COVID-19-associated encephalitis

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[lEditor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Wajeeha Aiman, M.D.[2], Fahimeh Shojaei, M.D.

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 meningitis, stroke, tumor, brain hemorrhage, neurosyphilis, migraine, hypertensive encephalopathy, wernicke’s encephalopathy, abscess, drug toxicity, and seizure.

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
Encephalitis	+	+	+/-	+/-	-	-	+	+/-	+	History of fever and malaise	+	↑ Leukocytes, ↓ Glucose	CSF PCR	Fever, seizures, focal neurologic abnormalities
Meningitis	+	-	-	-	-	+	+	-	-	History of fever and malaise	-	↑ Leukocytes, ↑ Protein ↓ Glucose	CSF analysis	Fever, neck rigidity
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,

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.

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.

Common Symptoms

• • Cough,
  • Shortness of breath
  • Headache,
  • Fever
  • Fatigue

Less Common Symptoms

• • Impaired consciousness,
  • Transient generalized seizure
  • Dizziness,
  • Paralysis
  • Sedation
  • Coma

• Clinical manifestation of the 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.
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.
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
  • Headache
  • Abnormal vital signs
  • Neck stiffness
  • 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 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:
  • 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 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 trials 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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