COVID-19-associated encephalitis

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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], Fahimeh Shojaei, M.D., Muhammad Adnan Haider, M.B.B.S.[3]

Synonyms and keywords: Encephalitis covid-19

Overview

Encephalitis is inflammation of the brain parenchyma and it is commonly caused by viruses. COVID-19 is a virus related to the severe acute respiratory syndrome coronavirus (SARS-CoV) group and named as SARS-CoV-2. COVID-19 associated 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. The association between COVID-19 and encephalitis was made early in the pandemic in the Wuhan province of China. There is no established system for the classification of COVID-19 associated encephalitis. The exact pathogenesis of COVID-19 encephalitis is not fully understood. COVID-19-associated encephalitis must be differentiated from other diseases that cause fever, headache, and altered mental status with or without cough.

Historical Perspective

• Covid-19 associated 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.

• The association between COVID-19 and encephalitis was made during this pandemic started in December in Wuhan, China and named as Wuhan coronavirus.
• In March 2020, Dr. Ali A. was the first to discover the association between COVID-19 and neurological diseases e.g. encephalitis. He made a clinical diagnosis along with his team and then MRI used to diagnose the disease.
• In January 2020, Chinese doctors confirmed the first case of encephalitis due to COVID-19 in a 56 year old male and they conducted gene sequencing on cerebrospinal fluid (CSF) samples and confirmed the novel virus inside the brain, but it was not published.
• There have been several outbreaks of SARS and MERS.

Classification

• There is no established system for the classification of COVID-19 associated encephalitis.
• Based on the duration of symptoms, this disease is classified as acute.

Pathophysiology

• The exact pathogenesis of COVID-19 encephalitis is not fully understood.

• It is thought that this viral encephalitis is the result of multiple pathophysiologic pathways.

SARS-CoV-2

ACE2

Direct Injury due to Infection

Immune Injury

Hypoxic Injury

Hypercoagulability

Viral Encephalitis

• ACE2: Angiotensin converting enzyme receptor 2 is present in multiple organs e.g. lungs, brain, and kidney, etc.
• Hypercoagulability: With elevated D-dimer
• Immune injury: Cytokine activation and vascular involvement.
• Direct injury: Due to hematogenous and neuronal pathway involvement.
• Hypoxic injury: Due to anaerobic metabolism.

Causes

• Coronavirus disease 2019 (COVID-19) associated encephalitis is caused by SARS-CoV-2.

• To read more about this virus, click here.

Case courtesy of Dr. Daniel J Bell, Radiopaedia.org, rID: 74536

Differentiating COVID-19-associated encephalitis 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

• There are approximately 50 cases of COVID-19-associated encephalitis reported in the first six months of the pandemic.
• MERS and SARS-CoV had neurologic manifestation like encephalitis at the time of outbreaks.
• Patients of all age groups may develop COVID-19-associated encephalitis
• The incidence of COVID-19-associated encephalitis increases with age; the median age at diagnosis is 54 years.
• There is no racial predilection to COVID-19-associated encephalitis but more cases were present in African Americans.
• COVID-19-associated encephalitis affects men and women equally.

Risk Factors

• Common risk factors in the development of COVID-19-associated encephalitis may be occupational, environmental, and genetic.
• Risk factors for this disease are the same as for COVID-19.
• To view the risk factors of COVID-19, click here.
• Auto-immune syndromes might be at higher risk of developing this disease due to immunosuppressive therapy.

Risk factors for COVID-19-associated encephalitis

Autoimmune disease	Immunosuppression
Multiple sclerosis	Interferon beta Glatiramer Corticosteroids
Myasthenia gravis	Corticosteroids
Neuromyelitis optica	Monoclonal antibody
Sarcoidosis	Corticosteroids Methotrexate Azathioprine
Sickle cell disease (SCD)	Crizanlizumab

Screening

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

Natural History, Complications, and Prognosis

• To view Natural History for COVID-19, click here.
• If left untreated, patients with COVID-19-associated encephalitis may progress to damage the brain and cause:

Encephalitis

Memory loss

Epilepsy

Personality changes

Hearing/vision loss

Coma/Death

Diagnosis

Diagnostic Study of Choice

• The diagnostic study of choice for COVID-19-associated encephalitis is CSF analysis for ruling out other viral and bacterial panels with the help of RT-PCR.

History and Symptoms

• The majority of patients with COVID-19-associated encephalitis present with respiratory symptoms. e.g. cough, shortness of breath etc.

Common Symptoms

• The common symptoms of COVID-19-associated encephalitis include:
  • Cough,
  • Shortness of breath
  • Headache,
  • Fever
  • Fatigue
  • Impaired consciousness

Less Common Symptoms

• Less common symptoms of COVID-19-associated encephalitis include:
  • Transient generalized seizure
  • Dizziness,
  • Paralysis
  • Sedation
  • Coma

• Clinical manifestation of 3 cases of COVID-19 associated encephalitis are shown below:

Patient No.	Early symptoms	Later presentation	GCS	Lab. Findings		Specific Tests	Imaging studies
				CBC	CSF		MRI/CT scan
24-year-old man from Japan	Headache, Fever, Fatigue	Worsening headache, Sore throat. (Day 5) Impaired consciousness and transient generalized seizure, (Day 9)	E4V1M1	↑WBCs and neutrophils ↓lymphocytes ↑ CRP	Clear and colorless fluid, Pressure=320 mmH2O, Cell count was 12/μL–10 mononuclear and 2 polymorphonuclear cells	RT-PCR of SARS-CoV-2 RNA was positive in CSF	Brain MRI: Hyperintensity in the right lateral ventricle's inferior horn along the wall, pan-paranasal sinusitis.
In Wuhan, in a letter to editor, Ye M et.al, reported COVID-19 associated encephalitis case in a male with laboratory finding	Fever SOB Myalgia	Confusion	NA	WBC count (3.3 × 109/L) and lymphopenia (0.8 × 109/L)	Pressure=220 mmg WBC (0.001 × 109/L) protein (0.27 g/L) sugar (3.14 mmol/L)	SARS-CoV-2 was positive on nasopharyngeal swab but negative on CSF testing All other bacterial and viral causes of encephlitis were negative	skull CT was normal chest CT showed multiple subpleural ground glass opacities
35-year-old woman from Turkey whose COVID-19 associated encephalitis mimicking as glial tumor of CNS	Flu like symptoms	Headache, nausea, dizziness, and drug-refractory seizures.	E4V5M6	NA	NA	RT-PCR and antibody tests positive	Brain MRI: Hyperintensity in the left temporal lobe. MR Spectroscopy: Decrease N-acetyl aspartate peak along with a marked elevated choline peak.
31-year-old African American woman	SCD patient with dyspnea	Paralysis and sedation (Day 13) Comatose (Day 15) and death (Day 16)	E0V0M0	NA	Pressure=30cmH2O 115 nucleated cell /ml 7374 erythrocytes /ml Protein> 200mg/dl	RT=PCR for SARS-CoV-2 was positive in nasopharyngeal swab	Brain MRI: Nonenhancing cerebral edema and restricted diffusion in the right cerebral hemisphere with brain herniation.

Physical Examination

• Common physical examination findings of COVID-19-associated encephalitis include

Neuromuscular

• Generalized seizure
• Headache
• Neck stiffness
• Focal neurological deficits can be present in this disease.

Laboratory Findings

• Positive RT-PCR in CSF or nasopharyngeal swab is diagnostic of COVID-19-associated encephalitis.

• Laboratory findings consistent with the diagnosis of COVID-19-associated encephalitis include CSF analysis, RT-PCR and brain MRI.

• D-dimer or white blood cells can be normal among patients with COVID-19-associated encephalitis.
• Some patients with COVID-19-associated encephalitis may have elevated erythrocytes in CSF which is usually suggestive of COVID-19-associated encephalitis.

Electrocardiogram

• There are no ECG findings associated with COVID-19-associated encephalitis.

X-ray

• There are no x-ray findings associated with COVID-19-associated encephalitis.
• However, an x-ray chest may be helpful in the diagnosis of COVID-19-associated respiratory disease.

Echocardiography or Ultrasound

• There are no echocardiography findings associated with COVID-19-associated encephalitis.

CT scan

• The findings on the CT scans associated with COVID-19-associated encephalitis are similar to MRI which is the preferred modality.

MRI

• Brain MRI may be helpful in the diagnosis of COVID-19 associated encephalitis. Findings on MRI suggestive of COVID-19-associated encephalitis include:
  • Hyper-intensity in the right lateral ventricle's inferior horn along the wall and pan-paranasal sinusitis.
  • Hyper-intensity in the left temporal lobe.
  • MR Spectroscopy: Decrease N-acetyl aspartate peak along with a marked elevated choline peak.
  • Non-enhancing cerebral edema and restricted diffusion in the right cerebral hemisphere with brain herniation.

Other Diagnostic Studies

• Other diagnostic studies for COVID-19-associated encephalitis include:
  • RT-PCR of SARS-CoV-2 RNA positive in CSF and nasopharyngeal swab,
  • Antibody IgM for acute infection, and
  • Antibody IgG for resolved or chronic infection.

Treatment

Medical Therapy

The mainstays of medical therapy for viral encephalitis are:

Symptomatic treatments:

• Anti-epileptic drugs like levetiracetam (50-60 mg/kg/day) is necessary for seizure management.
• Anti-inflammatory like pulse steroids (methylprednisolone 1,000 mg/day) are also helpful in this disease.
• Severe disease in these patients required intubation and mechanical ventilation.
• IVIG can be administrated in severe cases.
• Hydorxychloroquine and some antivirals were used in these patients but they did not resolve the condition.

Surgery

• Focal epilepsy having focal involvement of brain parenchyma can be treated with surgery.
• One of these patients undergone left anterior temporal lobectomy, which improved symptoms completely without any postoperative neurologic deficit.

Primary Prevention

• There are no established measures for the primary prevention of COVID-19 associated encephalitis.
• Effective measure for the primary prevention of COVID-19 associated encephalitis. include social distancing and avoidance behaviors.
• There are no available vaccines against COVID-19 associated encephalitis. Multiple trials are under process for vaccinations.
• To view primary prevention for COVID-19 click here.

Secondary Prevention

• There are no established measures for the secondary prevention of COVID-19 associated encephalitis.
• To view secondary prevention for COVID-19 click here.

References

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