COVID-19-associated encephalopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Muhammad Adnan Haider, M.B.B.S.[2] Wajeeha Aiman, M.D.[3]

Synonyms and Keywords: Encephalopathy in COVID-19, COVID-19 encephalopathy

Overview

Encephalopathy is an alteration of the level or contents of consciousness due to brain dysfunction and can result from global or focal brain lesions. SARS-CoV-2 which is the member of coronavirus family has caused many neurological complications including encephalopathy. Acute toxic encephalopathy is caused by toxemia, hypoxia and metabolic disorders due the systemic viral infection (viral sepsis).

Historical Perspective

  • COVID-19, a disease caused by SARS-CoV-2 first emerged in Wuhan, China in December 2019.
  • It then spread so rapidly that it was declared as pandemic in Feb, 2020.
  • It mostly presents with respiratory symptoms like flue, dry cough, fever, fatigue, dyspnea.
  • Although rare but neurological manifestations have been reported throughout the spectrum of COVID-19 pandemic.
  • These neurological symptoms range from headache, anosmia, meningitis, encephalitis, Guillain Berre Syndrome,and stroke. Encephalopathy is rare and few case has been reported with acute encephalopathy during the severe systemic SARS-CoV-2 infection.

Classification

Pathophysiology

  • Severe COVID-19 infection can lead to dysfunction of multiple organs of the body that can lead to hypoxic or metabolic insults to brain and cause encephalopathy.
  • Encephalitis/meningitis are caused by neurotropism of SARS-CoV-2 to brain and meninges through ACE2 receptors.[1]
  • Encephalopathy is caused by hyper inflammation of brain by following three mechanisms;
  • cytokine storm
  • Hypoxic brain injury
  • molecular mimicry

Cytokine storm

  • SARS-CoV-2 causes several neurological complications through production of inflammatory cytokines (mainly IL-6) from glial cells called cytokine storm syndrome.[2]
  • SARS-CoV-2 activates CD4 cells of the immune system and CD4 cells activate macrophages by producing granulocyte-macrophage colony stimulating factors. Actiavted macrophages now produce IL-6.
  • IL-6 is a major cytokine of cytokine storm syndrome and leads to multiple organ failure. This severe organ damage leads to metabolic and toxic changes in the body which causes brain dysfunction and leads to SARS-CoV-2 related encephalopathy.[3]
  • This fact can be supported by the evidence that tocilizumab which is IL-6 antagonist is used in severe COVID-19 infections.[4]

Hypoxic Brain Injury

  • The hall mark of severe COVID-19 infection is dyspnea and hypoxemia due Acute Respiratory distress syndrome (ARDS).
  • This hypoxia and hypoxemia is sometimes enough to cause diffuse brain injury and cause encephalopathy.[5]

Molecular Mimicry

  • Post-infectious encephalomyelitis, an autoimmune demyelinating disease of the brain, can be triggered by the SARS‐CoV‐2 virus.[6]
  • SARS-CoV-2 is considered to have similar antigenic determinants as that of some antigens present on human neuronal cells.
  • Immunological response to the SARS‐CoV‐2 virus cross-react with the myelin autoantigens, resulting in post-infectious encephalomyelitis.
  • Neuropathological findings confirmed vascular and demyelinating pathology in a patient who died from COVID-19.[7]

Causes

  • COVID-19-associated encephalopathy may be caused by SARS-CoV-2.
  • To read more about this virus, click here.

Differentiating COVID-19-associated encephalopathy 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

Natural History, Complications, and Prognosis

Complications


 
 
 
 
 
 
 
 
Encephalopathy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memory loss
 
Epilepsy
 
Personality changes
 
Hearing/vision loss
 
Coma/Death

Diagnosis

Diagnostic Study of Choice

Signs and symptoms

Common Symptoms

Less Common Symptoms

13 cases of COVID-19-associated encephalopathy cases have been analyzed in the table below:

Patient No. Early symptoms Later presentation Lab. Findings Specific Tests Imaging studies
CSF bacterial panel viral panel (VZV, CMV, HSV1, HSV2) SARS-CoV-2 MRI/CT scan
on nasopharyngeal sawab on CSF
1. Poyiadji et.al reported a case report of a female in her late fifties who presented with COVID-19 associated acute hemorrhagic necrotizing encephalopathy[8] fever

cough

altered mentation Not possible due to traumatic rupture Negative Negative RT-PCR for SARS-CoV-2 positive on nasopharyngeal swab Negative
  • Noncontrast head CT images demonstrated symmetric hypoattenuation within the bilateral medial thalami with a normal CT angiogram and CT venogram
  • Brain MRI demonstrated hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions
2. A 74 year male who had traveled from Europe to USA was presented to emergency with COVID-19 related encephalopathy[9] Fever

cough

headache

altered mentationn

  • WBCs =4
  • RBCs = 0
  • Glucose 75
  • Proteins 68
Negative Negative positive Negative CT scan normal
3. 59 year female with history of aplastic anemia presented with COVID-19 related acute necrotizing encephalopathy involving brain stem. She returned from trip to Afghanistan[10] fever

cough

headache

  • seizure
  • reduced consciousness
  • flexion of upper limbs
  • speech arrest


  • CSF opening pressure = 28 cm water
  • Protein 2.3
  • WBCs= 4 cells
Negative Negative RT-PCR positive Negative MRI showed diffuse swelling and hemorrhage in the brain stem and both amygdalae
4. Benameur et. al reported a 31 year old african american presented with COVID-19 related encephalopathy.[11] fever

dyspnea

  • ARDS and was intubated
  • Comatosed post intubation
  • absent brain reflexes
  • CSF opening pressure= 30 cm water
  • proteins >200mg/dl
  • WBCs 115 nucleated cells
  • Glucose normal
Negative Negative RT-PCR positive for SARS-CoV-2 Negative MRI howed nonenhancing cerebral edema and diffusion weighted imaging abnormalities predominantly involving the right cerebral hemisphere, as well as brain herniation
5.Benameur et. al reported a 34 year old african american with hypertension presented with COVID-19 related encephalopathy.[11] fever

cough

dyspnea

  • multiple myoclonus
  • absent corneal and gag reflexes
  • comatosed
  • CSF opening pressure= 48 cm of water
  • no pleocytosis
  • normal glucose
  • mildly elevated proteins
Negative Negative positive RT-PCR for SARS-CoV-2 Negative Brain MRI on day 15 showed a nonenhancing hyperintense lesion within the splenium of the corpus callosum
6. Benameur et. al reported a 64 year old african american with hypertension presented with COVID-19 related encephalopathy.[11] Fever

Cough

Dyspnea

  • profound encephalopathy
  • absent with withdrawl to pain stimuli
  • myoclonus
  • absent deep tendon reflexes
Normal Negative Negative RT-PCR positive for SARS-CoV-2 Negative MRI showed an equivocal nonenhancing area of fluid-attenuated inversion recovery abnormality in the right temporal lobe.
7. Espinosa et. al presented a case report of COVID-19 related encephalopathy[12] Fever

Dry cough

  • ARDS
  • comatosed after he was off ventilator
  • no response to painful stimuli
  • decreased activity of brain on EEG
WBCs =2 cells

proteins = 27

glucose = 68

Negative Negative Positive PCR for SARS-CoV-2 Negative on MRI diffusion-weighted imaging shows an area of restricted diffusion in the left parietocoritcal region
8. Byrness et. al reported a case of 36 years old male who was suspected to have drug overdose but later was diagnosed with COVID-19 related encephalopathy [13] Presented with suspected drug overdose. urine screen positive for cocaine, opiates and benzodiazepenes
  • Fever 39.8 (2nd day)
  • agitation
  • choreiform movements of upper extremities
CSF findings negative for bacterial or viral meningitis/encephalitis Negative Negative RT-PCR positive for SARS-CoV-2 Negative (MRI) was obtained which demonstrated multiple focal enhancing lesions primarily affecting the bilateral medial putamen and left cerebellum
9. A 64 year old female presented with posterior reversible encephalopathy syndrome (PRES) and was reported by reported by Cariddi et. al[14] fever

dyspnea

On 25th day of admission when she was weaned off sedation she had:
  • blurred vision
  • altered mentation
  • left nasolabial fold was reduced
  • reduced reflexes
CSF negative for bacterial or viral findings Negative negative RT-PCR positive for SARS-CoV-2 negative
  • Brain CT and CTA were consistent with hemorrhagic Posterior Reversible Encephalopathy Syndrome
  • On day 56 a brain MRI showed a reduction of the bilateral edema with bilateral occipital foci of subacute hemorrhage
10. A 48 year old male, ail pilot presented with hemorrhagic posterior reversible encephalopathy syndrome[15] fever

dyspnea

  • High grade fever (2nd day)
  • altered mentation
  • ARDS
NA Negative negative RT-PCR positive for SARS-CoV-2 negative MRI showed vasogenic edema in the posterior parieto-occipital regions with subacute blood products suggestive of hemorrhagic posterior reversible encephalopathy syndrome (PRES)
11. Hayashi et.al reported the first case of COVID-19-associated mild encephalitis/encephalopathy with a reversible splenial lesion in 75-year-old male[16]
  • Left dominant kinetic tremors
  • walking instability
  • urinary incontinence
  • fever day 2
  • Hypoxemia
NA negative negative RT-PCR on throat swab positive for SARS-CoV-2 Negative (MRI) of the brain revealed an abnormal hyperintensity in the splenium of corpus callosum (SCC), suspicious for clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)
12. Cani et. al reported Frontal encephalopathy related to hyperinflammation in 77-year-old female with COVID-19[17] fever

respiratory symptoms

  • Altered consciousness
  • no goal directed activity
  • myoclonus
  • positive primitive reflexes
normal negative negative SARS-CoV-2 positive on RT-PCR Negative MRI displayed diffuse white-matter lesions consistent with chronic small vessel disease without contrast enhancement
13. Encephalopathy and seizure activity in a 41-year-old COVID-19 well-controlled HIV patient was reported by Haddad S et.al[18] Fever

fatigue

chills

cough

  • confusion
  • agitation
  • seizure
  • EEG showed evidence of diffuse slowing but no epileptiform activity.
WBCs = 0

RBCs = 5 cells

Proteins = 102

Glucose = 81

Negative negative SARS-CoV-2 positive on RT-PCR neagtive NA

Physical Examination

  • Physical examination of COVID-19 associated encephalopathy is usually difficult to perform as patients are confused and non cooperative.
  • So, clinicians usually do focused examinations in encephalopathic patients.

Appearance of the patient

  • Generally, the patients with COVID-19 associated encephalopathy are not oriented to time, place and persons.
  • Patients are usually agitated and sedated medically sometimes.
  • Patients have dusky appearance usually due to concurrent pulmonary disease in most cases of COVID-19 associated encephalopathy.

Vital signs

Neurological examination

Common findings in COVID-19 associated neurological examinations are:

  • Inattention
  • Altered mentation
  • speech arrest
  • Multifocal myoclonus
  • Postural action tremors
  • flapping motions of an outstretched, dorsiflexed hand (asterixis)
  • reduced reflexes

Laboratory Findings

Electrocardiogram

X-ray

  • A Chest x-ray may be helpful in the diagnosis of COVID-19-associated respiratory disease.

Echocardiography or Ultrasound

CT scan

  • Head CT scan may be helpful in the diagnosis of COVID-19-associated encephalopathy.
  • Findings on head CT scan suggestive of COVID-19-associated encephalopathy include:
    • Noncontrast head CT images demonstrated symmetric hypoattenuation within the bilateral medial thalami with a normal CT angiogram and CT venogram,
    • Hemorrhagic Posterior Reversible Encephalopathy Syndrome.

MRI

  • Brain MRI is helpful in the diagnosis of COVID-19-associated encephalopathy.
  • Findings on brain MRI suggestive of COVID-19-associated encephalopathy include:
    • Hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions,
    • Diffuse swelling and hemorrhage in the brain stem and both amygdalae,
    • Nonenhancing cerebral edema and diffusion weighted imaging abnormalities,
    • Brain herniation
    • Nonenhancing hyperintense lesion.

Other Imaging Findings

Other imaging studies may be helpful in the diagnosis of COVID-19-associated encephalopathy include:

Other Diagnostic Studies

Other diagnostic studies for COVID-19-associated encephalopathy include:

Treatment

Medical Therapy

The mainstay of medical therapy for viral encephalitis are:

Symptomatic Treatment

Surgery

Primary Prevention

Secondary Prevention

References

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  2. Chen C, Zhang XR, Ju ZY, He WF (2020) [Advances in the research of mechanism and related immunotherapy on the cytokine storm induced by coronavirus disease 2019.] Zhonghua Shao Shang Za Zhi 36 (6):471-475. DOI:10.3760/cma.j.cn501120-20200224-00088 PMID: 32114747
  3. Bohmwald K, Gálvez NMS, Ríos M, Kalergis AM (2018). "Neurologic Alterations Due to Respiratory Virus Infections". Front Cell Neurosci. 12: 386. doi:10.3389/fncel.2018.00386. PMC 6212673. PMID 30416428.
  4. 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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  6. Parsons T, Banks S, Bae C, Gelber J, Alahmadi H, Tichauer M (2020). "COVID-19-associated acute disseminated encephalomyelitis (ADEM)". J Neurol. doi:10.1007/s00415-020-09951-9. PMC 7260459 Check |pmc= value (help). PMID 32474657 Check |pmid= value (help).
  7. Reichard RR, Kashani KB, Boire NA, Constantopoulos E, Guo Y, Lucchinetti CF (2020). "Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology". Acta Neuropathol. 140 (1): 1–6. doi:10.1007/s00401-020-02166-2. PMC 7245994 Check |pmc= value (help). PMID 32449057 Check |pmid= value (help).
  8. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B (2020). "COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features". Radiology: 201187. doi:10.1148/radiol.2020201187. PMC 7233386 Check |pmc= value (help). PMID 32228363 Check |pmid= value (help).
  9. Filatov A, Sharma P, Hindi F, Espinosa PS (2020). "Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy". Cureus. 12 (3): e7352. doi:10.7759/cureus.7352. PMC 7170017 Check |pmc= value (help). PMID 32328364 Check |pmid= value (help).
  10. Dixon L, Varley J, Gontsarova A, Mallon D, Tona F, Muir D; et al. (2020). "COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia". Neurol Neuroimmunol Neuroinflamm. 7 (5). doi:10.1212/NXI.0000000000000789. PMC 7286661 Check |pmc= value (help). PMID 32457227 Check |pmid= value (help).
  11. 11.0 11.1 11.2 Benameur K, Agarwal A, Auld SC, Butters MP, Webster AS, Ozturk T; et al. (2020). "Encephalopathy and Encephalitis Associated with Cerebrospinal Fluid Cytokine Alterations and Coronavirus Disease, Atlanta, Georgia, USA, 2020". Emerg Infect Dis. 26 (9). doi:10.3201/eid2609.202122. PMID 32487282 Check |pmid= value (help).
  12. Espinosa PS, Rizvi Z, Sharma P, Hindi F, Filatov A (2020). "Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy, MRI Brain and Cerebrospinal Fluid Findings: Case 2". Cureus. 12 (5): e7930. doi:10.7759/cureus.7930. PMC 7266087 Check |pmc= value (help). PMID 32499974 Check |pmid= value (help).
  13. Byrnes S, Bisen M, Syed B, Huda S, Siddique Z, Sampat P; et al. (2020). "COVID-19 encephalopathy masquerading as substance withdrawal". J Med Virol. doi:10.1002/jmv.26065. PMC 7283690 Check |pmc= value (help). PMID 32458578 Check |pmid= value (help).
  14. Princiotta Cariddi L, Tabaee Damavandi P, Carimati F, Banfi P, Clemenzi A, Marelli M; et al. (2020). "Reversible Encephalopathy Syndrome (PRES) in a COVID-19 patient". J Neurol. doi:10.1007/s00415-020-10001-7. PMC 7312113 Check |pmc= value (help). PMID 32583053 Check |pmid= value (help).
  15. Franceschi AM, Ahmed O, Giliberto L, Castillo M (2020). "Hemorrhagic Posterior Reversible Encephalopathy Syndrome as a Manifestation of COVID-19 Infection". AJNR Am J Neuroradiol. 41 (7): 1173–1176. doi:10.3174/ajnr.A6595. PMC 7357664 Check |pmc= value (help). PMID 32439646 Check |pmid= value (help).
  16. Hayashi M, Sahashi Y, Baba Y, Okura H, Shimohata T (2020). "COVID-19-associated mild encephalitis/encephalopathy with a reversible splenial lesion". J Neurol Sci. 415: 116941. doi:10.1016/j.jns.2020.116941. PMC 7251406 Check |pmc= value (help). PMID 32474220 Check |pmid= value (help).
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  18. Haddad S, Tayyar R, Risch L, Churchill G, Fares E, Choe M; et al. (2020). "Encephalopathy and seizure activity in a COVID-19 well controlled HIV patient". IDCases: e00814. doi:10.1016/j.idcr.2020.e00814. PMC 7228895 Check |pmc= value (help). PMID 32426230 Check |pmid= value (help).
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  22. 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).
  23. [+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).