Modelling the Anatomic Distribution of Neurologic Events in Patients with COVID-19: A Systematic
Review of MRI Findings

Neurologic Events in White and Gray Matter

White matter events were identified most frequently in the corticospinal tract and corpus callosum. The corticospinal tract is a major white matter pathway connecting critical subcortical brain regions such as the basal ganglia and thalamus and, thus, facilitates information related to voluntary motor control. As a result, diffuse aberrations in the corticospinal tract are associated with motor symptoms such as tendon reflexes, ankle clonus, and bilateral extensor plantar reflexes, which have been commonly reported in patients with COVID-19.²¹ Similarly, the corpus callosum plays an important role in interhemispheric communication, which can result in a disconnection syndrome and broad neurocognitive deficits.²²

In gray matter regions, events were identified most frequently in the temporal and precentral gyrus as well as the bilateral thalamus. Alterations in thalamocortical connectivity can disrupt the regulation of consciousness and arousal.²³ Thus, acute events in these regions may explain symptoms such as confusion, disorientation, agitation, and loss of consciousness.^10,24 Despite their acute manifestation, the accumulation of neurologic events in subcortical structures and consequent disruption to distal cortical regions can increase susceptibility to cognitive impairment and decline, which have ramifications for long-term cognitive prognosis.^25,26

Infiltration and Spread Mechanism: Olfactory Pathway

Patients with neurologic symptoms also presented with anosmia, encephalopathy, seizures, and changes in vision including cortical blindness and visual confabulation.^27⇓-29 Alterations in olfaction may therefore have a neurologic basis, particularly in light of the identified pathology implicating the olfactory bulb in clinical imaging, including the presence of microbleeds among these patients. It is plausible that these symptoms relate closely to the mode of infiltration of SARS-CoV-2, with a potential mechanism being direct injury to the nervous system via angiotensin-converting enzyme 2 receptor expression on nerve cells, including the olfactory bulb.

Given the potential for SARS-CoV-2 neurotropism, neuropathology in the piriform cortex could be caused initially by the introduction of a virus through a direct axonal connection with the olfactory bulb. Although we were not able to mathematically model the piriform cortex specifically within the Desikan-Killiany brain atlas, we found only 7 patients from 3 studies who presented with small lesions within this cortex (olfactory bulb). Indeed, some have found intranasal infection of other coronaviruses such as SARS-CoV in the respiratory tract, which were subsequently neuroinvasive.³⁰ However, this mechanism remains to be established in the newly discovered SARS-CoV-2.

Infiltration and Spread Mechanism: Axonal Transport

An important question arises from our finding of the cerebellum and putamen as the seeds of spread—that is, how likely is it that these are indeed epicenters? Herein, note that NDMs are high-level generative models and only model the macroscopic consequences of the pathology in gray matter regions, and that the NDM does not require that the seed region itself presents with the highest number of pathologic events. Indeed, a neurobiologic explanation for the identification of these seed regions is beyond the scope of this article. Therefore, the mechanism underpinning the potential spread from these sites and subsequent distribution of SARS-CoV-2 throughout the brain remains to be thoroughly examined. However, while the cerebellum and putamen may serve as epicenters, SARS-CoV-2 may then travel to cortical sites such as the precentral gyrus via retrograde transsynaptic transmission through the corticospinal tract by hijacking axonal transport mechanisms.²² While in transit, direct neuronal or endothelial cell disruption may exacerbate the systemic pathophysiology, facilitating cerebrovascular complications and mixed type I/II respiratory failure.^3,22

Indeed, the first site of infection of other SARS-CoV viruses is the epithelial cells of the respiratory tract, where they bind to angiotensin-converting enzyme 2 receptors;³¹ however, angiotensin-converting enzyme 2 is also expressed on nerve cells. Therefore, coronaviruses may easily be transported to infect the endothelial cells of the blood-brain barrier.³¹ However, SARS-CoV-2 has rarely been isolated from CSF samples, precluding the characterization of its neurotropism and direct role in neurologic event pathogenesis.

Neuroinflammation and Cytokine Storm

Other proposed pathologic mechanisms may explain the distribution of neurologic events, including neuroinflammatory responses and cytokine- and hypoxia-induced injury.³ Emerging evidence is characterizing COVID-19 as a vascular disease, a hyperinflammatory response with an ensuing cytokine storm and coagulopathy that may synergistically contribute to neurologic event pathogenesis.^2,3 COVID-19-associated coagulopathy occurs proportional to disease severity and leads to treatment-resistant thrombotic and hemorrhagic events, characterized by D-dimer elevation with prothrombin prolongation and thrombocytopenia.

Furthermore, cytokine- and hypoxia-induced injury to the corpus callosum, particularly the splenium, has been reported in critical illness, including acute respiratory distress syndrome and high-altitude cerebral edema, potentially contributing to a vulnerability in COVID-19.¹⁷ Hypoxia directly induces chemical and hydrostatic endothelial cell disruption, promoting vascular permeability and hence contributing to neurologic event pathogenesis.³² Relative to the cortex, the thalamus, basal ganglia, and deep white matter are poorly perfused due to their watershed end-arterial vascular architecture, which could exacerbate their baseline hypoxic vulnerability and ultimately promote subcortical neurologic events. While the pathogenesis of white matter hyperintensities remains under debate, roles for hypoxia, immune activation, endothelial cell dysfunction, and altered metabolism have been posited, not dissimilar to the neuropathologic associations of COVID-19.^15,18,33

Clinical Relevance

In addition to their acute manifestations, the accumulation of neurologic events in subcortical structures and consequent disruption of distal cortical regions may lead to microstructural injury, independently contributing to cognitive impairment and dementia—a clinically impacting patient morbidity.^11,34 Microbleeds and white matter hyperintensities also signify a hemorrhage-prone brain, which is more susceptible to larger neurologic events such as ischemic stroke and intracranial hemorrhage, whereby patients demonstrate worse deterioration from premorbid functioning and increased mortality.¹⁷ Indeed, in patients with COVID-19, the presence of small neurologic events has been associated with increased disease severity, the length of hospital admission, mortality, and worse functional status on discharge.³⁵ Given the established adverse effects of small neurologic events and these early findings, the potential long-term cognitive and cerebrovascular impact on patients with COVID-19 may become more apparent with time. If found, careful consideration should be given to the prescription of anticoagulation, given that these neurologic events suggest a propensity for further hemorrhage.

Limitations

This review has several important limitations. First, we translated neurologic events into a standard MR imaging atlas space using a partly qualitative method, whereby these pathologies were localized using the radiologic description of the location or MR images when available. While this method may lack specificity, we used multiple neuroimaging and medical experts and included only data with specific spatial information or MR images. Thus, the partly qualitative nature of the translation should be considered with caution while interpreting our findings. Furthermore, the white matter tracts used to visualize the summary of the white matter findings are only coarse grain reorientations. Given that few tracts (eg, corpus callosum) completely match the labels used in the atlas, we localized events on the basis of the descriptions and available MR images regarding approximate corresponding tracts. Second, most of the included articles were cross-sectional case studies and hence cannot directly attribute the observed neuropathology to SARS-CoV-2.

The question remains as to whether neurologic events are the direct consequence of viral infection/sequalae or instead indicate an underlying propensity for neurologic events in these patients.³⁶ To answer this question, studies must use large samples in which a specific etiology can be isolated in a case-control, longitudinal design.³⁶ These etiologies must be separated into those of unrelated vascular origin and those that may be a direct consequence of viral infection. Therein, an additional challenge ensues: to determine whether there are, indeed, overlapping or isolated pathologies in patients with COVID-19. This question could be approached by including patients with previous MR images, in whom existing pathology can essentially be modelled out. We acknowledge that some of the neurologic events included in our study may be explained by the healthy ageing process, whereby white matter hyperintensities are correlated with age.¹⁴ Furthermore, IIT tractography data were used for visualization of abnormalities in the white matter. Because only a few labels (eg, corpus callosum) completely match the names of the tracts, the locations are only approximate. Hence, the findings regarding white matter changes, for example, white matter hyperintensities in the centrum semiovale, should be interpreted with caution.