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]

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 during this pandemic started in December in Wuhan, China and named as Wuhan coronavirus. 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 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

COVID-19-associated encephalitis must be differentiated from other diseases that cause fever, headache, and altered mental status with or without cough, such as:

Diseases	Symptoms				Physical Examination					Past medical history	Diagnostic tests			Other Findings
	Headache	↓LOC	Motor weakness	Abnormal sensory	Motor Deficit	Sensory deficit	Speech difficulty	Gait abnormality	Cranial nerves		CT /MRI	CSF Findings	Gold standard test
Meningitis	+	-	-	-	-	+	+	-	-	History of fever and malaise	-	↑ Leukocytes, ↑ Protein ↓ Glucose	CSF analysis	Fever, neck rigidity
Encephalitis	+	+	+/-	+/-	-	-	+	+/-	+	History of fever and malaise	+	↑ Leukocytes, ↓ Glucose	CSF PCR	Fever, seizures, focal neurologic abnormalities
Brain tumor	+	-	-	-	+	+	+	-	+	Weight loss, fatigue	+	Cancer cells	MRI	Cachexia, gradual progression of symptoms
Hemorrhagic stroke	+	+	+	+	+	+	+	+	-	Hypertension	+	-	CT scan without contrast	Neck stiffness
Subdural hemorrhage	+	+	+	+	+	-	-	-	+	Trauma, fall	+	Xanthochromia	CT scan without contrast	Confusion, dizziness, nausea, vomiting
Neurosyphilis	+	-	+	+	+	+	-	+	-	STIs	+	↑ Leukocytes and protein	CSF VDRL-specifc CSF FTA-Ab -sensitive	Blindness, confusion, depression, Abnormal gait
Complex or atypical migraine	+	-	+	+	-	-	+	-	-	Family history of migraine	-	-	Clinical assesment	Presence of aura, nausea, vomiting
Hypertensive encephalopathy	+	+	-	-	-	-	+	+	-	Hypertension	+	-	Clinical assesment	Delirium, cortical blindness, cerebral edema, seizure
Wernicke’s encephalopathy	-	+	-	-	-	+	+	+	+	History of alcohal abuse	-	-	Clinical assesment and lab findings	Ophthalmoplegia, confusion
CNS abscess	+	+	-	-	+	+	+	-	-	History of drug abuse, endocarditis, immunosupression	+	↑ leukocytes, ↓ glucose and ↑ protien	MRI is more sensitive and specific	High grade fever, fatigue,nausea, vomiting
Drug toxicity	-	+	-	+	+	+	-	+	-	-	-	-	Drug screen test	Lithium, Sedatives, phenytoin, carbamazepine
Conversion disorder	+	+	+	+	+	+	+	+		History of emotional stress	-	-	Diagnosis of exclusion	Tremors, blindness, difficulty swallowing
Metabolic disturbances (electrolyte imbalance, hypoglycemia)	-	+	+	+	+	+	-	-	+	-	-	Hypoglycemia, hypo and hypernatremia, hypo and hyperkalemia	Depends on the cause	Confusion, seizure, palpitations, sweating, dizziness, hypoglycemia
Multiple sclerosis exacerbation	-	-	+	+	-	+	+	+	+	History of relapses and remissions	+	↑ CSF IgG levels (monoclonal bands)	Clinical assesment and MRI	Blurry vision, urinary incontinence, fatigue
Seizure	+	+	-	-	+	+	-	-	+	Previous history of seizures	-	Mass lesion	Clinical assesment and EEG	Confusion, apathy, irritability,

• Meningitis
• Acute hypoglycemia
• Brain abscess
• Herpes simplex encephalitis
• Leptospirosis in humans
• Status epilepticus
• Systemic lupus erythematosus (SLE)
• Cat scratch disease
• Tuberculosis
• Sepsis
• Glial tumor

Epidemiology and Demographics

• There are only 3 cases reported till now.
• One in Japan, one in Turkey and the recent case was reported in Atlanta, Georgia, USA.
• MERS and SARS-CoV had neurologic manifestation like encephalitis at the time of outbreaks.

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.
• 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.

Natural History, Complications, and Prognosis

• 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.
• Three cases reported till now has specific clinical manifestations:

Patient No.	Early symptoms	Later presentation	GCS	Lab. Findings		Specific Tests	Imaging studies
				CBC	CSF		MRI/CT scan
1. 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.
2. 35-year-old woman from Turkey	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.
3. 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
  • Generalized seizure,
  • Hheadache,
  • Abnormal vital signs,
  • Nneck stiffness, or
  • 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 MRI brain.

• 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 may be helpful in the diagnosis of COVID-19 respiratory disease.

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound 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
  • Hyperintensity in the right lateral ventricle's inferior horn along the wall and pan-paranasal sinusitis.
  • Hyperintensity in the left temporal lobe.
  • MR Spectroscopy: Decrease N-acetyl aspartate peak along with a marked elevated choline peak.
  • Nonenhancing 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 is necessary for seizure management.
• Anti-inflammatory like steroids are also helpful in this disease.
• Severe disease in these patients required intubation and mechanical ventilation.
• 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 trial are under process for vaccinations.

Secondary Prevention

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

References

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