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.

• 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.^[1][2]

• The association between COVID-19 and encephalitis was made during this pandemic started in December in Wuhan, China and named as Wuhan coronavirus.^[3]
• 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.^[4]
• 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.

• 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.

• The exact pathogenesis of COVID-19 encephalitis is not fully understood.^[5]

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

• 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.

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

• To read more about this virus, click here.

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

• There are approximately 50 cases of COVID-19-associated encephalitis reported in the first six months of the pandemic.^[6][7]
• 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.

• Common risk factors in the development of COVID-19-associated encephalitis may be occupational, environmental, and genetic.^[8]
• 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.

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

• 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:

• 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.

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

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

• 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:

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

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

• 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.

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

• 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.

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

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

• 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 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.

The mainstays of medical therapy for viral encephalitis are:^{[10][13][2][14]}

• 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.^[15][16]
• Hydorxychloroquine and some antivirals were used in these patients but they did not resolve the condition.

• Focal epilepsy having focal involvement of brain parenchyma can be treated with surgery^[10].
• One of these patients undergone left anterior temporal lobectomy, which improved symptoms completely without any postoperative neurologic deficit^[10].

• 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.

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

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