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

• There is no established system for the classification of COVID-19-associated encephalopathy.
• On the basis of presentation, COVID-19-associated encephalopathy can be classified as acute.

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.
• 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.
• 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.
• This fact can be supported by the evidence that tocilizumab which is IL-6 antagonist is used in severe COVID-19 infections.

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.

Molecular Mimicry

• Post-infectious encephalomyelitis, an autoimmune demyelinating disease of the brain, can be triggered by the SARS‐CoV‐2 virus.

• 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.

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

• COVID-19-associated encephalopathy must be differentiated from other causes of headache, seizure and loss of consciousness.

• The symptoms of encephalopathy may overlap with the symptoms of other diseases:

• Encephalitis which is differentiated from encephalopathy by the presence of fever and other signs and symptoms of a viral infection.
• Meningitis which is differentiated from encephalopathy by the presence of neck stiffness, headache, meningeal signs, fever

• Postictal state which would be differentiated by the presence of seizures

• Intracranial lesions like tumors, masses, granulomas which are differentiated by the presence of focal neurologic signs and symptoms

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,

Other differentials

Toxic encephalopathy must also be differentiated from other diseases that cause personality changes, altered level of consciousness and hand tremors (asterixis). The differentials include the following:

Diseases	History and Symptoms			Physical Examination				Laboratory Findings
	Personality changes	Altered level of consciousness	Hand tremors (asterixis)	Slurred speech	Writing disturbances	Voice monotonous	Impaired memory	Elevated blood ammonia	Hyponatremia	hypokalemia
Hepatic encephalopathy	++	++	++	++	++	++	++	++	++	++
Alcohol intoxication	+	+	-/+	++	+	-	+	-	-/+	-/+
Alcohol withdrawal	+	+	-	++	+	-	+	-	-/+	-/+
Uremia	++	++	+	-/+	-/+	-/+		-	++	Hyperkalemia
Wernicke encephalopathy	+	+	-/+	+	+	+	++	-	-	-
Toxic encephalopathy from drugs	+	+	-/+	-/+	+	-/+	+	+	-/+	-/+
Altered intracranial pressure	+	-/+	-	-/+	-/+	-	-/+	-	-	-
Intoxication by chemical agents	-/+	-/+	-/+	-/+	-/+	-	-	-	-/+	-/+
Malnutrition	-/+	-	-	-	-/+	-	-/+	-	-/+	-/+
Hypoxic brain injury	-	-/+	-	-/+	-/+	-/+	-/+	-	-	-
Meningitis and encephalitis	-/+	-/+	-	-/+	+	-	-	-	-/+	-
Hypoglycemia	-/+	-/+	-	-/+	-/+	-	-	-	-/+	-/+

Epidemiology and Demographics

• The incidence of COVID-19-associated encephalopathy is approximately 93 patients worldwide.
• In July 2020, the incidence of COVID-19-associated encephalopathy is approximately 93 cases with 69% of the patients in intensive care unit.
• Patients of all age groups may develop COVID-19-associated encephalopathy.
• The incidence of COVID-19-associated encephalopathy increases with age; the median age at diagnosis is 54 years.
• There is no racial predilection to COVID-19-associated encephalopathy but more cases were present in African Americans.
• COVID-19-associated encephalopathy affects men and women equally.

Risk Factors

• There are no established risk factors for COVID-19-associated encephalopathy.

Screening

• There is insufficient evidence to recommend routine screening for COVID-19-associated encephalopathy.

Natural History, Complications, and Prognosis

• If left untreated, COVID-19-associated encephalopathy may cause long term neurological complications.
• To view Natural History for COVID-19, click here.
• Long term neurological complications can develop according to the involved brain parenchymal area.

Encephalopathy

Memory loss

Epilepsy

Personality changes

Hearing/vision loss

Coma/Death

Diagnosis

Diagnostic Study of Choice

• There are no established criteria for the diagnosis of COVID-19-associated encephalopathy.
• The diagnostic study of choice for COVID-19-associated encephalopathy is CSF analysis along with RT-PCR for SARS-CoV-2 positive on nasopharyngeal swab or on CSF.

Signs and symptoms

Common Symptoms

• These are the common presenting features:
  • Fever,
  • Shortness of breath
  • Headache,
  • Impaired consciousness
  • Cough
  • Fatigue

Less Common Symptoms

• There are few symptoms which are not present in all patients with COVID-19-associated encephalopathy:
  • Transient generalized seizure,
  • Absent brain reflexes,
  • Myoclonus,
  • Speech difficulty,
  • Choreiform movements,
  • Paralysis,
  • Dizziness,
  • Sedation,
  • Coma.

The 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	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	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	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.	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.	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.	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	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	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	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	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	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	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	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

• Patients with COVID-19-associated encephalopathy usually appear confused.
• Physical examination of patients with COVID-19-associated encephalopathy is usually remarkable for altered mentation, speech arrest, seizure, and neurological illness.
• The presence of seizures, confusion, and neurological illnesses on physical examination is highly suggestive of COVID-19-associated encephalopathy.

Laboratory Findings

• Laboratory findings consistent with the diagnosis of COVID-19-associated encephalopathy include CSF analysis, RT-PCR for SARS-CoV-2 on nasopharyngeal swab and on CSF.
• RT-PCR for SARS-CoV-2 on CSF is usually normal among patients with COVID-19-associated encephalopathy.
• Some patients with COVID-19-associated encephalopathy may have reduced activity of brain on EEG, whih is usually suggestive of progression.

Electrocardiogram

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

X-ray

• There are no x-ray findings associated with COVID-19-associated encephalopathy.

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

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:

• MR spectroscopy,
• CT angiogram and
• CT venogram may be helpful in the diagnosis of COVID-19-associated encephalopathy.

Other Diagnostic Studies

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

• Antibody IgM for acute infection, and
• Antibody IgG for resolved or chronic infection.
• RT-PCR of SARS-CoV-2 RNA positive in CSF or nasopharyngeal swab.

Treatment

Medical Therapy

The mainstay of medical therapy for viral encephalitis are:

Symptomatic Treatment

• There is no specific treatment for COVID-19-associated encephalopathy; the mainstay of therapy is supportive care.
• Supportive therapy for COVID-19-associated encephalopathy includes corticosteroids, anti-epileptic drugs, and treating underlying condition.
• COVID-19-associated encephalopathy can present in a medical emergency and requires prompt treatment.
• Severe disease require intubation and mechanical ventilation.
• Anti-inflammatory medicines like pulse steroids (1,000 mg/day) are helpful in this disease, some patients improved even with a very low dose (60mg/day).
• Anti-epileptic drugs like levetiracetam (50-60 mg/kg/day) is necessary for seizure management in patients with refractory seizures.
• Tocilizumab (8mg/kg/dose) is IL-6 anatgonist, that reduces cytokine storm syndrome responsible for neurological manifestations in a COVID-19 patient.
• To see treatment protocol to manage the underlying cause i.e., COVID-19, click here

Surgery

• Surgical intervention is not recommended for the management of COVID-19-associated encephalopathy.
• Focal epileptic involvement of brain parenchyma can be treated with resection of the area.

Primary Prevention

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

Secondary Prevention

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

References

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