SARS-CoV-2 infection. Nerve conduction studies disclosed both demyelinating and axonal neuropathies (n=4 and n=4, respectively). All but one case occurred with a time lag from the respiratory symptoms, the Accepted Article range was 5 to 22 days. In the remaining case the clinical manifestation of GBS preceded COVID-19 symptoms by 8 days [20] . In the case series of five GBS patients, three patients had high protein levels and all tested negative for SARS-Cov-2 in CSF, as well as for anti-ganglioside antibodies [11] . The other reports did not perform PCR for SARS-CoV-2 or testing for immunoglobulin levels, and did not investigate antiganglioside antibodies in CSF or serum. In addition to the GBS cases, a case of Miller-Fisher syndrome with positive GD1b-IgG and a case of multiple cranial neuropathies, both with negative SARS-CoV-2 PCR in CSF, were found [21] . Nine cases of encephalitis/meningitis and presumed association with COVID-19 were reported in 8 publications. Amongst was a case of encephalitis in a patient with negative SARS-CoV-2 testing in both nasopharyngeal swab and CSF (normal cell count), no MRI was performed [22] . Another patient with presumed encephalitis had normal cell count and negative SARS-CoV-2 PCR in CSF, an MRI was not performed [23] . A similar constellation was reported for another case [24] . There is a patient with a diagnosis of COVID-19 related encephalitis for which data could only be retrieved from the hospital report [25] . In that case, the neurological symptoms included seizures and hiccups and SARS-CoV-2 PCR of CSF was positive. For the case of acute necrotizing encephalitis, a SARS-CoV-2 PCR was not performed in CSF [26] . A pathogenesis triggered by a COVID-19-related cytokine storm was subsequently assumed. A positive SARS-CoV-2 PCR in CSF was present in a patient with right temporal lobe encephalitis and ventriculitis [27] . Two patients were classified as meningo-encephalitis in association with COVID-19 [28] . Both had encephalitic symptoms, including non-convulsive status epilepticus and mental changes, with normal MRI and negative SARS-CoV-2 PCR in CSF. A case of meningoencephalitis was described, the patient had meningism, headache, fever and seizures, and was PCR was negative for SARS-CoV-2 in CSF [29] . There were 5 further case reports, which were related to various aspects. A patient in whom the authors assumed myelitis as final diagnosis [30] . In detail, the patient had a myelopathic syndrome 7 days after the onset of respiratory symptoms but was not evaluated with MRI nor lumbar puncture. There is a case of presumed acute disseminated encephalomyelitis (ADEM) with only minimal contrast-enhancement on brain MRI [31] . CSF examination was normal (cell count, protein, glucose), SARS-CoV-2 PCR was only performed for nasopharyngeal swab, which was positive. Furthermore, there is a patient with pre-existing epilepsy related to Herpes-simplex virus encephalitis who presented with non-convulsive status epilepticus in the context of COVID-19 infection [32] . The authors discuss fever as the cause of lowering the threshold for seizures in a brain with structural damage. The case of intracerebral hemorrhage which occurred 3 days after fever and respiratory symptoms did not have obvious coagulation disturbances [33] . This article is protected by copyright. All rights reserved Vascular imaging and CSF diagnostic were not performed. A patient with headache, altered mental status, fever, and cough was classified as acute encephalopathy [34] . EEG ruled out status epilepticus, CSF showed normal results and SARS-CoV-2 PCR in CSF was not done. Overall, there were 2 patients positive for SARS-CoV-2 PCR of CSF among the 4 examined patients [25, 27] . Our systematic search yielded only a limited number of studies and a significant reporting bias. This does not enable an in-depth characterization of neuroinfectious diseases associated with COVID-19. Indeed, quality, design and sample size of the available studies detains us from conclusion on possible direct neuroinvasive disease caused by SARS-CoV-2. The available literature does, however, provide evidence for unspecific symptoms commonly seen in viral infections including smell and taste disturbances, and the chance of immune-mediated peripheral nerve involvement. Our analysis also suggests that there is an overdiagnosis of neurological disorders due to the inappropriate use of case definitions and restricted exclusion of potential mimics. Nervous system involvement has been reported during previous coronavirus epidemics. Interestingly, the analysis of the SARS-CoV-1 and MERS epidemic identified only a few anecdotal case reports and could not provide comprehensive insights to the clinical and radiological picture of neurological disease [1] . Moreover, there are preclinical studies reporting the neuroinvasive potential of coronaviruses and their immunogenicity [3] . The GBS we identified in our analysis are more consistent with a parainfectious disorder, i.e. a syndrome occurring during or soon after the viral syndrome, rather than a postinfectious syndrome. The limited literature for the COVID-19 outbreak could be seen in the restricted documentation due to the tying up of resources posed by the medical challenges. Indeed, it is conceivable that most emphasis was placed on the management of severe respiratory symptoms and restricted ICU capacity. It is obvious that neurologists are required for the care of COVID-19 patients [35, 36] . Their active involvement is not only mandatory for the work-up of presumed infectious and immune-mediated conditions but also for patients with reduced consciousness and nervous system complications of cardiac, pulmonary and coagulation disturbances related to SARS-CoV-2 [36] . Moreover, hypoxic brain injury may be the reason for clinical deterioration in a subgroup of patients. The potential association of SARS-CoV-2 with cerebrovascular diseases needs to be assessed in more detail; prospective trials with systematic use of ancillary investigations to confirm direct and indirect mechanism of action are mandatory in order to Accepted Article gain further insights. From a neuroinfectiologic viewpoint, the major limitation of the available reports were that precise case definitions were not used, CSF testing was performed only in a subgroup of patients and exclusion of potential other diagnoses were reported only on occasion. There were just 2 cases with positive SARS-CoV-2 PCR in CSF among 27 patients with potential neurologic symptoms and proven COVID-19. However, to date nothing is known about the sensitivity of this detection method for the examination and CSF. Indeed, CSF examination for tick-borne encephalitis virus with PCR is not a standard due to a low sensitivity of the method and probably also transient presence of the virus in CSF. The best diagnostic approach to diagnose CNS infection with SARS-CoV-2 or parainfectious immune reaction associated with SARS-CoV-2 remains to be elucidated. Until now, no reports about intrathecal SARS-CoV-2-specific IgG synthesis in these cases is available but could be key for diagnosis. In addition, a better understanding of the reported non-specific symptoms including olfactory and gustatory disturbances, impaired consciousness and encephalopathy is needed. The systemic inflammatory response is a relevant feature of severe COVID-19 and could explain some of these scenarios. The current analysis tells us that we do need more careful clinical, diagnostic and epidemiological studies to define the manifestations and burden of neurological disease caused by SARS-CoV-2. In this regard, we see a clear need for the use of precise case definitions and focused diagnostic work-up to distinguish nonspecific complications of severe disease and focused reporting of neurological involvement in association with SARS-CoV-2 infection. Moreover, appropriate investigations are required to rule out other established causes of brain infections and parainfectious disease before attributing a condition to SARS-CoV-2. It also needs to kept in mind that SARS-CoV-2 causes a large number of asymptomatic or mildly symptomatic infections. A coincidental infection may exacerbate a so far asymptomatic or known neurological disease of other causes. Here, we provide guidance for assembling key clinical and paraclinical data which are required to establish insights to true spectrum of direct and indirect effects of SARS-CoV-2 infection on the nervous system ( Table 2) :: 1. The timing and results from nasopharyngeal swab PCR needs to be reported. Most important is the relation to the development of respiratory and neurological signs/symptoms. As soon as the antibody testing gets more widely available, this also pertains to this method. Both IgM and IgG need to be reported. For all detection methods, the testing kit and ideally the exact values need to be mentioned. 2. Potential differentials need to be ruled out: frequent mimics in a report from Spain of patients evaluated for SARS-CoV-2 infection included hypercapnia, renal or liver failure and side-effects of Accepted Article drug therapy [37] . Comorbidities are frequent in certain patients and risk factors for neurological complications need to be identified. 3 . If neuroinvasion or immune-mediated disease of the nervous system is suspected, it is mandatory to perform PCR testing for SARS-CoV-2 in CSF and anti-SARS-CoV-2 IgM/IgG testing in serum and CSF to check for intrathecal humoral immune reaction. It will be of major importance to determine whether PCR of CSF specimen is sensitive enough and define the time window of potential SARS-CoV-2 detection in relation to respiratory and neurological symptoms. The list of differential diagnoses for meningitis, encephalitis and myelitis is extensive [38, 39] . A guidance is shown in Table 2 . We recently summarized potential indications for CSF examination [1] . Briefly, a permissive strategy for CSF testing should be exerted  on suspicion of encephalitis  new focal neurological deficit of no plausible differential etiology/no better explanation  delirious condition of no plausible differential etiology or no better explanation  acute cerebrovascular disorders  convulsive or non-convulsive seizures of no plausible differential etiology or no better explanation and  ICU patients with disorders of consciousness of no plausible differential etiology or no better explanation. The distinction of encephalopathy and encephalitis needs to be done according to standard criteria [40] . Brain MRI is critical and contrast-enhanced sequences are mandatory [41] . Coagulation disorders are relatively frequently encountered among COVID-19 patients and need to be considered in the workup of cerebrovascular disorders [42, 43] . In cases of peripheral nervous system involvement nerve conduction studies and electromyographic findings need to be reported, and antibodies to specific for immune-mediated conditions to provide differentials with critical illness neuropathy, acute non-inflammatory neuropathies and myopathy [44] . 4. Reporting of timing and type of treatment. There is currently no study evidence for efficacy of a specific treatment for SARS-CoV-2 [45] . Guideline for the management of respiratory symptoms and systemic complications are outlined elsewhere, many be regionally distinct and are likely to be updated on a regular basis. With regard to neuroinfectious manifestations, one should be adhere to guidance on the management of viral meningitis and encephalomyelitis [46] . The management of immune-mediated conditions including GBS and Miller-Fisher syndrome should follow standard guidelines, with intravenous immunoglobulin (IVIG) or plasma exchange as first- This article is protected by copyright. All rights reserved line options [44] . Coagulation disorders and other systemic complications of SARS-CoV-2 are likely to be of relevance for neurological care and complications. While an increased risk of seizures has not been reported so far, the potential interaction of antiepileptics and antiviral/-microbial therapy need to be kept in mind. 5. We do need information on critical care illness, prognostic factors and outcome. The authors confirm that the data supporting the findings of this study are available within the article. This article is protected by copyright. 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