Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports

Abstract

Coronavirus disease 2019 (COVID-19) is a highly infectious pandemic caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It frequently presents with unremitting fever, hypoxemic respiratory failure, and systemic complications (e.g., gastrointestinal, renal, cardiac, and hepatic involvement), encephalopathy, and thrombotic events. The respiratory symptoms are similar to those accompanying other genetically related beta-coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East Respiratory Syndrome CoV (MERS-CoV). Hypoxemic respiratory symptoms can rapidly progress to Acute Respiratory Distress Syndrome (ARDS) and secondary hemophagocytic lymphohistiocytosis, leading to multi-organ system dysfunction syndrome. Severe cases are typically associated with aberrant and excessive inflammatory responses. These include significant systemic upregulation of cytokines, chemokines, and pro-inflammatory mediators, associated with increased acute-phase proteins (APPs) production such as hyperferritinemia and elevated C-reactive protein (CRP), as well as lymphocytopenia. The neurological complications of SARS-CoV-2 infection are high among those with severe and critical illnesses. This review highlights the central nervous system (CNS) complications associated with COVID-19 attributed to primary CNS involvement due to rare direct neuroinvasion and more commonly secondary CNS sequelae due to exuberant systemic innate-mediated hyper-inflammation. It also provides a theoretical integration of clinical and experimental data to elucidate the pathogenesis of these disorders. Specifically, how systemic hyper-inflammation provoked by maladaptive innate immunity may impair neurovascular endothelial function, disrupt BBB, activate CNS innate immune signaling pathways, and induce para-infectious autoimmunity, potentially contributing to the CNS complications associated with SARS-CoV-2 infection. Direct viral infection of the brain parenchyma causing encephalitis, possibly with concurrent neurovascular endotheliitis and CNS renin angiotensin system (RAS) dysregulation, is also reviewed.

Keywords: ACE2; Blood-brain barrier; COVID-19; Cytokines; Encephalitis; Encephalopathy; Endothelial cells; Microglia; SARS-CoV-2; Stroke.

Fig. 1

Integrative concepts of the pathophysiology of COVID-19-related central nervous system complications. This figure integrates the clinical and experimental data linking maladaptive innate immunity-related systemic hyper-inflammation (provoked by the binding of SARS-CoV-2 spike protein (S1) to ACE2 expressing cells in the lung and intestine) to neurovascular endothelial dysfunction, BBB breakdown, and CNS innate immune activation, potentially contributing to SARS-CoV-2-related CNS complications. It demonstrates subsequent endothelial injury in the peripheral vasculature due to direct viral endothelial infection causing endotheliitis and potential endothelial ACE2 downregulation: similar mechanisms may also involve neurovascular unit. It also depicts the proposed role of infiltrating protective immune cells, migrating from the bloodstream into the CNS parenchyma through disrupted BBB, in limiting CNS injury and promoting viral clearance. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme II; AT type 1 receptor, angiotensin type 1 receptor; BBB, blood-brain barrier; CNS, central nervous system; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; IL, interleukin; MAP, microglial activation and proliferation; MMPs, matrix metalloproteinases; NK, natural killer; PRRs, pattern recognition receptors, SARS CoV-2 (S1), severe acute respiratory syndrome coronavirus 2 (spike glycoprotein1), receptor-binding subunit; TNFα, tumor necrosis factor-α

Fig. 2

Seizure and malignant EEG pattern associated with rapid rise in serum CRP. A 71-year-old SARS-CoV-2 positive female presented with altered mental status necessitating intubation. While on sedation, she was witnessed to have a convulsive seizure, with CRP elevating from 16.64 to 30.28 mg/dl. Despite continued sedation with Diprivan and treatment with anti-seizure medications, EEG showed prolonged runs of 2 Hz GPDs concerning for refractory non-convulsive status epilepticus associated with a peak CRP level reaching 52.59 mg/dl. a Serum CRP trend graph. b Diffusion-weighted magnetic resonance (DW MR) imaging showing numerous punctate foci of diffusion restriction, with corresponding reduced signal intensity on attenuation diffusion coefficient (ADC), in the cerebral subcortical white matter bilaterally, more in a watershed distribution. c EEG day 2 showing persistent non-convulsive status epilepticus (generalized periodic discharges (GPDs))

Fig. 3

Para-infectious autoimmunity. a Acute necrotizing encephalopathy (ANE). A 23-year-old SARS-CoV-2-positive female presented mainly with encephalopathy progressed to catatonia. C-reactive protein (CRP) was 72.3 mg/dl. CSF analysis was completely normal. Coronal (1) and axial (2) fluid-attenuated inversion recovery (FLAIR)/T2-weighted (T2W) MR images reveal signal hyperintensities of the ventromedial thalami and hippocampi. DWI (3) and ADC (4) images show slightly increased signal intensity on DWI but without low signal intensity on ADC to suggest diffusion restriction. Bilateral thalamic involvement is highly characteristic for ANE. Her neurological condition improved substantially following immune therapies that included intravenous immunoglobulin, intravenous pulse methylprednisolone, and rituximab. b Acute disseminated encephalomyelitis (ADEM). A 56-year-old SARS-COV-2 positive female admitted for diarrhea and hypoxemic respiratory symptoms that progressed to ARDS necessitating intubation. Notable laboratory findings were CRP of 31 mg/dl (reference range 0.00–0.40), ferritin of 799 ng/ml (reference range 15–150 ng/ml), D-Dimer of 362 ng/ml (reference range < 230 ng/ml), and IL-6 of 42 (reference range less < 5 pg/ml). Neurological examination was notable for severe encephalopathy and severe quadriplegia. Axial FlAIR MR images (1, 2, 3) demonstrate multiple periventricular white matter hyperintensity lesions, without corpus callosal involvement. There is no enhancement or restricted diffusion on DWI (4, 5, 6). These findings are consistent with acute disseminated encephalomyelitis. Patient received a 5-day course of intravenous pulse methylprednisolone (1000 mg/day) and tocilizumab 750 mg (8 mg/kg) intravenously. She improved substantially to the point of becoming fully awake and alert with 4/5 power of upper extremities and 3–4/5 power of lower extremities. Patient was discharged to an acute rehabilitation facility and then went home showing a steady neurological improvement

Fig. 4

COVID-19 related stroke and posterior reversible encephalopathy syndrome. a Ischemic and hemorrhagic infarcts. A 73-year-old female presented with respiratory difficulty related to COVID-19 necessitating intubation. Following extubation and cessation of sedation, she remained persistently somnolent and was noted to have weakness of all extremities. Initial NIHSS was 12. Past medical history was notable for coronary artery disease, congestive heart failure, hypertension, and diabetes mellitus. Laboratory findings were notable for slightly elevated CRP (1.2 mg/dl) and significant elevation of ferritin (754 ng/ml) and D-Dimer (4184 ng/ml). Axial FlAIR MR images (1, 2, 3) demonstrate multifocal areas of signal abnormalities involving both cerebellar hemispheres, right occipital lobe, and right frontal lobe, with a hemorrhagic component (mostly involving right frontal region). Smaller foci of signal abnormality were present in the parietal cortices and centrum semiovale. Axial DWI (4, 5, 6) display multifocal areas of diffusion restriction consistent with acute ischemia. Hypercoagulopathy is the likely etiology of strokes. The patient had been on clopidogrel and low dose enoxaparin (DVT prophylaxis) before her stroke. Her neurological condition improved substantially with only minimal residual left hemiparesis and mild ataxia were noted at the first follow-up visit, which was several weeks after hospital discharge. b Posterior reversible encephalopathy syndrome (PRES). A 43-year-old SARS-CoV-2-positive female presented with respiratory distress that progressed rapidly to ARDS. Serological findings were notable for elevation of CRP (32 mg/dl), ferritin (259 ng/ml), and D-Dimer (7643 ng/ml). Post-extubation, she remained lethargic despite discontinuation of sedatives. She was slightly hypotensive to normotensive. The neurological exam showed lethargy, dysconjugate gaze, and triplegia. CSF analysis was entirely normal. Oligoclonal bands were absent. IgG index 0.8 (normal < 0.7). Notably, the neurological recovery was slow and concurrent with the return of serum inflammatory markers to normal levels. T2W MR images (1, 2) demonstrate bilateral parietal, and to a lesser extent frontal lobe, signal hyperintensities consistent with vasogenic edema. There is no corresponding high signal intensity on DWI (3, 4) or low signal intensity on ADC (5, 6) to suggest diffusion restriction. The findings are suggestive of PRES associated with high circulating markers of inflammation and coagulation pathways activation. The patient exhibited a slow, but steady, recovery concurrent with the reduction of serum levels of the inflammatory markers. This recovery was further enhanced by a 3-day course of intravenous pulse methylprednisolone (1000 mg/day). She was discharged home with only mild cognitive and motor impairment

Fig. 5

Strokes and concurrent subacute inflammatory necrotizing response. An 84-year-old SARS-CoV-2-positive female presented solely with rapidly progressive encephalopathy and neurological decline associated with mild left sided hemiparesis and left sided-visuospatial neglect. There were no concurrent respiratory or any other systemic symptoms. Serological findings were remarkable for CRP of 5.89 mg/dl, ferritin of 383 ng/dl, and D-Dimer of 852 ng/dl, and positive anticardiolipin IgM antibodies of 32.CSF analysis revealed elevated protein (153 mg/dl), normal glucose, and a cell count of three nucleated cells. Computed tomography (CT) scan (1, 2) shows prominent vasogenic edema nearly involving the entire right temporal lobe (green arrow), watershed subacute-chronic ischemic infarction of the right anterior frontal (red arrow), and old cystic encephalomalacia of the left parietal (blue arrow). 3D CT angiogram (3) shows normal flow through the right middle cerebral artery without evidence of large vessel occlusion or high grade stenosis. Axial T1-(4) and T1-weighted post-gadolinium [axial (5) and sagittal (6)] MR images show diffuse gyral cortical enhancement with subcortical areas of necrosis involving right temporal lobe (green arrow). Axial FLAIR (7) and axial T2W (8) MR images reveal signal hyperintensities with gyral swelling nearly involving the entire right temporal lobe and insula (green arrow) associated with petechial hemorrhage, best seen on the gradient echo image (9). In addition, there are subacute-chronic infarct of the right anterior lateral frontal lobe (red arrow) and a wedge-shaped old cystic encephalomalacia of the left parietal lobe (blue arrow). Following treatment with tocilizumab 560 mg (4 mg/kg), the patient exhibited significant improvement of the mental status and left hemiparesis and was subsequently discharged home. Hypercoagulopathy is the likely etiology of the right frontal and left parietal strokes. The appearance of the concurrent right temporal lobe and insula abnormalities is highly suggestive of an independent subacute inflammatory-necrotizing, rather than ischemic, process. This is supported by the findings of completely patent right middle cerebral artery, diffuse gyral swelling and enhancement with concurrent prominent subcortical vasogenic edema and necrosis, and significantly elevated CSF protein. Although the precise mechanisms underlying vasogenic edema and necrosis remain unclear, we suggest that localized hyper-inflammation provoked by exuberant innate immune response (CNS cytokine response) might be pathogenetically relevant. Direct viral neuroinvasion and involvement of the neurovascular endothelial cells were subsequently excluded by the brain biopsy from the right temporal necrotizing lesion

Fig. 6

Inflammatory vasculopathy. A 45-year-old SARS-CoV-2-positive man presented chiefly with encephalopathy and aphasia, without concurrent respiratory or any other systemic symptoms. Serum levels of inflammatory makers (CRP; 152.4 mg/dl, ESR; 91 mm/h) and D-Dimer (464 mg/dl) were elevated. Anticardiolipin IgM antibodies were 52.3 (normal range 0–12.5). Past medical history is notable for diabetes and hypertension. Axial FLAIR (1, 4) MR images show gyriform signal hyperintensity of the left paramedian frontal lobe and genu of the corpus callosum with corresponding high signal intensity on DWI (2, 5) and low signal intensity on ADC (3, 6) compatible with an acute ischemia. The maximum intensity projection (MIP) of CT angiogram demonstrates irregular areas of narrowing of the left A1 and M1 segments. These findings are consistent with inflammatory vasculopathy, likely related to the interplay among systemic inflammation, immune dysregulation, and anticardiolipin antibodies. Direct infection of the endothelial cells and its contribution to the vascular irregularity of the affected vascular segments cannot be excluded. The patient received tocilizumab 8 mg/kg intravenously and a 5-day course of intravenous pulse methylprednisolone (1000 mg/day). He was discharged to a subacute rehabilitation facility with mild improvement of aphasia and cognitive deficit