Neurovirulence of COVID-19- the Etiopathogenesis

Neurological manifestations of COVID-19 are unique in exhibiting additional pathophysiological aspects. While the exact pathogenesis is still not established fully, the primary target of COVID-19 is believed to be the respiratory epithelium. Neurological complications are considered secondary and may arise due to direct invasion, immune-mediated damage or secondary complications like hypoxia or shock.

1. Direct Neuroinvasion

   Neurotropism of SARS-CoV-2 has been well-established. It should be remembered that the brain becomes more susceptible to direct invasion when the blood–brain barrier is disrupted due to an uncontrolled systemic inflammatory response. The routes by which it enters the central nervous system (CNS) are as follows:3 4

   • Olfactory epithelium: Retrograde entry to CNS may occur through cribriform plate

   • Cellular infection and invasions: The infected macrophages act as a viral reservoir and spread to the brain. Both hematogenous as well as lymphatic routes have been described

   • Endothelial cells of the blood–brain barrier are known to express SARS-CoV receptors–the angiotensin-converting enzyme-2(ACE-2) and CD209L. ACE-2 is also expressed in glial cells, cerebral blood vessels, spinal cord, and skeletal muscles.5

   • Transsynaptic route: Transmission may also occur through the peripheral nerves

2. Immune-mediated Injury–An aberrant immune-mediated response may be incited, giving rise to many parainfectious/postinfectious neurological complications.

   The virus effectively evades the host’s immune response, while the uncontrolled systemic inflammatory response/cytokine storm is a major cause of mortality in COVID-19.6

3. Systemic Involvement: Severe respiratory distress causes systemic hypoxia. Hypercarbia and vasodilatation are indirect consequences, worsening the anerobic metabolism and causing neuronal cell death. SARS-Cov-2 can lead to multiorgan failure and systemic involvement, causing uremic encephalopathy or hypoxic encephalopathy. Disseminated intravascular coagulopathy (DIC)-mediated intracranial bleed or thrombosis is another major cause of mortality in these patients.

CNS Manifestations

CNS manifestations may arise due to focal or diffuse involvement of meninges, parenchymal structures, spinal cord and involvement of cerebral vasculature. CNS involvement is rather the most common neurological presentation. Symptomology may vary, depending upon the anatomical substrate involvement.

Headache and dizziness are the most commonly described symptoms of neurological involvement. Incidence of headache among various available reports ranges from 8 to 13.6%.2 11 Meningeal irritation, meningeal inflammation, and increased intracranial pressure have been postulated as possible mechanisms causing headache. Worsening of an underlying primary headache syndrome, new onset personnel protective equipment (PPE)-related headache, stress, and tension type headaches can be other causes of headache. A thorough clinical history and examination should be done in all patients for an early recognition of the ominous causes of headache.

Meningeal involvement causing meningitis and meningoencephalitis have also been reported in observational studies, case series and case reports.10 Seizure and altered sensorium are common presentations. SARS-CoV-2 RNA was detected in cerebrospinal fluid (CSF) of a few patients of COVID-19 mediated meningoencephalitis. Viral clearance in CSF may precede the neurological involvement and therefore the detection may be delayed.12 13

Acute necrotizing hemorrhagic encephalitis related to intracranial cytokine storm may occur and has been related to a worse prognosis.14 Dogan et al also considered autoimmune encephalitis in their six patients, based upon their clinical symptomatology and response to plasmapheresis.15 Another case of anti-NMDA-R antibody positivity was reported by Panareillo et al. These findings highlight the importance of activation of an indirect pathway involving the immune system in SARS-CoV-2 infection.16

Rhombencephalitis causing ataxia, leukoencephalopathy with diffuse corticospinal involvement, delirium, executive disturbances, behavioral disturbances, sleep disorders, dementia, and movement disorders are other syndromes associated with COVID-19.17

No conclusive laboratory (including CSF analysis) or neuro–radiological investigations have been described. In a recently published series by Franke et al, varied neurological symptoms like myoclonus, oculomotor disturbances, delirium, dystonia, stroke, seizures, etc., were noted in 11 severely ill COVID-19 patients. They also noted increased levels of neurofilament light chain in the CSF of these patients. All patients in their cohort had antineuronal autoantibodies in serum or CSF.18

In a multi-institutional French cohort, authors reported various radiological abnormalities, including medial temporal lobe hyperintensities, nonconfluent multifocal white matter hyperintense signal intensities, and extensive, isolated white matter hemorrhages in nonstroke patients of COVID-19.19

Vascular Involvement

Of particular interest is the cerebrovascular involvement with COVID-19. Incidence of strokes reported in European and Chinese hospital COVID-19 registries is up to 2.5 to 6%. Mao et al in his cohort noted strokes in 6 (2.8%) out of 214 hospitalized COVID-19 patients (5 ischemic and 1 hemorrhagic stroke). These were large vessel strokes and were seen in association with severe COVID-19 illness. Cortical venous thrombosis has also been reported in small series.20 In the series by Oxley et al, large vessel strokes were noted in four men and one woman. In their cohort, all reported strokes were in the middle cerebral artery territory. No typical symptoms of COVID-19 infection were present at the outset in 3 of the 5 patients. D dimer was raised in all but one.

The proinflammatory and prothrombotic mechanisms causing stroke in COVID-19 have aroused a great deal of interest. Endothelial dysfunction, DIC and thrombotic microangiopathy associated with thrombocytopenia, elevated D-dimer and prolonged prothrombin time have been hypothesized as precursors. With profoundly elevated D-dimer levels, COVID-19 has been considered as a highly prothrombotic state. Combined with factors like immobilization, hypoxia, inflammation and stress, accelerated thrombosis has been seen to occur in severely ill/ICU-bound patients. Role of antiphospholipid antibodies causing multifocal infarction has also been suggested by few. Prevalence of lupus anticoagulant in as high as 91% patients has been reported. Autopsy studies have suggested associated venous thrombosis in lower limbs, lungs and pulmonary circulation. Endothelitis in kidney and small intestine vessels has also been reported. Extrapolating these findings to cerebral vasculature may explain the etiopathogenesis of ischemic and hemorrhagic arterial and venous strokes.21 22 23

Neurological Complications Due to Secondary/Systemic Involvement

Hypoxia, hypotension or multiorgan failure related encephalopathy needs due consideration as it is a major cause of mortality. Uremia and acute respiratory distress syndrome (ARDS) may themselves be associated with many metabolic alterations. Similarly, critical illness associated neuropathy and myopathy also deserve mention, keeping in mind prolonged ventilatory support, immobilization and nutrition deprivation in these patients.

Depression and COVID-19

COVID-19 has negatively affected society’s mental health to a large extent. Uncertain disease course and prognosis, persistent shortage of resources for diagnosis and personnel protective gears, and limited available treatment options have been disturbing both for the care providers as well as patients. Mass home confinement, excessive media exposure, limited access to public/social gatherings and resultant financial losses during the pandemic have negatively contributed toward mental health. In a cross-sectional study involving 81 participants, depression was noted in 23.6% patients and 45.1% patients reported anxiety. Similar findings were noted in other studies.26 Healthcare workers are in particular at higher risk. In a multinational, multicenter study of 906 healthcare workers, Chew et al noted an extremely high-incidence of stress, anxiety, headache and lethargy.27

Neurological Complications Associated with Treatment of COVID-19

Chloroquine and hydroxychloroquine have been hyped with respect to prophylaxis and treatment of mild-to-moderate disease. The potential spectrum of neuropsychiatric manifestations includes agitation, sleep disturbances, mania, hallucinations, paranoia, depression, catatonia, psychosis, and suicidal ideations. De-novo headaches may occur in nearly 2.8% of patients. Other minor side effects are dizziness, visual field defects, paresthesia, and insomnia. Toxicity and overdose may cause seizures, syncope, hypokalemia, and cardiovascular collapse.37

Neurological Implications of the Personnel Protective Equipment (PPE)

In a cross-sectional study involving 158 frontline HCWs, it was noted that PPE was associated with de-novo headache and also exacerbates preexisting headache disorders.38 Psychopathological implications of facemask was studied in another nationwide online survey which suggested that use of facemask could provide a sense of false security due to an increased level of self-perceived protection notion. This may adversely undermine other infection control measures39

Neurologist’s Perspective of Lockdown in COVID-19 Crisis

A general view of the lockdown-related issues can be extrapolated from a report published by the neurological alliance of Ireland which discussed the neurological impacts of restrictions imposed during the COVID-19 pandemic. Due to restrictions of physical visit to treating clinicians, limited access for healthcare providers, and withdrawal of home care by providers, 26% patients had difficulty in accessing neurological care and had reported subjective worsening.