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


   
   

Revision as of 23:16, 13 July 2020

COVID-19 Microchapters

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Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

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Case #1

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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] Syed Musadiq Ali M.B.B.S.[5]


COVID-19 Microchapters

Home

Long COVID

Frequently Asked Outpatient Questions

Frequently Asked Inpatient Questions

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating COVID-19 from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Interventions

Surgery

Primary Prevention

Vaccines

Secondary Prevention

Future or Investigational Therapies

Ongoing Clinical Trials

Case Studies

Case #1

COVID-19-associated meningitis On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of COVID-19-associated meningitis

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on COVID-19-associated meningitis

CDC on COVID-19-associated meningitis

COVID-19-associated meningitis in the news

Blogs on COVID-19-associated meningitis

Directions to Hospitals Treating Psoriasis

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

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.

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.
  • Covid-19 associated 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 [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 SARS-CoV-2 related meningitis.

Pathophysiology

The exact pathogenesis of SARS-CoV-2 associated meningitis is not fully understood.

  • Severe acute respiratory syndrome (SARS) and Middle East respiratory Syndrome (MERS) caused some neurological manifestations in 2002 and 2012 respectively[4]. As neucleic acid of SARS-CoV and MERS-CoV was found in cerebrospinal fluid and later on the autopsy of brain[5].
  • SARS-CoV-2 is 79% identical to SARS-CoV and 50% to MERS-CoV[6]. 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

SARS-CoV-2 directly reaches brain through cribriform plate which is located in close proximity to olfactory bulb[7]. This is supported by the facts that some patients of COVID-19 present with anosmia and hyposmia.

2. Blood circulation pathway

  • Angiotensin converting enzyme-2 (ACE2) is the functional receptor of the SARS-CoV-2[8]. ACE2 is expressed on glial tissue, neurons and brain vasculature[9]
  • SARS-CoV-2 binds with ACE2 precsent on vascular endothelial cells and glial tissues with the help of spike S protein.[10]
  • Subsequent viral budding from endothelial cells and resultant damage to capillary endothelium favors viral entry into milieu of brain[11].
  • Viral interaction with ACE2 expressed on neurons lead to damage to neurons and inflamation (encephalitis) and inflammation of brain membranes (meningitis)

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.[12]
  • SARS-CoV-2 causes some gastrointestinal problems in COVID-19 patients and can reach CNS from enteric nerve and sympathetic afferent via neuronal pathway.[13]
  • Exosomal cellular transport is also a pathway for SARS-CoV-2 systemic dissemination and spread to CNS.[14]



Causes

Differentiating COVID-19-associated meningitis from other Diseases

COVID-19-associated meningitis must be differentiated from other diseases that cause fever, headache, and neck stiffness, photophobia with or without cough, such as:


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:[15][16][17][18][19]

Cerebrospinal fluid level Normal level Bacterial meningitis[18] SARS-CoV-2 meningitis Viral meningitis[18] Fungal meningitis Tuberculous meningitis[20] Malignant meningitis[15]
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)[16] > 0.5 < 0.3 > 0.6 > 0.6 <0.3 < 0.5 <0.5
Lactate (mmols/l)[17] < 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

Epidemiology and Demographics

  • More data is needed to establish the to understand the epidemiology of COVID-19 associated meningitis[21].
  • However, direct infection of the neurological system appears to be extremely rare.


Risk Factors

Screening

  • Screening for COVID-19-associated meningitis is not currently done.
  • To view screening for COVID-19, click here.

Natural History, Complications, and Prognosis

History

  • So far, the cases of COVID-19 associated meningitis have shown acute presentations.
  • 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:

Five cases of meningitis in COVID-19 patients have been reported. The disease course of these patients is given in the table.

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[22]
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)[23] 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[24] 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)[25] 7 day history of

fever

cough

myalgia

cervical pain

ageusia

anosmia

Severe headache

neck stifness

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[26] 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 noraml

Symtoms:

Physical Examination

Vitals:

Physical Exam:

Laboratory Findings

  • COVID-19 meningitis is differentiated from other causes of meningitis by the following CSF findings:[15][16][17][18][19]
Cerebrospinal fluid level Normal level Bacterial meningitis[18] SARS-CoV-2 meningitis Viral meningitis[18] Fungal meningitis Tuberculous meningitis[20] Malignant meningitis[15]
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)[16] > 0.5 < 0.3 > 0.6 > 0.6 <0.3 < 0.5 <0.5
Lactate (mmols/l)[17] < 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

  • There are no ECG findings associated with COVID-19-associated meningitis.
  • To view the electrocardiogram findings on COVID-19, click here.

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

  • There are no echocardiography/ultrasound findings associated with COVID-19-associated meningitis.
  • To view the echocardiographic findings on COVID-19, click here.

CT scan

  • CT scan of brain may detect brain inflammation.
  • To view the CT scan findings on COVID-19, click here.

MRI

  • MRI of brain may show hyperintense areas due to brain inflammation.
  • To view other imaging findings on COVID-19, click here.

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:

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.
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  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.
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  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.
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  17. 17.0 17.1 17.2 17.3 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.
  18. 18.0 18.1 18.2 18.3 18.4 18.5 Negrini B, Kelleher KJ, Wald ER (2000). "Cerebrospinal fluid findings in aseptic versus bacterial meningitis". Pediatrics. 105 (2): 316–9. PMID 10654948.
  19. 19.0 19.1 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.
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  21. 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).
  22. 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).
  23. 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).
  24. 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).
  25. 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).
  26. 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).
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  30. 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).
  31. 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).
  32. 32.0 32.1 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).


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