COVID-19-associated meningitis: Difference between revisions

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'''For COVID-19 frequently asked outpatient questions, click [[COVID-19 frequently asked outpatient questions|here]]'''.
'''For COVID-19 frequently asked inpatient questions, click [[COVID-19 frequently asked inpatient questions|here]]'''.
'''For COVID-19 patient information, click [[COVID-19 (patient information)|here]]'''.
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{{COVID-19}}
{{SI}}
 
{{CMG}}; {{AE}} {{Wd}}, {{MAH}} [[User:Tayebah Chaudhry|Tayebah Chaudhry]][mailto:dr.thch@yahoo.com] {{Fs}}, {{sali}}


{{CMG}}; {{Wd}}, {{MAH}} [[User:Tayebah Chaudhry|Tayebah Chaudhry]][mailto:dr.thch@yahoo.com] {{sali}}


{{COVID-19}}


==Overview==
==Overview==
In December of 2019, unknown cases of [[pneumonia]] began to spread in the Wuhan city of China. A Novel [[coronavirus]] was isolated from these cases and was later named as severe acute respiratory syndrome-coronavirus-2 ([[SARS-CoV-2]]) in early January 2020. SARS-CoV-2 seems to be partially similar to severe acute respiratory syndrome coronavirus ([[SARS]]) and Middle East respiratory syndrome coronavirus ([[MERS]])'''.''' The SARS-CoV-2 is a positive-strand [[RNA virus]] belonging to the [[Orthocoronavirinae]] subfamily'''.''' The pneumonia disease caused by SARS-CoV-2 was named COVID-19 by WHO. COVID-19 was declared a [[pandemic]] by WHO on March 11, 2020'''.''' To date, around 10 million people have been infected by SARS-COV-2 in more than 215 countries and more than half a million people have been killed by the COVID-19. These numbers are increasing daily. The main mode of transmission for SARS-CoV-2 from person to person is through respiratory droplets'''.''' It can be identified in the samples of sputum, nasal and pharyngeal swabs, bronchoalveolar fluid, blood and faeces, suggesting faecal-oral transmission could be a possible route. COVID-19 has a wide range of clinical manifestations. The clinical symptoms of COVID-19 are predominantly of respiratory. The patient may be asymptomatic or can present with fever, cough, [[sore throat]], fatigue and [[dyspnea]]. Majority of COVID-19 cases have been recognized as mild, but severe cases leading to [[respiratory failure]], [[septic shock]], and/or multiple organ dysfunction have also been identified. Although rare but spectrum of neurological manifestations have been reported throughout the pandemic. These neurological presentations range from [[headache]], [[anosmia]], [[encephalitis]], [[meningitis]], Guillain Barre syndrome and [[stroke]]. Meningitis is the inflammation of the coverings of the brain and spinal cord.
Covid-19 associated  meningitis was first discovered by Moriguchi T. et al. a Japanese [[critical care]] [[physician]] in late February 2020 during the [[pandemic]] of [[SARS-CoV-2]]. Duong L et. reported a case of a young female with COVID-19 who developed [[meningoencephalitis]] without [[respiratory failure]] in Downtown Los Angeles in early April, 2020. Bernard-Valnet R et al. reported two cases of [[meningoencephalitis]] in [[patients]] with concomitant [[SARS-CoV-2]] infection. There is no established system for the classification of [[SARS-CoV-2]] related meningitis. There are three mechanisms proposed for pathophysiology of COVID-19-associated meningitis. [[SARS-CoV-2]] directly reaches brain through [[cribriform plate]] which is located in close proximity to [[olfactory bulb]]. This is supported by the facts that some [[patients]] of [[COVID-19]] present with [[anosmia]] and [[hyposmia]]. Viral interaction with [[ACE|ACE2]] expressed on [[neurons]] lead to damage to [[neurons]] and inflamation ([[encephalitis]]) and [[inflammation]] of [[Meninges|brain membranes]] ([[meningitis]]). [[SARS-CoV-2]] can reach [[brain]] via anterograde or retrograde transport with the help of motor proteins [[kinesin]] and [[dynein]] via sensory nerve endings, especially afferent [[Nerve ending|nerve endings]] of [[vagus nerve]] from [[Lung|lungs]].  


==Historical Perspective==
==Historical Perspective==


* Neurological symptoms in [[COVID-19]] patients were first reported in February 2020 in a retrospective case series study by Mao L. et al. in hospitalized COVID-19 patients in Wuhan. Ling Mao from Tongji Medical College in Wuhan, and his group reviewed the data retrospectively from January 16, 2020, to February 19, 2020. One third of the 214 hospitalized laboratory- confirmed [[COVID-19]] patients included in this study reported at least one neurologic symptom.
*[[Neurological]] [[symptoms]] in [[COVID-19]] patients were first reported in February 2020 in a retrospective case series study by Mao L. et al. in hospitalized COVID-19 patients in Wuhan.
* [[COVID-19|Covid-19]] associated  [[meninigitis|meningitis]]/[[encephalitis]] was first discovered by Moriguchi T. et al. a Japanese [[critical care]] [[physician]] in late February 2020 during the [[pandemic]] of [[SARS]]-[[Coronavirus]]-2: [[SARS-CoV-2]] <ref name="pmid32251791">{{cite journal| author=Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J | display-authors=etal| title=A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. | journal=Int J Infect Dis | year= 2020 | volume= 94 | issue=  | pages= 55-58 | pmid=32251791 | doi=10.1016/j.ijid.2020.03.062 | pmc=7195378 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32251791  }}</ref>.
*Ling Mao from Tongji Medical College in Wuhan, and his group reviewed the data retrospectively from January 16, 2020, to February 19, 2020.  
* Duong L et. reported a case of a young female with COVID-19 who developed [[meningoencephalitis]] without respiratory failure in Downtown Los Angeles in early April, 2020 <ref name="pmid32305574">{{cite journal| author=Duong L, Xu P, Liu A| title=Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020. | journal=Brain Behav Immun | year= 2020 | volume= 87 | issue=  | pages= 33 | pmid=32305574 | doi=10.1016/j.bbi.2020.04.024 | pmc=7162766 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32305574  }}</ref>.
*One third of the 214 hospitalized laboratory- confirmed [[COVID-19]] patients included in this study reported at least one [[neurological]] [[symptom]].
* Bernard-Valnet R et al. reported two cases of meningoencephalitis in patients with concomitant SARS-CoV-2 infection <ref name="pmid32383343">{{cite journal| author=Bernard-Valnet R, Pizzarotti B, Anichini A, Demars Y, Russo E, Schmidhauser M | display-authors=etal| title=Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection. | journal=Eur J Neurol | year= 2020 | volume=  | issue=  | pages=  | pmid=32383343 | doi=10.1111/ene.14298 | pmc=7267660 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32383343  }}</ref>
* Covid-19 associated  meningitis was first discovered by Moriguchi T. et al. a Japanese [[critical care]] [[physician]] in late February 2020 during the [[pandemic]] of [[SARS]]-[[Coronavirus]]-2: [[SARS-CoV-2]] <ref name="pmid32251791">{{cite journal| author=Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J | display-authors=etal| title=A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. | journal=Int J Infect Dis | year= 2020 | volume= 94 | issue=  | pages= 55-58 | pmid=32251791 | doi=10.1016/j.ijid.2020.03.062 | pmc=7195378 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32251791  }}</ref>.
* Duong L et. reported a case of a young female with COVID-19 who developed [[meningoencephalitis]] without [[Respiratory failure CT|respiratory failure]] in Downtown Los Angeles in early April, 2020 <ref name="pmid32305574">{{cite journal| author=Duong L, Xu P, Liu A| title=Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020. | journal=Brain Behav Immun | year= 2020 | volume= 87 | issue=  | pages= 33 | pmid=32305574 | doi=10.1016/j.bbi.2020.04.024 | pmc=7162766 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32305574  }}</ref>.
* Bernard-Valnet R et al. reported two cases of [[meningoencephalitis]] in patients with concomitant [[SARS-CoV-2]] infection.<ref name="pmid32383343">{{cite journal| author=Bernard-Valnet R, Pizzarotti B, Anichini A, Demars Y, Russo E, Schmidhauser M | display-authors=etal| title=Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection. | journal=Eur J Neurol | year= 2020 | volume=  | issue=  | pages=  | pmid=32383343 | doi=10.1111/ene.14298 | pmc=7267660 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32383343  }}</ref>


==Classification==
==Classification==
There is no established system for the classification of SARS-CoV-2 related meningitis.
 
* There is no established system for the classification of COVID-19-associated meningitis.


== Pathophysiology ==
== Pathophysiology ==


The exact pathogenesis of COVID-19-associated meningitis is not fully understood.


The exact pathogenesis of SARS-CoV-2 associated meningitis is not fully understood.
* Severe acute respiratory syndrome ([[Severe acute respiratory syndrome|SARS]]) and Middle East respiratory Syndrome ([[MERS]]) caused some neurological manifestations in 2002 and 2012 respectively<ref name="pmid16252612">{{cite journal| author=Tsai LK, Hsieh ST, Chang YC| title=Neurological manifestations in severe acute respiratory syndrome. | journal=Acta Neurol Taiwan | year= 2005 | volume= 14 | issue= 3 | pages= 113-9 | pmid=16252612 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16252612  }}</ref>.
*As [[neucleic acid]] of [[SARS-CoV]] and [[MERS-CoV]] was found in [[cerebrospinal fluid]] and later on the [[autopsy]] of brain<ref name="pmid311330312">{{cite journal| author=Schoeman D, Fielding BC| title=Coronavirus envelope protein: current knowledge. | journal=Virol J | year= 2019 | volume= 16 | issue= 1 | pages= 69 | pmid=31133031 | doi=10.1186/s12985-019-1182-0 | pmc=6537279 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31133031  }}</ref>.
*[[SARS-CoV-2]] is 79% identical to SARS-CoV and 50% to [[MERS-CoV]]. <ref name="pmid32007145">{{cite journal| author=Lu R, Zhao X, Li J, Niu P, Yang B, Wu H | display-authors=etal| title=Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. | journal=Lancet | year= 2020 | volume= 395 | issue= 10224 | pages= 565-574 | pmid=32007145 | doi=10.1016/S0140-6736(20)30251-8 | pmc=7159086 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32007145  }}</ref> Due to structural [[homology]] it is safe to say that SARS-CoV-2 causes neurological problems by the same mechanism as caused by [[SARS-CoV]] and [[MERS-CoV]].


* Severe acute respiratory syndrome ([[Severe acute respiratory syndrome|SARS]]) and Middle East respiratory Syndrome ([[MERS]]) caused some neurological manifestations in 2002 and 2012 respectively<ref name="pmid16252612">{{cite journal| author=Tsai LK, Hsieh ST, Chang YC| title=Neurological manifestations in severe acute respiratory syndrome. | journal=Acta Neurol Taiwan | year= 2005 | volume= 14 | issue= 3 | pages= 113-9 | pmid=16252612 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16252612  }}</ref>. As [[neucleic acid]] of [[SARS-CoV]] and [[MERS-CoV]] was found in [[cerebrospinal fluid]] and later on the [[autopsy]] of brain<ref name="pmid311330312">{{cite journal| author=Schoeman D, Fielding BC| title=Coronavirus envelope protein: current knowledge. | journal=Virol J | year= 2019 | volume= 16 | issue= 1 | pages= 69 | pmid=31133031 | doi=10.1186/s12985-019-1182-0 | pmc=6537279 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31133031  }}</ref>.
The proposed pathophysiology of COVID-19-associated meningitis is by following three mechanisms;
*[[SARS-CoV-2]] is 79% identical to SARS-CoV and 50% to MERS-CoV<ref name="pmid32007145">{{cite journal| author=Lu R, Zhao X, Li J, Niu P, Yang B, Wu H | display-authors=etal| title=Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. | journal=Lancet | year= 2020 | volume= 395 | issue= 10224 | pages= 565-574 | pmid=32007145 | doi=10.1016/S0140-6736(20)30251-8 | pmc=7159086 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32007145  }}</ref>. Due to structural [[homology]] it is safe to say that SARS-CoV-2 causes neurological problems by the same mechanism as caused by SARS-CoV and MERS-CoV.


The proposed pathophysiology of SARS-CoV-2 associated meningitis is by following three mechanisms;
'''1.Direct pathway'''


'''1.Direct pathway'''
* [[SARS-CoV-2]] directly reaches brain through [[cribriform plate]] which is located in close proximity to [[olfactory bulb]]<ref name="pmid32167747">{{cite journal| author=Baig AM, Khaleeq A, Ali U, Syeda H| title=Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. | journal=ACS Chem Neurosci | year= 2020 | volume= 11 | issue= 7 | pages= 995-998 | pmid=32167747 | doi=10.1021/acschemneuro.0c00122 | pmc=7094171 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32167747  }}</ref>.


SARS-CoV-2 directly reaches brain through [[cribriform plate]] which is located in close proximity to [[olfactory bulb]]<ref name="pmid32167747">{{cite journal| author=Baig AM, Khaleeq A, Ali U, Syeda H| title=Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. | journal=ACS Chem Neurosci | year= 2020 | volume= 11 | issue= 7 | pages= 995-998 | pmid=32167747 | doi=10.1021/acschemneuro.0c00122 | pmc=7094171 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32167747  }}</ref>. This is supported by the facts that some patients of COVID-19 present with [[anosmia]] and [[hyposmia]].
* This is supported by the facts that some [[patients]] of COVID-19 present with [[anosmia]] and [[hyposmia]].


'''2. Blood circulation pathway'''
'''2. Blood circulation pathway'''


* Angiotensin converting enzyme-2 (ACE2) is the functional receptor of the SARS-CoV-2<ref name="pmid24172901">{{cite journal| author=Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH | display-authors=etal| title=Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. | journal=Nature | year= 2013 | volume= 503 | issue= 7477 | pages= 535-8 | pmid=24172901 | doi=10.1038/nature12711 | pmc=5389864 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24172901  }}</ref>. ACE2 is expressed on glial tissue, neurons and brain vasculature<ref name="pmid15165741">{{cite journal| author=Turner AJ, Hiscox JA, Hooper NM| title=ACE2: from vasopeptidase to SARS virus receptor. | journal=Trends Pharmacol Sci | year= 2004 | volume= 25 | issue= 6 | pages= 291-4 | pmid=15165741 | doi=10.1016/j.tips.2004.04.001 | pmc=7119032 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15165741  }}</ref>
*[[Angiotensin converting enzyme|Angiotensin converting enzyme-2]] (ACE2) is the functional receptor of the [[SARS-CoV-2]]. <ref name="pmid24172901">{{cite journal| author=Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH | display-authors=etal| title=Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. | journal=Nature | year= 2013 | volume= 503 | issue= 7477 | pages= 535-8 | pmid=24172901 | doi=10.1038/nature12711 | pmc=5389864 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24172901  }}</ref> [[ACE|ACE2]] is expressed on [[Glial cell|glial tissue]], [[neurons]] and [[brain]] vasculature. <ref name="pmid15165741">{{cite journal| author=Turner AJ, Hiscox JA, Hooper NM| title=ACE2: from vasopeptidase to SARS virus receptor. | journal=Trends Pharmacol Sci | year= 2004 | volume= 25 | issue= 6 | pages= 291-4 | pmid=15165741 | doi=10.1016/j.tips.2004.04.001 | pmc=7119032 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15165741  }}</ref>
* SARS-CoV-2 binds with ACE2 precsent on vascular endothelial cells and glial tissues with the help of spike S protein.<ref name="pmid32075877">{{cite journal| author=Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O | display-authors=etal| title=Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. | journal=Science | year= 2020 | volume= 367 | issue= 6483 | pages= 1260-1263 | pmid=32075877 | doi=10.1126/science.abb2507 | pmc=7164637 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32075877  }}</ref>
*[[SARS-CoV-2]] binds with [[ACE|ACE2]] precsent on vascular [[endothelial cells]] and [[Glial cell|glial tissues]] with the help of spike S protein.<ref name="pmid32075877">{{cite journal| author=Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O | display-authors=etal| title=Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. | journal=Science | year= 2020 | volume= 367 | issue= 6483 | pages= 1260-1263 | pmid=32075877 | doi=10.1126/science.abb2507 | pmc=7164637 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32075877  }}</ref>
* Subsequent viral budding from endothelial cells and resultant damage to capillary [[endothelium]] favors viral entry into milieu of brain<ref name="pmid321677472">{{cite journal| author=Baig AM, Khaleeq A, Ali U, Syeda H| title=Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. | journal=ACS Chem Neurosci | year= 2020 | volume= 11 | issue= 7 | pages= 995-998 | pmid=32167747 | doi=10.1021/acschemneuro.0c00122 | pmc=7094171 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32167747  }}</ref>.
* Subsequent viral budding from endothelial cells and resultant damage to capillary [[endothelium]] favors viral entry into milieu of brain<ref name="pmid321677472">{{cite journal| author=Baig AM, Khaleeq A, Ali U, Syeda H| title=Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. | journal=ACS Chem Neurosci | year= 2020 | volume= 11 | issue= 7 | pages= 995-998 | pmid=32167747 | doi=10.1021/acschemneuro.0c00122 | pmc=7094171 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32167747  }}</ref>.
* Viral interaction with ACE2 expressed on neurons lead to damage to neurons and inflamation (encephalitis) and inflammation of brain membranes (meningitis)
* Viral interaction with [[Angiotensin-converting enzyme|ACE2]] expressed on [[Neuron|neurons]] lead to damage to [[Neuron|neurons]] and [[inflamation]] ([[encephalitis]]) and [[inflammation]] of [[Meninges|brain membranes]] ([[meningitis]]).


'''3. Neuronal Pathway'''
'''3. Neuronal Pathway'''


* SARS-CoV-2 can reach brain via anterograde or retrograde transoport with the help of motor proteins [[kinesin]] and [[dynein]] via sensory nerve endings, especially afferent nerve endings of vagus nerve from lungs.<ref name="pmid25681709">{{cite journal| author=Swanson PA, McGavern DB| title=Viral diseases of the central nervous system. | journal=Curr Opin Virol | year= 2015 | volume= 11 | issue=  | pages= 44-54 | pmid=25681709 | doi=10.1016/j.coviro.2014.12.009 | pmc=4456224 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25681709  }}</ref>
*[[SARS-CoV-2]] can reach [[brain]] via anterograde or retrograde transoport with the help of motor proteins [[kinesin]] and [[dynein]] via sensory [[Nerve ending|nerve endings]], especially afferent [[nerve ending]]<nowiki/>s of [[vagus nerve]] from [[Lung|lungs]].<ref name="pmid25681709">{{cite journal| author=Swanson PA, McGavern DB| title=Viral diseases of the central nervous system. | journal=Curr Opin Virol | year= 2015 | volume= 11 | issue=  | pages= 44-54 | pmid=25681709 | doi=10.1016/j.coviro.2014.12.009 | pmc=4456224 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25681709  }}</ref>
* SARS-CoV-2 causes some gastrointestinal problems in COVID-19 patients and can reach CNS from enteric nerve and sympathetic afferent via neuronal pathway.<ref name="pmid32215956">{{cite journal| author=Wong SH, Lui RN, Sung JJ| title=Covid-19 and the digestive system. | journal=J Gastroenterol Hepatol | year= 2020 | volume= 35 | issue= 5 | pages= 744-748 | pmid=32215956 | doi=10.1111/jgh.15047 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32215956  }}</ref>
*[[SARS-CoV-2]] causes some [[gastrointestinal]] problems in COVID-19 [[Patient|patients]] and can reach [[CNS]] from enteric nerve and sympathetic afferent via neuronal pathway.<ref name="pmid32215956">{{cite journal| author=Wong SH, Lui RN, Sung JJ| title=Covid-19 and the digestive system. | journal=J Gastroenterol Hepatol | year= 2020 | volume= 35 | issue= 5 | pages= 744-748 | pmid=32215956 | doi=10.1111/jgh.15047 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32215956  }}</ref>
* Exosomal cellular transport is also a pathway for SARS-CoV-2 systemic dissemination and spread to CNS.<ref name="pmid26393640">{{cite journal| author=Alenquer M, Amorim MJ| title=Exosome Biogenesis, Regulation, and Function in Viral Infection. | journal=Viruses | year= 2015 | volume= 7 | issue= 9 | pages= 5066-83 | pmid=26393640 | doi=10.3390/v7092862 | pmc=4584306 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26393640  }}</ref>
* Exosomal cellular transport is also a pathway for [[SARS-CoV-2]] systemic dissemination and spread to [[CNS]].<ref name="pmid26393640">{{cite journal| author=Alenquer M, Amorim MJ| title=Exosome Biogenesis, Regulation, and Function in Viral Infection. | journal=Viruses | year= 2015 | volume= 7 | issue= 9 | pages= 5066-83 | pmid=26393640 | doi=10.3390/v7092862 | pmc=4584306 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26393640  }}</ref>
 
<br />[[File:Meningitis-1.jpg|700px|center]]


[[File:Meningitis Pathophysiology.png|center|600x600px]]
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==Differentiating COVID-19-associated meningitis from other Diseases==
==Differentiating COVID-19-associated meningitis from other Diseases==


 
* For further information about the differential diagnosis, [[COVID-19-associated meningitis differential diagnosis|click here]].
[[COVID-19]]-associated [[meningitis]] must be differentiated from other [[diseases]] that cause [[fever]], [[headache]], and [[neck stiffness]], [[photophobia]] with or without [[cough]], such as:
* To view the differential diagnosis of COVID-19, [[COVID-19 differential diagnosis|click here]].
 
* [[Bacterial meningitis]]
* [[Encephalitis]]
* [[Aseptic meningitis]] due to other viruses
* [[Brain abscess]]
* [[Herpes simplex encephalitis]]
* [[Leptospirosis]] in [[humans]]
* [[Status epilepticus]]
* [[Systemic lupus erythematosus]] ([[SLE]])
* [[Cat scratch disease]]
* [[Tuberculosis]]
* [[Sepsis]]
* [[Glial tumor]]
 
<br />
===Differentiating SARS-CoV-2 associated meningitis from other causes of meningitis===
COVID-19 meningitis may be differntiated from other causes of meningitis by cerebrospinal fluid examination:<ref name="pmid23717798">{{cite journal| author=Le Rhun E, Taillibert S, Chamberlain MC| title=Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. | journal=Surg Neurol Int | year= 2013 | volume= 4 | issue= Suppl 4 | pages= S265-88 | pmid=23717798 | doi=10.4103/2152-7806.111304 | pmc=3656567 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23717798  }}</ref><ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618  }}</ref><ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096  }}</ref><ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948  }}</ref><ref name="pmid20610819">{{cite journal| author=Brouwer MC, Tunkel AR, van de Beek D| title=Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. | journal=Clin Microbiol Rev | year= 2010 | volume= 23 | issue= 3 | pages= 467-92 | pmid=20610819 | doi=10.1128/CMR.00070-09 | pmc=2901656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20610819  }}</ref>
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
! style="background: #4479BA; width: 150px;" |{{fontcolor|#FFF|Cerebrospinal fluid level}}
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Normal level}}
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Bacterial meningitis}}<ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948  }} </ref>
! style="background: #4479BA; width: 150px;" |{{fontcolor|#FFF|SARS-CoV-2 meningitis}}
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Viral meningitis}}<ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948  }} </ref>
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Fungal meningitis}}
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Tuberculous meningitis}}<ref name="pmid20146981">{{cite journal| author=Caudie C, Tholance Y, Quadrio I, Peysson S| title=[Contribution of CSF analysis to diagnosis and follow-up of tuberculous meningitis]. | journal=Ann Biol Clin (Paris) | year= 2010 | volume= 68 | issue= 1 | pages= 107-11 | pmid=20146981 | doi=10.1684/abc.2010.0407 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20146981  }}</ref>
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Malignant meningitis}}<ref name="pmid23717798">{{cite journal| author=Le Rhun E, Taillibert S, Chamberlain MC| title=Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. | journal=Surg Neurol Int | year= 2013 | volume= 4 | issue= Suppl 4 | pages= S265-88 | pmid=23717798 | doi=10.4103/2152-7806.111304 | pmc=3656567 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23717798  }} </ref>
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Cells/ul'''
| style="padding: 5px 5px; background: #F5F5F5;" |< 5
| style="padding: 5px 5px; background: #F5F5F5;" |>300
| style="padding: 5px 5px; background: #F5F5F5;" |10-1000
| style="padding: 5px 5px; background: #F5F5F5;" |10-1000
| style="padding: 5px 5px; background: #F5F5F5;" |10-500
| style="padding: 5px 5px; background: #F5F5F5;" |50-500
| style="padding: 5px 5px; background: #F5F5F5;" |>4
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Cells'''
| style="padding: 5px 5px; background: #F5F5F5;" |Lymphos:Monos 7:3
| style="padding: 5px 5px; background: #F5F5F5;" |Gran. > Lymph
| style="padding: 5px 5px; background: #F5F5F5;" |predominantly lymphocytes
| style="padding: 5px 5px; background: #F5F5F5;" |Lymph. > Gran.
| style="padding: 5px 5px; background: #F5F5F5;" |Lympho.>Gran
| style="padding: 5px 5px; background: #F5F5F5;" |Lymphocytes
| style="padding: 5px 5px; background: #F5F5F5;" |Lymphocytes
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Total protein (mg/dl)'''
| style="padding: 5px 5px; background: #F5F5F5;" |45-60
| style="padding: 5px 5px; background: #F5F5F5;" |Typically 100-500
| style="padding: 5px 5px; background: #F5F5F5;" | Normal or slightly high
| style="padding: 5px 5px; background: #F5F5F5;" |Normal or slightly high
| style="padding: 5px 5px; background: #F5F5F5;" |High
| style="padding: 5px 5px; background: #F5F5F5;" |Typically 100-200
| style="padding: 5px 5px; background: #F5F5F5;" |>50
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Glucose ratio (CSF/plasma)<ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618  }} </ref>'''
| style="padding: 5px 5px; background: #F5F5F5;" |> 0.5
| style="padding: 5px 5px; background: #F5F5F5;" |< 0.3
| style="padding: 5px 5px; background: #F5F5F5;" |> 0.6
| style="padding: 5px 5px; background: #F5F5F5;" |> 0.6
| style="padding: 5px 5px; background: #F5F5F5;" |<0.3
| style="padding: 5px 5px; background: #F5F5F5;" |< 0.5
| style="padding: 5px 5px; background: #F5F5F5;" |<0.5
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Lactate (mmols/l)<ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096  }} </ref>'''
| style="padding: 5px 5px; background: #F5F5F5;" |< 2.1
| style="padding: 5px 5px; background: #F5F5F5;" |> 2.1
| style="padding: 5px 5px; background: #F5F5F5;" |N/A
| style="padding: 5px 5px; background: #F5F5F5;" |< 2.1
| style="padding: 5px 5px; background: #F5F5F5;" |>3.2
| style="padding: 5px 5px; background: #F5F5F5;" |> 2.1
| style="padding: 5px 5px; background: #F5F5F5;" |>2.1
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Others'''
| style="padding: 5px 5px; background: #F5F5F5;" |ICP:6-12 (cm H2O)
| style="padding: 5px 5px; background: #F5F5F5;" |CSF gram stain, CSF culture, CSF bacterial antigen
| style="padding: 5px 5px; background: #F5F5F5;" |RT-PCR for SARS-CoV-2 RNA in CSF (still not approved by FDA)
| style="padding: 5px 5px; background: #F5F5F5;" |PCR of HSV-DNA, VZV
| style="padding: 5px 5px; background: #F5F5F5;" |CSF gram stain, CSF india ink
| style="padding: 5px 5px; background: #F5F5F5;" |PCR of TBC-DNA
| style="padding: 5px 5px; background: #F5F5F5;" |CSF tumour markers such as alpha fetoproteins, CEA
|-
|}
 
==Epidemiology and Demographics==
==Epidemiology and Demographics==


* More data is needed to establish the to understand the epidemiology of COVID-19 associated meningitis<ref name="pmid32565914">{{cite journal |vauthors=Tsivgoulis G, Palaiodimou L, Katsanos AH, Caso V, Köhrmann M, Molina C, Cordonnier C, Fischer U, Kelly P, Sharma VK, Chan AC, Zand R, Sarraj A, Schellinger PD, Voumvourakis KI, Grigoriadis N, Alexandrov AV, Tsiodras S |title=Neurological manifestations and implications of COVID-19 pandemic |journal=Ther Adv Neurol Disord |volume=13 |issue= |pages=1756286420932036 |date=2020 |pmid=32565914 |pmc=7284455 |doi=10.1177/1756286420932036 |url=}}</ref>.
* More data is needed to establish the understanding of the [[epidemiology]] of COVID-19 associated meningitis<ref name="pmid32565914">{{cite journal |vauthors=Tsivgoulis G, Palaiodimou L, Katsanos AH, Caso V, Köhrmann M, Molina C, Cordonnier C, Fischer U, Kelly P, Sharma VK, Chan AC, Zand R, Sarraj A, Schellinger PD, Voumvourakis KI, Grigoriadis N, Alexandrov AV, Tsiodras S |title=Neurological manifestations and implications of COVID-19 pandemic |journal=Ther Adv Neurol Disord |volume=13 |issue= |pages=1756286420932036 |date=2020 |pmid=32565914 |pmc=7284455 |doi=10.1177/1756286420932036 |url=}}</ref>.
* However, direct infection of the neurological system appears to be extremely rare.
* However, direct [[infection]] of the [[Neurology|neurological system]] appears to be extremely rare.
 
* To view [[epidemiology]] and [[demographics]] for COVID-19, [[COVID-19 epidemiology and demographics|click here]].<br />


<br />
* To view [[epidemiology]] and [[demographics]] for COVID-19, [[COVID-19 epidemiology and demographics|click here]].


==Risk Factors==
==Risk Factors==
Line 159: Line 83:
== Screening ==
== Screening ==


* Screening for COVID-19-associated meningitis is not currently done.
* There is insufficient evidence to recommend routine [[screening]] for COVID-19-associated meningitis.
* To view screening for COVID-19, [[COVID-19 screening|click here]].<br />
* To view screening for COVID-19, [[COVID-19 screening|click here]].


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
* So far, the cases of COVID-19 associated meningitis have shown acute presentations.
* Exact [[prognosis]] of COVID-19 associated meningitis is not known. However, treating the underlying cause i.e., [[COVID-19]], including treatment with [[steroids]], have shown improvement in meningitis symptoms in a COVID-19 patient.


If left untreated, meningitis in COVID-19 patients may develop following complications.
'''History'''
* If left untreated, COVID-19-associated meningitis may cause long term neurological [[Complication (medicine)|complications]].
* To view Natural History for COVID-19, [[COVID-19 natural history, complications and prognosis|click here]].<br />


'''Complications'''
If left untreated, meningitis in COVID-19 patients may develop following [[complications]].
* [[Encephalitis]]
* [[Encephalitis]]
* [[Encephalopathy]]
* [[Encephalopathy]]
* [[Psychomotor]] changes
* [[Psychomotor]] changes
* Uncontrolled seizures
* Uncontrolled [[Seizure|seizures]]
* [[Cerebral vasculitis]]
* [[Cerebral vasculitis]]
* [[Cranial nerves]] involvement
* [[Cranial nerves]] involvement
* [[Sepsis]] (However more common in bacterial meningitis, sepsis can be caused by viral meningitis)
* [[Sepsis]] (However more common in [[bacterial meningitis]], sepsis can be caused by viral meningitis)
* [[Herniation]] of swollen brain tissue
* [[Herniation]] of swollen brain tissue
* [[Hydrocephalus]]
* [[Hydrocephalus]]
* [[coma]]/death
* [[coma]]/ death
* To view Complications for COVID-19, [[COVID-19 natural history, complications and prognosis|click here]].<br />
 
'''Prognosis'''
* Exact [[prognosis]] of COVID-19 associated meningitis is not known.
*However, treating the underlying cause i.e., [[COVID-19]], including treatment with [[steroids]], have shown improvement in meningitis symptoms in a COVID-19 patient.
* To view Prognosis for COVID-19, [[COVID-19 natural history, complications and prognosis|click here]].


==Diagnosis==
==Diagnosis==
===Diagnostic Study of Choice===
===Diagnostic Study of Choice===
* The diagnostic study of choice for meningitis in COVID-19 patients is [[CSF]] analysis and ruling out other causes of meningitis (e.g., other viruses, bacteria, fungi).
* The diagnostic study of choice for meningitis in COVID-19 patients is [[CSF analysis]] and ruling out other causes of meningitis (e.g., other viruses, bacteria, fungi).


===History and Symptoms===
===History and Symptoms===


'''History:'''
'''History'''
 
* The disease course of 5 cases of COVID-19 associated meningitis include:


Five cases of meningitis in COVID-19 patients have been reported. The disease course of these patients is given in the table.
<br />
{| class="wikitable"
{| class="wikitable"
|+
|+
! style="background: #4479BA; color: #FFFFFF; text-align: center;" rowspan="2" |<small>Patient No.</small>
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>Patient No.</small>
! style="background: #4479BA; color: #FFFFFF; text-align: center;" rowspan="2" |<small>Early symptoms</small>
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>Early symptoms</small>
! style="background: #4479BA; color: #FFFFFF; text-align: center;" rowspan="2" |<small>Late symptoms</small>
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>Late symptoms</small>
! style="background: #4479BA; color: #FFFFFF; text-align: center;" colspan="3" |<small>CSF analysis</small>
! colspan="3" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>CSF analysis</small>
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>Viral panel (HSV,VZV, enterovirus)</small>
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>Viral panel (HSV,VZV, enterovirus)</small>
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Bacterial panel
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Bacterial panel
! style="background: #4479BA; color: #FFFFFF; text-align: center;" colspan="2" |<small>SARS-CoV-2 analysis</small>
! colspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>SARS-CoV-2 analysis</small>
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>Imaging CT/MRI</small>
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |<small>Imaging CT/MRI</small>
|-
|-
Line 273: Line 206:
anosmia
anosmia
|Severe headache
|Severe headache
neck stifness
neck stiffness


confusion
confusion
Line 304: Line 237:
|NA
|NA
|positive
|positive
|CT head without contrast was noraml
|CT head without contrast was normal
|-
|-
|}
|}


'''Symtoms:'''
'''Common Symptoms'''
* Fever
 
* Headache
*[[Fever]]
* Neck stiffness
*[[Headache]]
*[[Nausea]]/ [[vomiting]]
*[[Irritability]]
*[[Malaise]]
*[[Neck stiffness]]
* Light sensitivity/ [[photophobia]]
* Light sensitivity/ [[photophobia]]
* [[Nausea]]/vomiting
 
* [[Malaise]]
'''Less Common Symptoms'''
* [[Myalgias]]
 
* Confusion
*[[Myalgias]]
* Irritability
*[[Confusion]]
* [[Seizures]] (with concomitant [[encephalitis]])
*[[Seizures]] (with concomitant [[encephalitis]])


===Physical Examination===
===Physical Examination===


'''Vitals:'''
'''Vitals:'''
* Fever
*[[Fever]]
* [[Tachycardia]]
* [[Tachycardia]]
* Increased respiratory rate
* Increased [[respiratory rate]]


'''Physical Exam:'''
'''Neuromuscular:'''
* [[Altered mental status]]
* [[Altered mental status]]
* [[Photophobia]]
* [[Photophobia]]
* Neck rigidity
*[[Neck stiffness|Neck rigidity]]
* Positive [[Kernig]] sign
* Positive [[Kernig's sign|Kernig sign]]
* Positive [[Brudzinski's]] sign
* Positive [[Brudzinski's sign]]


===Laboratory Findings===
===Laboratory Findings===


* [[Blood test]] including [[C-reactive protein]], [[Complete Blood Count]], and [[blood culture]] may determine the cause of meningitis. <ref name="pmid15494903">{{cite journal |vauthors=Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ |title=Practice guidelines for the management of bacterial meningitis |journal=Clin. Infect. Dis. |volume=39 |issue=9 |pages=1267–84 |date=November 2004 |pmid=15494903 |doi=10.1086/425368 |url=}}</ref> <ref name="pmid18582342">{{cite journal |vauthors=Chaudhuri A, Martinez-Martin P, Martin PM, Kennedy PG, Andrew Seaton R, Portegies P, Bojar M, Steiner I |title=EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults |journal=Eur. J. Neurol. |volume=15 |issue=7 |pages=649–59 |date=July 2008 |pmid=18582342 |doi=10.1111/j.1468-1331.2008.02193.x |url=}}</ref>
* [[Blood test]] including [[C-reactive protein]], [[Complete Blood Count]], and [[blood culture]] may determine the cause of meningitis. <ref name="pmid15494903">{{cite journal |vauthors=Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ |title=Practice guidelines for the management of bacterial meningitis |journal=Clin. Infect. Dis. |volume=39 |issue=9 |pages=1267–84 |date=November 2004 |pmid=15494903 |doi=10.1086/425368 |url=}}</ref> <ref name="pmid18582342">{{cite journal |vauthors=Chaudhuri A, Martinez-Martin P, Martin PM, Kennedy PG, Andrew Seaton R, Portegies P, Bojar M, Steiner I |title=EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults |journal=Eur. J. Neurol. |volume=15 |issue=7 |pages=649–59 |date=July 2008 |pmid=18582342 |doi=10.1111/j.1468-1331.2008.02193.x |url=}}</ref>
* [[Lumbar Puncture]] may show [[lymphocyte]]-predominant [[CSF]] with normal glucose and normal to high protein. <ref name="pmid15494903">{{cite journal |vauthors=Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ |title=Practice guidelines for the management of bacterial meningitis |journal=Clin. Infect. Dis. |volume=39 |issue=9 |pages=1267–84 |date=November 2004 |pmid=15494903 |doi=10.1086/425368 |url=}}</ref>
*[[Lumbar puncture|Lumbar Puncture]] may show [[lymphocyte]]-predominant [[CSF]] with normal [[Glucose-1-phosphatase|glucose]] and normal to high [[protein]]. <ref name="pmid15494903">{{cite journal |vauthors=Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ |title=Practice guidelines for the management of bacterial meningitis |journal=Clin. Infect. Dis. |volume=39 |issue=9 |pages=1267–84 |date=November 2004 |pmid=15494903 |doi=10.1086/425368 |url=}}</ref>
 
* COVID-19 meningitis is differentiated from other causes of [[meningitis]] by the following [[CSF]] findings:<ref name="pmid23717798">{{cite journal| author=Le Rhun E, Taillibert S, Chamberlain MC| title=Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. | journal=Surg Neurol Int | year= 2013 | volume= 4 | issue= Suppl 4 | pages= S265-88 | pmid=23717798 | doi=10.4103/2152-7806.111304 | pmc=3656567 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23717798  }}</ref><ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618  }}</ref><ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096  }}</ref><ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948  }}</ref><ref name="pmid20610819">{{cite journal| author=Brouwer MC, Tunkel AR, van de Beek D| title=Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. | journal=Clin Microbiol Rev | year= 2010 | volume= 23 | issue= 3 | pages= 467-92 | pmid=20610819 | doi=10.1128/CMR.00070-09 | pmc=2901656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20610819  }}</ref>
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
! style="background: #4479BA; width: 150px;" |{{fontcolor|#FFF|Cerebrospinal fluid level}}
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Normal level}}
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Bacterial meningitis}}<ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948  }} </ref>
! style="background: #4479BA; width: 150px;" |{{fontcolor|#FFF|SARS-CoV-2 meningitis}}
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Viral meningitis}}<ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948  }} </ref>
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Fungal meningitis}}
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Tuberculous meningitis}}<ref name="pmid20146981">{{cite journal| author=Caudie C, Tholance Y, Quadrio I, Peysson S| title=[Contribution of CSF analysis to diagnosis and follow-up of tuberculous meningitis]. | journal=Ann Biol Clin (Paris) | year= 2010 | volume= 68 | issue= 1 | pages= 107-11 | pmid=20146981 | doi=10.1684/abc.2010.0407 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20146981  }}</ref>
! style="background: #4479BA; width: 350px;" |{{fontcolor|#FFF|Malignant meningitis}}<ref name="pmid23717798">{{cite journal| author=Le Rhun E, Taillibert S, Chamberlain MC| title=Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. | journal=Surg Neurol Int | year= 2013 | volume= 4 | issue= Suppl 4 | pages= S265-88 | pmid=23717798 | doi=10.4103/2152-7806.111304 | pmc=3656567 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23717798  }} </ref>
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Cells/ul'''
| style="padding: 5px 5px; background: #F5F5F5;" |< 5
| style="padding: 5px 5px; background: #F5F5F5;" |>300
| style="padding: 5px 5px; background: #F5F5F5;" |10-1000
| style="padding: 5px 5px; background: #F5F5F5;" |10-1000
| style="padding: 5px 5px; background: #F5F5F5;" |10-500
| style="padding: 5px 5px; background: #F5F5F5;" |50-500
| style="padding: 5px 5px; background: #F5F5F5;" |>4
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Cells'''
| style="padding: 5px 5px; background: #F5F5F5;" |Lymphos:Monos 7:3
| style="padding: 5px 5px; background: #F5F5F5;" |Gran. > Lymph
| style="padding: 5px 5px; background: #F5F5F5;" |predominantly [[Lymphocyte|lymphocytes]]
| style="padding: 5px 5px; background: #F5F5F5;" |Lymph. > Gran.
| style="padding: 5px 5px; background: #F5F5F5;" |Lympho.>Gran
| style="padding: 5px 5px; background: #F5F5F5;" |[[Lymphocyte|Lymphocytes]]
| style="padding: 5px 5px; background: #F5F5F5;" |Lymphocytes
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Total protein (mg/dl)'''
| style="padding: 5px 5px; background: #F5F5F5;" |45-60
| style="padding: 5px 5px; background: #F5F5F5;" |Typically 100-500
| style="padding: 5px 5px; background: #F5F5F5;" | Normal or slightly high
| style="padding: 5px 5px; background: #F5F5F5;" |Normal or slightly high
| style="padding: 5px 5px; background: #F5F5F5;" |High
| style="padding: 5px 5px; background: #F5F5F5;" |Typically 100-200
| style="padding: 5px 5px; background: #F5F5F5;" |>50
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Glucose ratio (CSF/plasma)<ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618  }} </ref>'''
| style="padding: 5px 5px; background: #F5F5F5;" |> 0.5
| style="padding: 5px 5px; background: #F5F5F5;" |< 0.3
| style="padding: 5px 5px; background: #F5F5F5;" |> 0.6
| style="padding: 5px 5px; background: #F5F5F5;" |> 0.6
| style="padding: 5px 5px; background: #F5F5F5;" |<0.3
| style="padding: 5px 5px; background: #F5F5F5;" |< 0.5
| style="padding: 5px 5px; background: #F5F5F5;" |<0.5
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Lactate (mmols/l)<ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096  }} </ref>'''
| style="padding: 5px 5px; background: #F5F5F5;" |< 2.1
| style="padding: 5px 5px; background: #F5F5F5;" |> 2.1
| style="padding: 5px 5px; background: #F5F5F5;" |N/A
| style="padding: 5px 5px; background: #F5F5F5;" |< 2.1
| style="padding: 5px 5px; background: #F5F5F5;" |>3.2
| style="padding: 5px 5px; background: #F5F5F5;" |> 2.1
| style="padding: 5px 5px; background: #F5F5F5;" |>2.1
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Others'''
| style="padding: 5px 5px; background: #F5F5F5;" |ICP:6-12 (cm H2O)
| style="padding: 5px 5px; background: #F5F5F5;" |[[CSF]] [[Gram staining|gram stain]], [[CSF]] culture, [[CSF]] bacterial antigen
| style="padding: 5px 5px; background: #F5F5F5;" |[[RT-PCR]] for [[SARS-CoV-2]] [[RNA]] in [[CSF]] (still not approved by FDA)
| style="padding: 5px 5px; background: #F5F5F5;" |[[Polymerase chain reaction|PCR]] of [[Herpes simplex virus|HSV]]-[[DNA]], [[VZV]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[CSF]] [[Gram staining|gram stain]], [[CSF]] india ink
| style="padding: 5px 5px; background: #F5F5F5;" |PCR of TBC-DNA
| style="padding: 5px 5px; background: #F5F5F5;" |CSF tumour markers such as alpha fetoproteins, CEA
|-
|}


===Electrocardiogram===
===Electrocardiogram===
* There are no [[ECG]] findings associated with COVID-19-associated meningitis.
 
* To view the electrocardiogram findings on COVID-19, [[COVID-19 electrocardiogram|click here]].<br />
* To view the [[electrocardiogram]] findings on COVID-19, [[COVID-19 electrocardiogram|click here]].
*There are no [[ECG]] findings associated with COVID-19-associated meningitis


===X-ray===
===X-ray===
* There are no x-ray findings associated with COVID-19-associated meningitis.
* There are no [[X-rays|x-ray]] findings associated with COVID-19-associated meningitis.
* To view the x-ray finidings on COVID-19, [[COVID-19 x ray|click here]].<br />
* To view the [[x-ray]] finidings on COVID-19, [[COVID-19 x ray|click here]].


===Echocardiography or Ultrasound===
===Echocardiography or Ultrasound===
*There are no echocardiography/ultrasound  findings associated with COVID-19-associated meningitis.
*There are no [[Echocardiography and ultrasound|echocardiography]]/[[ultrasound]] findings associated with COVID-19-associated meningitis.
* To view the echocardiographic findings on COVID-19, [[COVID-19 echocardiography and ultrasound|click here]].<br />
* To view the [[Echocardiography|echocardiographic]] findings on COVID-19, [[COVID-19 echocardiography and ultrasound|click here]].


===CT scan===
===CT scan===
* CT scan of brain may detect brain inflammation.
*[[CT scan]] of the [[brain]] may detect brain [[inflammation]].
* To view the CT scan findings on COVID-19, [[COVID-19 CT scan|click here]].
* To view the [[CT scan]] findings on COVID-19, [[COVID-19 CT scan|click here]].


===MRI===
===MRI===
* MRI of brain may show hyperintense areas due to brain inflammation.
*[[MRI]] of [[brain]] may show hyperintense areas due to brain inflammation.
* To view other imaging findings on [[COVID-19]], [[COVID-19 other imaging findings|click here]].<br />
* To view other imaging findings on [[COVID-19]], [[COVID-19 other imaging findings|click here]].<br />


===Other Imaging Findings===
===Other Imaging Findings===
There are no other imaging findings associated with COVID-19 associated meningitis.
 
* There are no other imaging findings associated with COVID-19 associated meningitis.


===Other Diagnostic Studies===
===Other Diagnostic Studies===
There are no other diagnostic studies associated with COVID-19 associated meningitis.
 
* There are no other diagnostic studies associated with COVID-19 associated meningitis.


==Treatment==
==Treatment==
<br />
=== Medical Therapy===
=== Medical Therapy===
The mainstays of [[medical]] [[therapy]] for viral meningitis are:
The mainstays of [[medical]] [[therapy]] for viral meningitis are:<ref name="pmid322517913">{{cite journal| author=Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J | display-authors=etal| title=A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. | journal=Int J Infect Dis | year= 2020 | volume= 94 | issue=  | pages= 55-58 | pmid=32251791 | doi=10.1016/j.ijid.2020.03.062 | pmc=7195378 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32251791  }}</ref><ref name="pmid32043983">{{cite journal |vauthors=Russell CD, Millar JE, Baillie JK |title=Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury |journal=Lancet |volume=395 |issue=10223 |pages=473–475 |date=February 2020 |pmid=32043983 |pmc=7134694 |doi=10.1016/S0140-6736(20)30317-2 |url=}}</ref><ref name="pmid32256705">{{cite journal| author=Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S | display-authors=etal| title=Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. | journal=Ecancermedicalscience | year= 2020 | volume= 14 | issue=  | pages= 1022 | pmid=32256705 | doi=10.3332/ecancer.2020.1022 | pmc=7105343 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32256705  }}</ref><ref name="pmid25174548">{{cite journal |vauthors=Ueda R, Saito Y, Ohno K, Maruta K, Matsunami K, Saiki Y, Sokota T, Sugihara S, Nishimura Y, Tamasaki A, Narita A, Imamura A, Maegaki Y |title=Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase |journal=Brain Dev. |volume=37 |issue=5 |pages=471–7 |date=May 2015 |pmid=25174548 |doi=10.1016/j.braindev.2014.08.003 |url=}}</ref><ref name="pmid32479911">{{cite journal| author=Efe IE, Aydin OU, Alabulut A, Celik O, Aydin K| title=COVID-19-Associated Encephalitis Mimicking Glial Tumor. | journal=World Neurosurg | year= 2020 | volume= 140 | issue=  | pages= 46-48 | pmid=32479911 | doi=10.1016/j.wneu.2020.05.194 | pmc=7256557 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32479911  }}</ref><ref name="urlA Study to Evaluate the Efficacy and Safety of Tocilizumab in Hospitalized Participants With COVID-19 Pneumonia - Full Text View - ClinicalTrials.gov">{{cite web |url=+https://clinicaltrials.gov/ct2/show/NCT04372186 |title=A Study to Evaluate the Efficacy and Safety of Tocilizumab in Hospitalized Participants With COVID-19 Pneumonia - Full Text View - ClinicalTrials.gov |format= |work= |accessdate=}}</ref><ref name="pmid32234467">{{cite journal| author=Zhang C, Wu Z, Li JW, Zhao H, Wang GQ| title=Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. | journal=Int J Antimicrob Agents | year= 2020 | volume= 55 | issue= 5 | pages= 105954 | pmid=32234467 | doi=10.1016/j.ijantimicag.2020.105954 | pmc=7118634 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32234467  }}</ref>
=====Symptomatic treatments:=====
=====Symptomatic treatments:=====


*[[Anti-epileptic drugs]] like [[levetiracetam]] is necessary for [[seizure]] management'''<ref name="pmid322517913">{{cite journal| author=Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J | display-authors=etal| title=A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. | journal=Int J Infect Dis | year= 2020 | volume= 94 | issue=  | pages= 55-58 | pmid=32251791 | doi=10.1016/j.ijid.2020.03.062 | pmc=7195378 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32251791  }}</ref>'''.
*[[Anti-inflammatory]] drugs like [[steroids]] are helpful to decrease brain [[inflammation]] in COVID-19 associated meningitis.
*[[Anti-inflammatory]] like [[steroids]] are also helpful in this [[disease]]'''<ref name="pmid322517913" />'''. Corticosteroids in severe COVID-19 patients reduces the mortality. <ref name="pmid32256705">{{cite journal| author=Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S | display-authors=etal| title=Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. | journal=Ecancermedicalscience | year= 2020 | volume= 14 | issue=  | pages= 1022 | pmid=32256705 | doi=10.3332/ecancer.2020.1022 | pmc=7105343 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32256705  }}</ref>
*[[Corticosteroids]] ([[methylprednisolone]] 300 mg/day) in severe [[COVID-19]] patients are shown to reduce [[mortality]].  
*Tocilizumab is IL-6 anatgonist, reduces cytokine storm syndrome in severe COVID-19 patients and can be used in single dose. <ref name="pmid32234467">{{cite journal| author=Zhang C, Wu Z, Li JW, Zhao H, Wang GQ| title=Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. | journal=Int J Antimicrob Agents | year= 2020 | volume= 55 | issue= 5 | pages= 105954 | pmid=32234467 | doi=10.1016/j.ijantimicag.2020.105954 | pmc=7118634 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32234467  }}</ref>
* If a [[COVID-19]] patient with [[meningitis]] develops [[seizures]] [[anti-epileptic drugs]] like [[levetiracetam]] (50-60 mg/kg/day) may be necessary..
*Remdesivir reduces the time of recover in severe COVID-19 patients. <ref name="pmid32445440">{{cite journal| author=Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC | display-authors=etal| title=Remdesivir for the Treatment of Covid-19 - Preliminary Report. | journal=N Engl J Med | year= 2020 | volume=  | issue=  | pages=  | pmid=32445440 | doi=10.1056/NEJMoa2007764 | pmc=7262788 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32445440  }}</ref>
*[[Tocilizumab]] (8mg/kg/dose) is IL-6 anatgonist, that reduces cytokine storm syndrome responsible for neurological manifestations in a COVID-19 patient.  
*Severe disease in these [[patients]] required [[intubation]] and [[mechanical ventilation]]<ref name="pmid32479911">{{cite journal| author=Efe IE, Aydin OU, Alabulut A, Celik O, Aydin K| title=COVID-19-Associated Encephalitis Mimicking Glial Tumor. | journal=World Neurosurg | year= 2020 | volume= 140 | issue=  | pages= 46-48 | pmid=32479911 | doi=10.1016/j.wneu.2020.05.194 | pmc=7256557 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32479911  }}</ref>.
*[[Intubation]] and [[mechanical ventilation]] may be needed .
*[[Hydroxychloroquine|Hydorxychloroquine]] and some [[antivirals]] were used in these [[patients]] but they did not resolve the [[condition]]<ref name="pmid32479911" />.
* To see treatment protocol to manage the underlying cause i.e., COVID-19, [[COVID-19 medical therapy|click here]].<br />


===Surgery===
===Surgery===
Line 394: Line 400:
==References==
==References==
{{reflist|2}}
{{reflist|2}}
[[Category:Up-To-Date]]


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Latest revision as of 23:47, 12 December 2020

For COVID-19 frequently asked outpatient questions, click here.

For COVID-19 frequently asked inpatient questions, click here.

For COVID-19 patient information, click here.


WikiDoc Resources for COVID-19-associated meningitis

Articles

Most recent articles on COVID-19-associated meningitis

Most cited articles on COVID-19-associated meningitis

Review articles on COVID-19-associated meningitis

Articles on COVID-19-associated meningitis in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on COVID-19-associated meningitis

Images of COVID-19-associated meningitis

Photos of COVID-19-associated meningitis

Podcasts & MP3s on COVID-19-associated meningitis

Videos on COVID-19-associated meningitis

Evidence Based Medicine

Cochrane Collaboration on COVID-19-associated meningitis

Bandolier on COVID-19-associated meningitis

TRIP on COVID-19-associated meningitis

Clinical Trials

Ongoing Trials on COVID-19-associated meningitis at Clinical Trials.gov

Trial results on COVID-19-associated meningitis

Clinical Trials on COVID-19-associated meningitis at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on COVID-19-associated meningitis

NICE Guidance on COVID-19-associated meningitis

NHS PRODIGY Guidance

FDA on COVID-19-associated meningitis

CDC on COVID-19-associated meningitis

Books

Books on COVID-19-associated meningitis

News

COVID-19-associated meningitis in the news

Be alerted to news on COVID-19-associated meningitis

News trends on COVID-19-associated meningitis

Commentary

Blogs on COVID-19-associated meningitis

Definitions

Definitions of COVID-19-associated meningitis

Patient Resources / Community

Patient resources on COVID-19-associated meningitis

Discussion groups on COVID-19-associated meningitis

Patient Handouts on COVID-19-associated meningitis

Directions to Hospitals Treating COVID-19-associated meningitis

Risk calculators and risk factors for COVID-19-associated meningitis

Healthcare Provider Resources

Symptoms of COVID-19-associated meningitis

Causes & Risk Factors for COVID-19-associated meningitis

Diagnostic studies for COVID-19-associated meningitis

Treatment of COVID-19-associated meningitis

Continuing Medical Education (CME)

CME Programs on COVID-19-associated meningitis

International

COVID-19-associated meningitis en Espanol

COVID-19-associated meningitis en Francais

Business

COVID-19-associated meningitis in the Marketplace

Patents on COVID-19-associated meningitis

Experimental / Informatics

List of terms related to COVID-19-associated meningitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Wajeeha Aiman, M.D.[2], Muhammad Adnan Haider, M.B.B.S.[3] Tayebah Chaudhry[4] Fahimeh Shojaei, M.D., Syed Musadiq Ali M.B.B.S.[5]


Overview

Covid-19 associated meningitis was first discovered by Moriguchi T. et al. a Japanese critical care physician in late February 2020 during the pandemic of SARS-CoV-2. Duong L et. reported a case of a young female with COVID-19 who developed meningoencephalitis without respiratory failure in Downtown Los Angeles in early April, 2020. Bernard-Valnet R et al. reported two cases of meningoencephalitis in patients with concomitant SARS-CoV-2 infection. There is no established system for the classification of SARS-CoV-2 related meningitis. There are three mechanisms proposed for pathophysiology of COVID-19-associated meningitis. SARS-CoV-2 directly reaches brain through cribriform plate which is located in close proximity to olfactory bulb. This is supported by the facts that some patients of COVID-19 present with anosmia and hyposmia. Viral interaction with ACE2 expressed on neurons lead to damage to neurons and inflamation (encephalitis) and inflammation of brain membranes (meningitis). SARS-CoV-2 can reach brain via anterograde or retrograde transport with the help of motor proteins kinesin and dynein via sensory nerve endings, especially afferent nerve endings of vagus nerve from lungs.

Historical Perspective

  • Neurological symptoms in COVID-19 patients were first reported in February 2020 in a retrospective case series study by Mao L. et al. in hospitalized COVID-19 patients in Wuhan.
  • Ling Mao from Tongji Medical College in Wuhan, and his group reviewed the data retrospectively from January 16, 2020, to February 19, 2020.
  • One third of the 214 hospitalized laboratory- confirmed COVID-19 patients included in this study reported at least one neurological symptom.
  • Covid-19 associated meningitis was first discovered by Moriguchi T. et al. a Japanese critical care physician in late February 2020 during the pandemic of SARS-Coronavirus-2: SARS-CoV-2 [1].
  • Duong L et. reported a case of a young female with COVID-19 who developed meningoencephalitis without respiratory failure in Downtown Los Angeles in early April, 2020 [2].
  • Bernard-Valnet R et al. reported two cases of meningoencephalitis in patients with concomitant SARS-CoV-2 infection.[3]

Classification

  • There is no established system for the classification of COVID-19-associated meningitis.

Pathophysiology

The exact pathogenesis of COVID-19-associated meningitis is not fully understood.

The proposed pathophysiology of COVID-19-associated meningitis is by following three mechanisms;

1.Direct pathway

2. Blood circulation pathway

3. Neuronal Pathway


Causes

Differentiating COVID-19-associated meningitis from other Diseases

  • For further information about the differential diagnosis, click here.
  • To view the differential diagnosis of COVID-19, click here.

Epidemiology and Demographics

Risk Factors

Screening

  • There is insufficient evidence to recommend routine screening for COVID-19-associated meningitis.
  • To view screening for COVID-19, click here.

Natural History, Complications, and Prognosis

History

  • If left untreated, COVID-19-associated meningitis may cause long term neurological complications.
  • To view Natural History for COVID-19, click here.

Complications

If left untreated, meningitis in COVID-19 patients may develop following complications.

Prognosis

  • Exact prognosis of COVID-19 associated meningitis is not known.
  • However, treating the underlying cause i.e., COVID-19, including treatment with steroids, have shown improvement in meningitis symptoms in a COVID-19 patient.
  • To view Prognosis for COVID-19, click here.

Diagnosis

Diagnostic Study of Choice

  • The diagnostic study of choice for meningitis in COVID-19 patients is CSF analysis and ruling out other causes of meningitis (e.g., other viruses, bacteria, fungi).

History and Symptoms

History

  • The disease course of 5 cases of COVID-19 associated meningitis include:
Patient No. Early symptoms Late symptoms CSF analysis Viral panel (HSV,VZV, enterovirus) Bacterial panel SARS-CoV-2 analysis Imaging CT/MRI
Protein(mg/L) Glucose(CSF:serum ratio) Cells (mm3) RT-PCR CSF RT-PCR Nasopharyngeal swab
  1. 24 year old male, presented with meningitis in Japan[16]
 Headache,

Fever,

fatigue

Worsening headache, Sore throat. (Day 5)

Impaired consciousness and transient generalized seizure, (Day 9)

NA NA Cell count was 12/μL–10

mononuclear and 2 polymorphonuclear cells

Negative Positive Negative Brain MRI:

Hyperintensity in the right lateral ventricle's inferior horn along the wall,

pan-paranasal sinusitis.

2. 64 year old female with a known contact with SARS-CoV-2 (her husband tested positive 15 days before)[17] Mild flue like symptoms

myalgia

cough

Tonic-clonic seizures

disorientation

psychotic symptoms

466 mg/L 0.59 17 cells with 97% lymphocytes negative negative positive Brain MRI normal at admission
3. 67 year old female with known SARS-CoV-2 for 17 days with mild respiratory symptoms[18] wake up severe headache Drowsiness, disoriented was lying on the floor, brought to hospital with confusion, disorientation, 461

mg/L

0.62 21 cells with 87 % cells were lymphocytes negative negative positive Brain MRI normal at admission
4. 69 year old man who returned from Middle East 15 days ago (French Indies)[19] 7 day history of

fever

cough

myalgia

cervical pain

ageusia

anosmia

Severe headache

neck stiffness

confusion

84

mg/L

normal 37 cells, purely lymphocytes, with no RBCs negative neagtive negative on nasopharyngeal swab but became positive on bronchoalveolar lavage on 4th day of admission Brain MRI normal on admission
5. 41 year old female, presented with meningoencephalitis without respiratory failure in Downtown Los Angeles in April 2020[20] fever

headache

new onset seizure

severe headache

neck stiffness

photophobia

100

mg/L

0.60 70 cells with 100% lymphocytes negative NA positive CT head without contrast was normal

Common Symptoms

Less Common Symptoms

Physical Examination

Vitals:

Neuromuscular:

Laboratory Findings

Cerebrospinal fluid level Normal level Bacterial meningitis[26] SARS-CoV-2 meningitis Viral meningitis[26] Fungal meningitis Tuberculous meningitis[28] Malignant meningitis[23]
Cells/ul < 5 >300 10-1000 10-1000 10-500 50-500 >4
Cells Lymphos:Monos 7:3 Gran. > Lymph predominantly lymphocytes Lymph. > Gran. Lympho.>Gran Lymphocytes Lymphocytes
Total protein (mg/dl) 45-60 Typically 100-500 Normal or slightly high Normal or slightly high High Typically 100-200 >50
Glucose ratio (CSF/plasma)[24] > 0.5 < 0.3 > 0.6 > 0.6 <0.3 < 0.5 <0.5
Lactate (mmols/l)[25] < 2.1 > 2.1 N/A < 2.1 >3.2 > 2.1 >2.1
Others ICP:6-12 (cm H2O) CSF gram stain, CSF culture, CSF bacterial antigen RT-PCR for SARS-CoV-2 RNA in CSF (still not approved by FDA) PCR of HSV-DNA, VZV CSF gram stain, CSF india ink PCR of TBC-DNA CSF tumour markers such as alpha fetoproteins, CEA

Electrocardiogram

X-ray

  • There are no x-ray findings associated with COVID-19-associated meningitis.
  • To view the x-ray finidings on COVID-19, click here.

Echocardiography or Ultrasound

CT scan

MRI

Other Imaging Findings

  • There are no other imaging findings associated with COVID-19 associated meningitis.

Other Diagnostic Studies

  • There are no other diagnostic studies associated with COVID-19 associated meningitis.

Treatment

Medical Therapy

The mainstays of medical therapy for viral meningitis are:[29][30][31][32][33][34][35]

Symptomatic treatments:

Surgery

Primary Prevention

Secondary Prevention

References

  1. ↑ Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J; et al. (2020). "A first case of meningitis/encephalitis associated with SARS-Coronavirus-2". Int J Infect Dis. 94: 55–58. doi:10.1016/j.ijid.2020.03.062. PMC 7195378 Check |pmc= value (help). PMID 32251791 Check |pmid= value (help).
  2. ↑ Duong L, Xu P, Liu A (2020). "Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020". Brain Behav Immun. 87: 33. doi:10.1016/j.bbi.2020.04.024. PMC 7162766 Check |pmc= value (help). PMID 32305574 Check |pmid= value (help).
  3. ↑ Bernard-Valnet R, Pizzarotti B, Anichini A, Demars Y, Russo E, Schmidhauser M; et al. (2020). "Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection". Eur J Neurol. doi:10.1111/ene.14298. PMC 7267660 Check |pmc= value (help). PMID 32383343 Check |pmid= value (help).
  4. ↑ Tsai LK, Hsieh ST, Chang YC (2005). "Neurological manifestations in severe acute respiratory syndrome". Acta Neurol Taiwan. 14 (3): 113–9. PMID 16252612.
  5. ↑ Schoeman D, Fielding BC (2019). "Coronavirus envelope protein: current knowledge". Virol J. 16 (1): 69. doi:10.1186/s12985-019-1182-0. PMC 6537279 Check |pmc= value (help). PMID 31133031.
  6. ↑ Lu R, Zhao X, Li J, Niu P, Yang B, Wu H; et al. (2020). "Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding". Lancet. 395 (10224): 565–574. doi:10.1016/S0140-6736(20)30251-8. PMC 7159086 Check |pmc= value (help). PMID 32007145 Check |pmid= value (help).
  7. ↑ Baig AM, Khaleeq A, Ali U, Syeda H (2020). "Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms". ACS Chem Neurosci. 11 (7): 995–998. doi:10.1021/acschemneuro.0c00122. PMC 7094171 Check |pmc= value (help). PMID 32167747 Check |pmid= value (help).
  8. ↑ Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH; et al. (2013). "Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor". Nature. 503 (7477): 535–8. doi:10.1038/nature12711. PMC 5389864. PMID 24172901.
  9. ↑ Turner AJ, Hiscox JA, Hooper NM (2004). "ACE2: from vasopeptidase to SARS virus receptor". Trends Pharmacol Sci. 25 (6): 291–4. doi:10.1016/j.tips.2004.04.001. PMC 7119032 Check |pmc= value (help). PMID 15165741.
  10. ↑ Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O; et al. (2020). "Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation". Science. 367 (6483): 1260–1263. doi:10.1126/science.abb2507. PMC 7164637 Check |pmc= value (help). PMID 32075877 Check |pmid= value (help).
  11. ↑ Baig AM, Khaleeq A, Ali U, Syeda H (2020). "Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms". ACS Chem Neurosci. 11 (7): 995–998. doi:10.1021/acschemneuro.0c00122. PMC 7094171 Check |pmc= value (help). PMID 32167747 Check |pmid= value (help).
  12. ↑ Swanson PA, McGavern DB (2015). "Viral diseases of the central nervous system". Curr Opin Virol. 11: 44–54. doi:10.1016/j.coviro.2014.12.009. PMC 4456224. PMID 25681709.
  13. ↑ Wong SH, Lui RN, Sung JJ (2020). "Covid-19 and the digestive system". J Gastroenterol Hepatol. 35 (5): 744–748. doi:10.1111/jgh.15047. PMID 32215956 Check |pmid= value (help).
  14. ↑ Alenquer M, Amorim MJ (2015). "Exosome Biogenesis, Regulation, and Function in Viral Infection". Viruses. 7 (9): 5066–83. doi:10.3390/v7092862. PMC 4584306. PMID 26393640.
  15. ↑ Tsivgoulis G, Palaiodimou L, Katsanos AH, Caso V, Köhrmann M, Molina C, Cordonnier C, Fischer U, Kelly P, Sharma VK, Chan AC, Zand R, Sarraj A, Schellinger PD, Voumvourakis KI, Grigoriadis N, Alexandrov AV, Tsiodras S (2020). "Neurological manifestations and implications of COVID-19 pandemic". Ther Adv Neurol Disord. 13: 1756286420932036. doi:10.1177/1756286420932036. PMC 7284455 Check |pmc= value (help). PMID 32565914 Check |pmid= value (help).
  16. ↑ Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J; et al. (2020). "A first case of meningitis/encephalitis associated with SARS-Coronavirus-2". Int J Infect Dis. 94: 55–58. doi:10.1016/j.ijid.2020.03.062. PMC 7195378 Check |pmc= value (help). PMID 32251791 Check |pmid= value (help).
  17. ↑ Bernard-Valnet R, Pizzarotti B, Anichini A, Demars Y, Russo E, Schmidhauser M; et al. (2020). "Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection". Eur J Neurol. doi:10.1111/ene.14298. PMC 7267660 Check |pmc= value (help). PMID 32383343 Check |pmid= value (help).
  18. ↑ Bernard-Valnet R, Pizzarotti B, Anichini A, Demars Y, Russo E, Schmidhauser M; et al. (2020). "Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection". Eur J Neurol. doi:10.1111/ene.14298. PMC 7267660 Check |pmc= value (help). PMID 32383343 Check |pmid= value (help).
  19. ↑ Chaumont H, Etienne P, Roze E, Couratier C, Roger PM, Lannuzel A (2020). "Acute meningoencephalitis in a patient with COVID-19". Rev Neurol (Paris). 176 (6): 519–521. doi:10.1016/j.neurol.2020.04.014. PMC 7211749 Check |pmc= value (help). PMID 32414534 Check |pmid= value (help).
  20. ↑ Duong L, Xu P, Liu A (2020). "Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020". Brain Behav Immun. 87: 33. doi:10.1016/j.bbi.2020.04.024. PMC 7162766 Check |pmc= value (help). PMID 32305574 Check |pmid= value (help).
  21. ↑ 21.0 21.1 Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ (November 2004). "Practice guidelines for the management of bacterial meningitis". Clin. Infect. Dis. 39 (9): 1267–84. doi:10.1086/425368. PMID 15494903.
  22. ↑ Chaudhuri A, Martinez-Martin P, Martin PM, Kennedy PG, Andrew Seaton R, Portegies P, Bojar M, Steiner I (July 2008). "EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults". Eur. J. Neurol. 15 (7): 649–59. doi:10.1111/j.1468-1331.2008.02193.x. PMID 18582342.
  23. ↑ 23.0 23.1 Le Rhun E, Taillibert S, Chamberlain MC (2013). "Carcinomatous meningitis: Leptomeningeal metastases in solid tumors". Surg Neurol Int. 4 (Suppl 4): S265–88. doi:10.4103/2152-7806.111304. PMC 3656567. PMID 23717798.
  24. ↑ 24.0 24.1 Chow E, Troy SB (2014). "The differential diagnosis of hypoglycorrhachia in adult patients". Am J Med Sci. 348 (3): 186–90. doi:10.1097/MAJ.0000000000000217. PMC 4065645. PMID 24326618.
  25. ↑ 25.0 25.1 Leen WG, Willemsen MA, Wevers RA, Verbeek MM (2012). "Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice". PLoS One. 7 (8): e42745. doi:10.1371/journal.pone.0042745. PMC 3412827. PMID 22880096.
  26. ↑ 26.0 26.1 26.2 Negrini B, Kelleher KJ, Wald ER (2000). "Cerebrospinal fluid findings in aseptic versus bacterial meningitis". Pediatrics. 105 (2): 316–9. PMID 10654948.
  27. ↑ Brouwer MC, Tunkel AR, van de Beek D (2010). "Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis". Clin Microbiol Rev. 23 (3): 467–92. doi:10.1128/CMR.00070-09. PMC 2901656. PMID 20610819.
  28. ↑ Caudie C, Tholance Y, Quadrio I, Peysson S (2010). "[Contribution of CSF analysis to diagnosis and follow-up of tuberculous meningitis]". Ann Biol Clin (Paris). 68 (1): 107–11. doi:10.1684/abc.2010.0407. PMID 20146981.
  29. ↑ Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J; et al. (2020). "A first case of meningitis/encephalitis associated with SARS-Coronavirus-2". Int J Infect Dis. 94: 55–58. doi:10.1016/j.ijid.2020.03.062. PMC 7195378 Check |pmc= value (help). PMID 32251791 Check |pmid= value (help).
  30. ↑ Russell CD, Millar JE, Baillie JK (February 2020). "Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury". Lancet. 395 (10223): 473–475. doi:10.1016/S0140-6736(20)30317-2. PMC 7134694 Check |pmc= value (help). PMID 32043983 Check |pmid= value (help).
  31. ↑ Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S; et al. (2020). "Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence". Ecancermedicalscience. 14: 1022. doi:10.3332/ecancer.2020.1022. PMC 7105343 Check |pmc= value (help). PMID 32256705 Check |pmid= value (help).
  32. ↑ Ueda R, Saito Y, Ohno K, Maruta K, Matsunami K, Saiki Y, Sokota T, Sugihara S, Nishimura Y, Tamasaki A, Narita A, Imamura A, Maegaki Y (May 2015). "Effect of levetiracetam in acute encephalitis with refractory, repetitive partial seizures during acute and chronic phase". Brain Dev. 37 (5): 471–7. doi:10.1016/j.braindev.2014.08.003. PMID 25174548.
  33. ↑ 33.0 33.1 Efe IE, Aydin OU, Alabulut A, Celik O, Aydin K (2020). "COVID-19-Associated Encephalitis Mimicking Glial Tumor". World Neurosurg. 140: 46–48. doi:10.1016/j.wneu.2020.05.194. PMC 7256557 Check |pmc= value (help). PMID 32479911 Check |pmid= value (help).
  34. ↑ [+https://clinicaltrials.gov/ct2/show/NCT04372186 "A Study to Evaluate the Efficacy and Safety of Tocilizumab in Hospitalized Participants With COVID-19 Pneumonia - Full Text View - ClinicalTrials.gov"] Check |url= value (help).
  35. ↑ Zhang C, Wu Z, Li JW, Zhao H, Wang GQ (2020). "Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality". Int J Antimicrob Agents. 55 (5): 105954. doi:10.1016/j.ijantimicag.2020.105954. PMC 7118634 Check |pmc= value (help). PMID 32234467 Check |pmid= value (help).


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