Novel coronavirus disease (COVID-19) was declared a global pandemic on March 1, 2020. Neurological manifestations are now being reported worldwide, including emergent presentation with acute neurological changes as well as a comorbidity in hospitalized patients. There is limited knowledge on the neurologic manifestations of COVID-19 at present, with a wide array of neurological complications reported, ranging from ischemic stroke to acute demyelination and encephalitis. We report five cases of COVID-19 presenting to the ER with acute neurological symptoms, over the course of 1 month. This includes two cases of ischemic stroke, one with large-vessel occlusion and one with embolic infarcts. The remainders of the cases include acute tumefactive demyelination, isolated cytotoxic edema of the corpus callosum with subarachnoid hemorrhage, and posterior reversible encephalopathy syndrome (PRES).
The H1N1 influenza flu of 1918, also known as Spanish flu, was one of the worst pandemics known to mankind, wherein more than 500 million people were infected . More than a century later, the world witnessed another major pandemic: novel Severe Acute Respiratory Syndrome-coronavirus 2 pandemic, simply known as COVID-19.
The SARS-CoV-2 like other coronavirus primarily affects the pulmonary system, with respiratory failure being the cause for death in the majority of patients. The most established pattern on chest imaging includes multi-focal areas of consolidation in a peripheral distribution pattern. As our knowledge about the disease is expanding, it has become clear that other organ systems are also commonly involved, most prominently, involving acute cardiac and renal complications. Neurological complications are also relatively common ranging from 30 to 45% depending upon the severity of the disease, as reported in one of the first studies on the subject.These symptoms could be fairly specific like anosmia, ischemic, or hemorrhagic stroke or more nonspecific like mental status changes, headache, and seizures. A wide range of neuroimaging manifestations have now been reported, mainly in the form of case reports and case series. Recently, some original research articles have also been published. Mahammedi et al.  published a large study with 725 consecutive hospitalized COVID-19 patients, with 108 patients having neurological complications. To our knowledge, this was the first study to systematically characterize neurological symptoms and neuroimaging findings in COVID-19 patients. Table 1 provides a summary of the most common neuroimaging manifestations reported to date. There are two broad sets of neurological complications in COVID-19: (1) vascular complications with stroke secondary to arterial or venous thrombosis, related to the known hypercoagulable state seen in COVID, and (2) much broader gamut including diffuse leukoencephalopathy, acute demyelination, posterior reversible encephalopathy syndrome (PRES), necrotizing encephalopathy, and focal cytotoxic edema, primarily seen as a consequence of systemic inflammation and cytokine storm seen with COVID-19
Hypercoagulable state There is growing evidence and consensus that COVID-19 infection is associated with a pro-thrombotic state, leading to an increased incidence of arterial and venous thrombosis and microvascular coagulopathy . The cumulative incidence of venous thromboembolism (25–49%), acute ischemic stroke (0.9–5%), and acute myocardial injury (up to 20%) further underscore the coagulopathic effects of COVID-19. The increased thrombotic tendency is likely multifactorial. Immune hyperactivation and cytokine storm in severe COVID-19 are now well recognized and likely result from the cytopathic effects of the virus. Cerebral arterial or venous thrombosis is at present the most commonly reported neurological complication of COVID. Acute ischemic stroke in COVID-19 may be seen at presentation in the ER or during the course of the hospitalization, generally seen in patients with severe disease who often require intensive care. Stroke may be the presenting symptom or reason for admission in up to 44–46% of patients presenting with neurological complications . Dural venous sinus thrombosis is also increasingly being observed, with the largest series of three patients reported Arterial thrombi can involve medium and large-sized arteries across the body. In a study, by Dane et al., 9 (11%) out of a cohort of 82 patients had thromboembolic findings in the abdomen, pelvis, and lower extremities.The etiology of stroke is generally cryptogenic, with involvement of both the anterior and posterior circulation vessels. Large-vessel anterior circulation involvement is the most common observed pattern of ischemic stroke in COVID patients.
These patients are often put on empirical full dose of anticoagulants, given the significant hypercoagulability in COVID-19. Interestingly, the incidence of ischemic strokes in COVID-19 may be decreasing after the initial peak, possibly due to routine anticoagulation protocols in critically ill patients with higher d-dimer levels. However, this may be temporary, given the current trend and increasing number of positive cases in the USA.
Neurotropism and other pro-inflammatory state complications Neurotropism of SARS-CoV-2 and the sensitivity and specificity of its detection in the CSF have not been well established. The virus has been detected through RT-PCR in CSF samples and also in brain tissue on autopsy, suggesting high possibility that the virus can breach the blood brain barrier. COVID has known affinity for ACE2 receptors, also expressed by glial cells and neurons, making them potential targets of the virus. Very recently, Aragão et al. reported a series of five patients with hemorrhage or post-contrast enhancement within the olfactory bulbs on MRI, three of which presented with anosmia. This was proposed to be secondary to trans-synaptic transfer of the virus through the cribriform plate.
The CNS manifestations could be due to the direct effect of the virus on the brain or secondary to immune-mediated changes as seen with other viral illnesses like H1N1. COVID-19 is known to cause a severe cytokine storm with resultant pro-inflammatory state mediated predominantly by IL1, IL-6, and TNF α. Acute monophasic demyelination, like acute disseminated encephalomyelitis; tumefactive demyelination; and acute exacerbation of multiple sclerosis have now been reported with COVID-19. The exact mechanism is again unclear. The wide spectrum of neurological complications includes conditions like Guillain–Barré syndrome, cranial nerve enhancement, similar to other viral neuropathies. Vasculitis or leptomeningits could again be secondary to the cytokine storm or due to direct infection and inflammation of these structures. In a relatively large series, Radmanesh et al. reported COVID-associated leukoencephalopthy (with our without microhemorrhage) in 11 patients and proposed delayed post-hypoxic insult as the underlying mechanism, similar to what is seen in drug overdose and cardiac arrest. This second set of neurological complications in COVID-19 is less well defined with a very wide spectrum and subject to multiple other overlapping causative factors.
Conclusion The spectrum of neurological manifestations in COVID-19 is very wide at present. Understanding the neurological manifestations in COVID-19 is still at a very nascent phase. The most common neurological presentation reported has been ischemic stroke, secondary to arterial or venous thrombosis, because of the hypercoagulable state associated with COVID-19. However, the neurological manifestation can be quiet variable, as depicted in this paper
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