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Cerebrospinal fluid findings in COVID-19 patients with neurological symptoms

2020; Elsevier BV; Volume: 418; Linguagem: Inglês

10.1016/j.jns.2020.117090

1878-5883

Bernhard Neumann, Moritz L. Schmidbauer, Konstatinos Dimitriadis, Sören Otto, Benjamin Knier, Wolf‐Dirk Niesen, Jonas A. Hosp, Albrecht Günther, Sarah Lindemann, Gábor Nagy, Tim Steinberg, Ralf A. Linker, Bernhard Hemmer, Julian Bösel,

Traumatic Brain Injury and Neurovascular Disturbances

•Largest cohort of patients with COVID-19 and neurological symptoms who underwent LP.•In all 30 cases, RT-PCR for SARS-CoV-2 from CSF was negative.•CSF analysis findings, including WBC, were normal in most patients with COVID-19.•Neurological symptoms in COVID-19 seem to be caused mainly by indirect mechanism. Neurological symptoms in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are commen [[1]Helms J. Kremer S. Merdji H. et al.Neurologic features in severe SARS-CoV-2 Infection.N. Engl. J. Med. 2020; (NEJMc2008597)https://doi.org/10.1056/NEJMc2008597Crossref PubMed Scopus (1802) Google Scholar]. SARS-CoV-2-RNA was detected by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) in very few cases in cerebrospinal fluid (CSF) [[2]Moriguchi T. Harii N. Goto J. et al.A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.Int. J. Infect. Dis. 2020; 94: 55-58https://doi.org/10.1016/j.ijid.2020.03.062Abstract Full Text Full Text PDF PubMed Scopus (1421) Google Scholar] as well as virus particles in autopsy brain samples in single cases [[3]Puelles V.G. Lütgehetmann M. Lindenmeyer M.T. et al.Multiorgan and renal tropism of SARS-CoV-2 [published online ahead of print, 2020 May 13].N. Engl. J. Med. 2020; (NEJMc2011400)https://doi.org/10.1056/NEJMc2011400Crossref PubMed Scopus (1269) Google Scholar]. This has prompted an ongoing controversy whether neurological symptoms are caused by viral infection of the CNS or via other mechanisms. We report the neurologic features along with CSF analysis findings in an observational series of 30 COVID-19 patients admitted to six tertiary referral centers in Germany from March until June 2020 as a selection from the register study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19). Frequent neurologic symptoms were altered mental state (10; 33.3%), new paresis (9; 30.0%), impaired consciousness (7; 23.3%), hypo−/areflexia (9; 30.0%), anosmia/hyposmia or ageusia/hypogeusia (6; 20.0%, underreported in critical care patients) and seizures (5; 16.7%) (Table 1). Frequent neurologic diagnoses were encephalopathy (11; 36.7%), cerebrovascular events (5; 16.7%), and (poly)neuropathy (9; 30.0%) including one Miller-Fisher syndrome and two Guillain-Barré syndromes.Table 1Clinical characteristics of 30 patients with COVID-19 and neurologic symptoms.Pat No.AgeSexCOVID19-PCR positive in:Patient status at time point of LP:Neurologic symptomsNeurologic diagnosis181MaleNPSUncomplicatedHypogeusia, unilateral temporary paresis of legTIA225FemaleNPSUncomplicatedNew headache, nausea with vomitingCerebral venous sinus thrombosis348FemaleBALUncomplicatedRefractory status epilepticus, declined level of consciousnessEncephalitis with herpes simplex virus 1473FemaleNPSUncomplicatedInvoluntary hyperkinesia of left arm and legSuspected post-stroke movement disorder563MaleBALCriticalAreflexia, horizontal gaze palsy, multiple cranial nerve affection, paresis of the left armMiller-Fisher Syndrome658MaleBALCriticalDeclined level of consciousness and prolonged awakening from sedation, seizuresEncephalopathy with seizures, possibly originating from old ischemic lesion775FemaleNPSUncomplicatedHyposmia, hypogeusia, confusion, global aphasia, multimodal neglectSeptic encephalopathy DD limbic encephalitis866MaleNPS, BALUncomplicatedAcute brachio-facial hemiparesis, declined level of consciousnessIntracranial hemorrhage in left ventral basal ganglia956MaleOPS, BAL, peripheral bloodCriticalAltered mental state, meningism, hyporeflexiaEncephalopathy, CIP1041FemaleOPSCriticalGait disturbance, altered mental state, dysarthriaOsmotic demyelination syndrome1168MaleBAL, peripheral bloodCriticalClonic seizureSeizure1264MaleOPS, BAL, peripheral bloodCriticalAltered mental state, declined level of consciousness, areflexiaSeptic/toxic encephalopathy, CIP1357MaleOPS, BALCriticalGeneralized tonic clonic seizures and declined level of consciousness during non-convulsive seizuresNon-convulsive status epilepticus1475MaleOPS, BAL, peripheral bloodCriticalAltered mental state; increased muscle tone, tetraparesis, areflexiaEncephalopathy, CIP1547MaleOPS, BAL, peripheral bloodCriticalTetraplegia, fluctuating altered mental state, suspected meningism, areflexiaEncephalopathy, CIP1650MaleOPS, BALCriticalDeclined level of consciousness, generalized seizuresSeizures1751MaleOPS, BALCriticalAltered mental state, discrete meningismEncephalopathy1865FemaleOPSUncomplicatedConfusion and altered mental stateSeptic/metabolic encephalopathy1945MaleOPSUncomplicatedNew headacheUnclear headache2068FemaleOPSUncomplicatedAltered mental stateEncephalopathy2181MaleOPS, BALCriticalAltered mental stateEncephalopathy2248MaleOPSUncomplicatedHyposmia, hypogeusia, unilateral peripheral vestibular dysfunctionUnilateral vestibular neuritis2358FemaleOPSUncomplicatedUnilateral abducens nerve palsyUnilateral abducens nerve palsy2480MaleOPSUncomplicatedHyposmia, hypogeusia, saccadic ocular pursuit, gait disorder, short-time memory disturbanceSlight septic encephalopathy2570MaleOPS, BALCriticalTetraparesis, hyporeflexia, Cheyne-Stokes breathingCIP, multiple bilateral embolic ischemic strokes2676FemaleOPS, BALCriticalDeclined level of consciousnessProlonged coma2779FemaleOPS, BALCriticalAgeusia, tetraparesis, hyporeflexia, declined level of consciousnessGuillain-Barré Syndrome, encephalopathy2828FemaleOPSComplicatedAgeusia, anarthria, unilateral sensorimotor hemiparesis, multimodal neglectIschemic stroke due to unilateral MCA occlusion2968MaleOPSUncomplicatedAltered mental state, seizuresSeizures3086FemaleOPSRecoveryTetraparesis, areflexia, ataxiaGuillain-Barré SyndromeMCA = Middle Cerebral Artery, BAL = bronchoalveolar lavage, CIP = Critical Illness Polyneuropathy, DD = differential diagnosis, LP = lumbar puncture, NPS = nasopharyngeal swab, OPS = oropharyngeal swab, PCR = polymerase-chain-reaction, TIA = transient ischemic attack. Open table in a new tab MCA = Middle Cerebral Artery, BAL = bronchoalveolar lavage, CIP = Critical Illness Polyneuropathy, DD = differential diagnosis, LP = lumbar puncture, NPS = nasopharyngeal swab, OPS = oropharyngeal swab, PCR = polymerase-chain-reaction, TIA = transient ischemic attack. 15 patients underwent lumbar puncture (LP) during critical disease phases (definitions in supplemental material), one during a complicated, 13 during uncomplicated and one during recovery phases of COVID-19. The time between positive SARS-CoV2-PCR e.g. from orophyryngeal swab and LP was 5.9 ± 9.8 days (median 1; range 0–35 days; patients with additional positive SARS-CoV-2-PCRs after LP were counted as 0 days). Their CSF showed normal or slightly increased white blood cell count (WBC) (≤8/μl) in 28 cases, while the WBC was significantly elevated in two patients with herpes simplex virus 1 encephalitis and intracranial hemorrhage (Fig. 1). The CSF blood albumin ratio as a marker for the blood-CSF integrity was normal in most cases (14/25) nevertheless, five had a severe disruption. Of interest five of seven patients with severe or intermediate blood-CSF disruption received LP during critical disease phase. Oligoclonal bands were negative in 14 of 25 tested cases (56.0%), in ten cases we found identical oligoclonal bands in CSF and serum (40.0%) and in the case of HSVE oligoclonal bands in CSF and serum with additional bands in CSF (4.0%) were detected. In all 30 cases, RT-PCR for SARS-CoV-2 from CSF was negative. Our clinical findings are in concordant with several other reports of autoimmune neuropathies [[4]Tatu L. Nono S. Grácio S. Koçer S. Guillain-Barré syndrome in the COVID-19 era: another occasional cluster? [published online ahead of print, 2020 Jun 23].J. Neurol. 2020; : 1-3https://doi.org/10.1007/s00415-020-10005Crossref PubMed Google Scholar], the prevalence of cerebrovascular events [[5]Oxley T.J. Mocco J. Majidi S. et al.Large-vessel stroke as a presenting feature of Covid-19 in the young.N. Engl. J. Med. 2020; 382: e60https://doi.org/10.1056/NEJMc2009787Crossref PubMed Scopus (1532) Google Scholar] and the frequent occurrents of encephalopathies in patients with COVID-19. Cerebrovascular events might be explained by an endotheliitis during COVID-19 [[6]Varga Z. Flammer A.J. Steiger P. et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418https://doi.org/10.1016/S0140-6736(20)30937-5Abstract Full Text Full Text PDF PubMed Scopus (4433) Google Scholar] and autoimmune neuropathies also argue rather for an indirect affection of the nervous system by para-infectious immune phenomena than direct involvement of the nervous system. A recently published case of encephalopathy with significant increase of interleukin-6 (IL-6) in CSF and clinical response to methylprednisolon without detection of SARS-CoV-2 in CSF supports the theory of an autoimmune mediated hyperinflammatory process as a mechanism in COVID-19 patients with neurological symptoms suspicious for an involvement of the CNS [[7]Cani I. Barone V. D'Angelo R. et al.Frontal encephalopathy related to hyperinflammation in COVID-19 [published online ahead of print, 2020 Jul 11].J. Neurol. 2020; : 1-4https://doi.org/10.1007/s00415-020-10057-5Crossref PubMed Scopus (32) Google Scholar]. The absence of CSF findings specific for actual viral (meningo)encephalitis (e.g. increase WBC count) and lack of detection of SARS-CoV-2 by RT-PCR in the, up to date, largest cohort of COVID-19 patients with neurologic symptoms and LP in COVID-19 patients is another puzzle piece suggesting a more likely indirect affection of the nervous system, besides very rare cases of a possible direct affection by SARS-CoV-2. Our case series demonstrates that SARS-CoV-2 is usually not present in CSF of patients with neurological symptoms arguing against frequent active CNS invasion of the virus. Most neurological symptoms seem to be caused by indirect mechanisms such as cerebrovascular events, encephalopathies and neuropathies due to systemic critical illness and secondary immune phenomena. Reported detection of SARS-CoV-2-RNA or antibodies against the virus in the CSF in very few published cases may even be explained by dysfunction of the blood-CSF barrier or contamination with blood during difficult LP. Nevertheless, like in other virus infections of the brain, a negative PCR-test does not exclude the presence of the virus in the brain tissue. Therefore, further studies on antibodies against SARS-CoV2 in CSF would be useful. All authors have made a substantial contribution to the design, data collection and analysis of the research and the drafting of the manuscript and reviewed and accepted the contents of the manuscript prior to its submission. No funding was obtained for this study.