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Infectious and immune-mediated central nervous system disease in 48 COVID-19 patients

Objectives To summarise and discuss current knowledge about SARS-CoV-2-associated infectious/immune-mediated central nervous system (CNS)-disease. Method Literature review. Results Altogether 28 articles were found, which reported 48 patients with SARS-CoV-2-associated infectious/immune-mediated CNS-disease. Age ranged from 22 to 79y. There was male preponderance. There were 14 patients with infectious CNS-disease (meningitis (n = 1), encephalitis (n = 5), meningo-encephalitis (n = 5), myelitis (n = 3)), and 34 patients with parainfectious CNS-disease (encephalopathy (n = 18), autoimmune encephalitis (n = 11), acute, disseminated, encephalo-myelitis (n = 3), acute, haemorrhagic, necrotizing encephalopathy (n = 2)). The cerebrospinal fluid (CSF) was tested for SARS-CoV-2 in 40 patients and was positive for the virus in 4 patients with infectious CNS-disease but was negative for the virus in all patients with parainfectious CNS-disease. Immune-modulating treatment may be more effective than virostatics/antibiotics for SARS-CoV-2-associated infectious/parainfectious, non-vascular, non-hypoxic CNS-disease. In patients with autoimmune encephalitis plasmapheresis may be beneficial. Twenty-two patients recovered, 2 did not, and 6 patients died. Conclusions SARS-CoV-2 can cause infectious/immune-mediated CNS-disease. The CSF is positive for virus-RNA in only few patients with infectious CNS-disease but negative for virus-RNA in immune-mediated CNS-disease, suggesting an immune-mediated pathophysiological mechanism. The outcome of SARS-CoV-2-associated infectious/immune-mediated CNS-disease is favourable in the majority of cases but can be fatal in single cases.

This review shows that CNS disease in COVID-19 only rarely results from infection with SARS-CoV-2 but, more commonly, from the immune response to the virus. This is why immunosuppressive and immune-modulating treatment (steroids, immunoglobulins, plasma exchange), have a strong role in the management of immune-mediated CNS-disease in COVID-19 patients. The virus was found in the CSF in only four patients with infectious CNSdisease. The reason for the rare occurrence of the virus in the CSF remains speculative but possibly the virus is only transiently present in the CSF or invades neurons or glial cells immediately on arrival in the CNS. An argument in favour of the immediate invasion of neurons is that the virus has been found in neurons and endothelial cells of the frontal lobe [31]. There are even speculations that the CNS serves as a reservoir for the virus in the absence of clinical manifestations [32]. These considerations imply that virus-negative infectious CNS-disease is in fact immune-mediated. Pleocytosis does not exclude an autoimmune pathogenesis.
Arguments in favour of an immune-mediated pathogenesis of virus-negative/positive CNS-disease in COVID-19 are that several patients responded favourably to steroids, immunoglobulins, or  plasma exchange [20] and that CNS inflammatory proteins are increased in COVID-19 encephalopathy [20]. This corresponds with the general hyperinflammatory state (cytokine storm, dysregulated immune response) with massive release of cytokines and chemokines that impair blood-brain barrier permeability [20] and activate neuro-inflammatory cascades [33]. Cytokines elevated in the CSF of a 78yo female with acute encephalopathy included IL-17A, IL6, IL-8; OP-10, and MCP-1 [34]. In two cases with SARS-CoV-2 associated encephalitis cytokines elevated in the CSF were IL-1b, IL-6, IFN-1a, and IFB-1b [35]. Chemokines have not be determined in the CSF is far. Chemokines elevated in the serum include CCL2/ MCP-1, CCL3/MIP-1a, CXCL10/IP-10, CCL5/RANTES, and CCL20/ MIP-3a [36]. Furthermore, SARS-CoV-2 infection is more severe if the number of CD8 T-killer cells is low. Elevation of neutrophils reduces CD8 T-killer cells [37]. The immunologic pathogenesis is further supported by several reports presenting only non-specific CNS abnormalities in COVID-19 patients, such as impaired consciousness, confusion, disorientation, dizziness, delirium, hallucinations, psychosis, headache, ataxia, or seizures [38]. The route via which SARS-CoV-2 enters the CNS in some cases is unknown. Generally, the virus could enter the brain via retrograde, axonal migration in certain cranial nerves, via hematogenic spread, or encapsulated in immune cells via the blood brain barrier [39]. Recently, it has been proposed that the furin-like cleavage site of the virus could be an important determinant for its neurotropism [39]. S-protein cleavage by furin or furin-like proteases not only plays a key role in the invasion and virulence of SARS-CoV and Middle East Respiratory Syndrome (MERS) but also determines the host specificity and tissue tropism of these coronaviruses [39]. However, it is currently unknown if the furin-like cleavage site on the spike-protein of SARS-CoV-2 has a specific role in its invasion of the CNS [39]. Overall, the majority of scientists believes, that there is currently no pathological evidence to support a viral infection in nerve tissue and that there is need to study brain functions in SARS-CoV-2 infected patients with neurological involvement [39].
In conclusion, SARS-CoV-2 rarely causes infectious or immunemediated CNS-disease, such as meningitis/encephalitis, ventriculitis/endothelialitis, myelitis, encephalopathy, AIE, AHNE, or ADEM. Virus-RNA is absent in SARS-CoV-2-associated immune-mediated CNS-disease and present only in single cases with infectious CNS-disease. Treatment of infectious/immunemediated CNS disease in COVID-19 relies on virostatics, antibiotics, antiepileptics, steroids, immunoglobulins, plasma exchange, and mechanical ventilation. The outcome of infectious and immunemediated CNS-disease in COVID-19 patients is usually fair but can be fatal in some cases.

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