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Potential neuroinvasive pathways of SARS‐CoV‐2: Deciphering the spectrum of neurological deficit seen in coronavirus disease‐2019 (COVID‐19)

Abstract Coronavirus disease‐2019 (COVID‐19) was declared a global pandemic on 11 March 2020. Scientists and clinicians must acknowledge that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has the potential to attack the human body in multiple ways simultaneously and exploit any weaknesses of its host. A multipronged attack could potentially explain the severity and extensive variety of signs and symptoms observed in patients with COVID‐19. Understanding the diverse tactics of this virus to infect the human body is both critical and incredibly complex. Although patients diagnosed with COVID‐19 have primarily presented with pulmonary involvement, viral invasion, and injury to diverse end organs is also prevalent and well documented in these patients, but has been largely unheeded. Human organs known for angiotensin‐converting enzyme 2 (ACE2) expression including the gastrointestinal tract, kidneys, heart, adrenals, brain, and testicles are examples of extra pulmonary tissues with confirmed invasion by SARS‐CoV‐2. Initial multiple organ involvement may present with vague signs and symptoms to alert health care professionals early in the course of COVID‐19. Another example of an ongoing, yet neglected element of the syndromic features of COVID‐19, are the reported findings of loss of smell, altered taste, ataxia, headache, dizziness, and loss of consciousness, which suggest a potential for neural involvement. In this review, we further deliberate on the neuroinvasive potential of SARS‐CoV‐2, the neurologic symptomology observed in COVID‐19, the host‐virus interaction, possible routes of SARS‐CoV‐2 to invade the central nervous system, other neurologic considerations for patients with COVID‐19, and a collective call to action.

WHO declared COVID-19 a global pandemic. 1 As of 25 May 2020, per the Johns Hopkins COVID-19 Dashboard, there are currently 5 408 301 cases globally, with 345 104 associated deaths worldwide. 5 In the United States (US) alone, there are 1 643 499 cases (30.3% of global cases) with 97 722 associated deaths (28.3% of global deaths). 5 Despite entering the seventh month from the initial identification and spread of the zoonotic pathogen SARS-CoV-2, very little is known about viral transmission, organotropism, and pathogenesis, including the mechanisms behind the disturbing prevalence of cardiorespiratory failure in patients with COVID-19. The differential mortality observed in diverse populations concerning geography, culture, policy, age, sex, comorbidities, genetics, epigenetics, and systemic health inequity are captivating and require further study. Similarly, the overlaid and highly varied responses of the human immune system to SARS-CoV-2 are intriguing.
Since originating in China, the overarching spectrum of syndromic manifestations seen in patients with COVID-19 continues to perplex physicians and scientists worldwide. 6,7 After a comprehensive examination of the potential routes of infection available to SARS-CoV-2 in humans, we postulate that widespread organ invasion as the major life-threatening aspect of viral pathogenesis, which also corresponds with the varied symptomatology seen in patients with COVID-19 ( Figure 1). Involvement of the cardiorespiratory system and central nervous system (CNS) is particularly ominous, as they have been reported as the leading causes of morbidity and mortality in patients with COVID-19. 6 F I G U R E 1 Proposed pathogenesis of SARS-CoV-2 to invade the human CNS. Source: Possible access to the human CNS by viral invasion includes the hematogenous route, neuronal retrograde dissemination route, and transcribrial route detailed in this manuscript. The virus can access the CNS through the blood vessels, peripheral neurons, or cerebrospinal fluid (CSF), and then directly damage the brain and nerves, as evidenced by recent autopsy studies. [8][9][10][11][12][13] Access to the vasculature has been established by the extensive endothelial damage seen in postmortem examinations and pathological study of patients with COVID-19. 8-17 SARS-CoV-2 has been found in the mucosa of the nose, mouth, and eyes, lungs, liver, kidney, heart, brain, gastrointestinal tract, sperm, and placenta suggesting an affinity for organs with a higher angiotensinconverting enzyme 2 (ACE2) receptor count/expression. [8][9][10][11][12][13]18, Interestingly, the CNS, eyes, testes, and placenta are all immune-privileged organs. The local endotheliitis, tissue, and organ damage, can lead to widespread inflammation potentially resulting in a cytokine storm picture that has also been frequently observed in patients with COVID-19. [44][45][46][47] Furthermore, as the ACE2 receptor is the host binding site for SARS-CoV-2, there is potential for decreased available ACE2 in the serum and increased circulating angiotensin II (AngII), creating a hypercoagulative state, and predisposing patients with COVID-19 to pulmonary embolism (PE), deep vein thrombosis (DVT), disseminated intravascular coagulation (DIC), and stroke. 48 [52][53][54][55][56][57][58][59][60][61] In addition, one study of 18 autopsies positive for SARS-COV-1 found that viral "genome sequences were detected in the brains of all SARS autopsies with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays." 62 The route of initial SARS-CoV-1 infection to the brain remains unclear, but the viral presence was definitively established in the CNS. [63][64][65] Animal studies using transgenic mice have shown that SARS-CoV-1 administered via transnasal route could enter the brain, potentially along the olfactory nerves and spread to specific brain areas including the thalamus and brainstem. 66 3 | NEUROLOGIC SYMPTOMATOLOGY IN  COVID-19 3.1 | Hyposmia, hypogeusia, headache, and dizziness An ongoing, yet neglected element of the syndromic features of COVID-19, is the reported findings of loss of smell and altered taste (Figure 2A,B), ataxia, headache, dizziness, and loss of consciousness. 7,67-84 Initial reports from China detailed various clinical features of patients with COVID-19, including symptoms concerning for possible neurological deficit confirmed by physical examination ( Figure 2C-E). 67,68 Of over 200 initial patients evaluated in China, researchers found that severe neurological symptoms were more likely to occur in patients with severe disease. 67 However, nonsevere patients also had episodes of F I G U R E 2 Neurological manifestations in COVID-19. Neurological findings appearing as early symptoms in COVID-19 include anosmia (A) and dysgeusia (B), which are now included in the checklist of COVID-19 symptoms by CDC and WHO (C). A complete neurological examination should be performed including mental status, sensation (D), motor function, strength, balance, coordination, cranial nerves, and reflexes (E). Initial physical exam is pivotal in identifying early neurologic deficits in COVID-19 that could progress to acute respiratory failure necessitating the current global demand for mechanical ventilators (F), which could be a direct result of damage to the cardiorespiratory centers in the brain. 70

| Guillain-Barré syndrome
The New England Journal of Medicine, recently published a case series from Italy on five patients with COVID-19 who presented with Guillain-Barrésyndrome (GBS). 105 Of the five reported cases, four developed flaccid tetraparesis or tetraplegia, and three required mechanical ventilation. 105 Notably, the cerebrospinal fluid (CSF) of all five patients tested negative for SARS-CoV-2 by RT-PCR assay. 105 A recent publication from Spain also noted two patients with COVID-19 presenting with Miller Fisher syndrome, a variant of GBS, and polyneuritis cranialis. 106 The CSF of both patients tested negative for SARS-CoV-2 by RT-PCR assay. 106 Whether the prevalence of GBS is due to direct viral attack of the myelin sheath resulting in demyelination, or a secondary effect of blood-brain barrier (BBB) permeability due to widespread inflammatory response and cytokine storm in the CNS remains to be determined. 44 In addition, long and short term postviral sequelae will be important to monitor. Other neuroinvasive viruses including influenza, poliovirus, and human herpesviruses have invaded and damaged the CNS in a multitude of ways over time. 61,[107][108][109] Capacity for viral persistence, latency, or reactivation of SARS-CoV-2 are important areas of further study.

| Multisystem inflammatory syndrome in children
Of recent concern are the increasing cases in Italy, the United States (US), and the United Kingdom (UK) of a Kawasaki-type viral inflammatory illness in children newly termed multisystem inflammatory syndrome in children. A 14-year-old boy in the UK and three children in New York passed away from complications of this disease. 110,111 Out of the series of eight published in the UK, the 14-year-old boy presented with a headache and suffered from a right middle cerebral artery and anterior cerebral artery infarction. 110 The only other child to report an initial headache in the series had a severe biventricular impairment. 110 Despite having close SARS-CoV-2 positive contacts, most children tested negative for the virus via nasal swab. 110 However, five presented with conjunctivitis. Viral conjunctival swab results were not reported. Shockingly, all of the children "progressed to warm, vasogenic shock, refractory to volume resuscitation, and eventually requiring noradrenaline and milrinone for hemodynamic support," despite a lack of significant respiratory involvement by SARS-CoV-2. 110 In fact, seven children required mechanical ventilation for cardiovascular stabilization. 110  In addition to the cases cited above, there have been several other published case reports of encephalopathy in the literature. 74,[120][121][122][123] Of the five additional recently published cases of encephalopathy, three patients also had mild/moderate lung findings on chest radiograph and computed tomography (CT) of the chest. Two patients required intubation (Table S1)

| United States
In Michigan, a 58-year-old female with altered mental status (AMS), positive NP swab by RT-PCR assay, and suspected SARS-CoV-2 associated acute necrotizing encephalopathy was diagnosed by head CT and magnetic resonance imaging (MRI) of the brain. Unfortunately, the CSF sample was unable to be tested for SARS-CoV-2. 121 The cause of these symptoms is still unclear, as to whether they were a result of intracranial cytokine storm compromising the BBB or direct viral neuroinvasion. In Florida, a 74-year-old male was diagnosed with encephalopathy and had a positive NP swab by RT-PCR assay, but again, CSF was unable to be tested for SARS-CoV-2. 122 California also reported a 41-year-old female with meningoencephalitis and positive NP swab who presented with new-onset seizures in early April. 123 After 9 days of hospitalization, the physicians were still unable to test her CSF for SARS-CoV-2. In addition, a 5-year-old girl BAIG AND SANDERS | 1849 from Michigan with positive NP swab and meningoencephalitis requiring intubation and ventilation succumbed to her injuries on April 19th. 125 A case report has not yet been published. As this is the second documented case of encephalitis with COVID-19 in Michigan, exploration of a more virulent strain of SARS-CoV-2 to the CNS may be justified, as China has released preliminary evidence that SARS-CoV-2 has acquired mutations capable of substantially changing its pathogenicity. 126

| Italy
A case from Italy was recently published involving a 60-year-old male with new-onset akinetic mutism and encephalopathy, positive NP swab, and negative CSF by RT-PCR assay tested twice. 127 Specifics regarding the above cases have been detailed in Table S1; again exposing the diverse ways that COVID-19 challenges clinical diagnosis and management.

| VIRAL ATTACHMENT TO ACE2 EXPRESSED IN HOST CELLS
The variety of symptoms observed in patients with COVID-19 could be explained by the distribution of ACE2 receptors and multiplicity of their expression as described in the legend of  (Figures 1 and 3B).

| Olfactory/transcribial route to the CNS
Viruses causing upper respiratory tract infections can exploit the olfactory epithelium (OE) as a site for proliferation due to its location both being adjacent to the respiratory epithelium and having direct exposure to the host's environment. 128  In Italy, ultrastructural analysis of a postmortem patient with COVID-19 examined the olfactory nerve, the gyrus rectus, and the brainstem at the level of the medulla oblongata ( Figure 3B). 129 Researchers found severe and widespread tissue damage and SARS-CoV-2 virion particles involving the neurons, glia, nerve axons, and myelin sheath. 129 These findings support the potential for viral invasion of the olfactory mucosa ( Figure 3A). In addition, a postmortem MRI study of patients with COVID-19 from Belgium revealed asymmetric olfactory bulbs ( Figure 3A) with or without olfactory cleft obliteration in 4 out of 19 decedents. 130 Given the known cytopathic effects, replication of the virus likely potentiates cell rupture, resulting in the release of more virion into the surrounding tissues. It is well established that the OE via ON directly access the olfactory bulb (OB) through a horizontal segment of the ethmoid bone called the cribriform plate ( Figure 3A). [101][102][103][104] As the ON travel through the olfactory foramina in the cribriform plate, they also pass directly through the three layers of the cranial meninges (dura mater, arachnoid mater, and pia mater) before reaching the OB ( Figure 3A). [101][102][103][104] Consequently, the rupturing of infected cells through the subarachnoid space could directly release virion into the CSF ( Figure 3A, blue zone). As evidence of the presence of CSF in the meninges that support the OB above, is the phenomenon of CSF rhinorrhea resulting from a fracture of the cribriform plate in trauma involving the base of the skull. 131,132 The CSF circulation can then transport the virus throughout the CNS with or without overt damage to the BBB or the OB ( Figure 3A). The intrathecal reninangiotensin system and brain both express ACE2 and could also be potential targets for SARS-CoV-2. 133,134 SARS-CoV-2 selecting to manipulate this direct pathway would not be unexpected, as a plethora of viruses and pathogens have been reported to invade the CNS utilizing this exact route. [88][89][90][91][92][93][94][95][96][97][98][99][100] The transcribrial route ( Figure 3A, between the olfactory mucosa and olfactory bulb) has also been proposed as a potential route for drugs to bypass the BBB and also for stem cell delivery in neurodegenerative diseases. 96,97 Localized epithelial inflammation, destruction, and damage to the OB ( Figure 3A, TOP layer) has already been observed with other viral pathogens and correlated with decreased olfaction. [98][99][100] This mechanism could potentially explain the diminished senses of smell and associated altered taste (Figure 2A,B) in patients with COVID-19. 128 6.2 | Other potential routes to the CNS Primary transmission via respiratory droplets supports further investigation of the mucous membranes of the eyes and mouth as other possible candidates for viral peripheral nerve invasion (Figure 1), as both the oral and ocular epithelium express ACE2. 28-41 Direct invasion of the peripheral nerves in the nasal cavity leading to the trigeminal nerve has been proposed as a potential cause for headache symptoms in patients with COVID-19. 80 There is also the potential for the virus to enter the peripheral vasculature via epithelial erosion and directly invade the circulation. Once in the blood, the virus may be able to cross the BBB by causing damage to vessel integrity ( Figure 1) and thus increasing permeability. [48][49][50][51] Recently, the ultrastructural analysis of a postmortem patient with COVID-19 detected SARS-CoV-2 in the frontal lobe of the human brain ( Figure 3B), specifically in the neurons and propagating in the capillary endothelium, (Figure 3) bolstering the possibility of a hematogenous route. 78 7 | ADDITIONAL NEUROLOGIC CONSIDERATIONS WITH COVID-19 7.1 | Cytokine storm and blood-brain barrier  13 The same authors initially reported on nonspecific brain findings including two patients with cerebral sclerosis and another with suspected septic encephalomalacia, although brain dissections are still pending. 12

| Increased data acquisition from COVID-19 autopsies
Notably, China has had markedly more time than the rest of the world to perform clinical investigations and autopsy examinations.
Despite this advantage, there was an initial paucity of published autopsy and pathology reports on the CNS. Physicians and scientists from China have been vocal about their recommendations and need for more data. [135][136][137] Dr Bin Cong, physician, and dean of the Hebei Medical University School of Forensic Medicine published a paper in February 2020 requesting to strengthen the use of autopsy to better comprehend SARS-CoV-2. 136 Dr Hujun Wang, physician and chief expert in forensic medicine at Southern Medical University, also recognized the need of pathologic data on patients with COVID-19 to better understand human SARS-CoV-2 infection. 137 The majority of initial published and available reports from China involving autopsy, predominately focused on procedure safety with scarce actual autopsy and pathology reports. 11,[14][15][16][17]137,[138][139][140] Remarkably, only one full autopsy report was identified and able to be accessed in the full text during the early days of the COVID-19 outbreak in China. 11 Even after the spread of COVID-19 in the US and Europe, with hundreds of deaths daily, autopsy examinations were not routinely performed and crucial data on organ involvement, and the CNS in particular, remained uninvestigated. Coma Scale, opisthotonos, Adie's pupil, and trigeminal neuralgia will also be helpful to document an overt neurological deficit ( Figure 2D,E). Patient symptoms of anosmia, dysgeusia, headache, eye pain, conjunctivitis, and sore throat are also important to report to better understand possible transmission pathways (Figure 2A,B).

| Clinical attention to neurologic symptoms
Radiological notation of the orbits, sinus, and dura may help further explain the route of infection. CSF testing for SARS-CoV-2 by RT-PCR assay should be done whenever possible and a negative test should be repeated to avoid a testing error. Notation of anticoagulation or cardiac studies would also be beneficial. In addition to imaging studies, there may also be a role for electroencephalogram in these patients, but widespread utility and guidelines have not yet been established.

| CSF testing
Many countries currently lack any approved testing for SARS-CoV-2 in the CSF. Frontline health care professionals need appropriate RT-PCR assay for CSF, as well as national and global guidance on who to test, when to test, and when to repeat testing.

| CONCLUSION
As observed with the taxonomically related SARS-CoV-1, SARS-CoV-2 has the potential to invade the CNS, as this pathogen has been isolated BAIG AND SANDERS | 1851 from the brain and CSF of patients with COVID-19. 13,74,120,129 Regardless of the multiple routes (Figure 1), the virus could take to reach the CNS, data is continuously emerging on the true extent of neurologic involvement of SARS-CoV-2. Acute respiratory failure resulting from neuronal damage to the medullary centers ( Figure 2B) that control the spontaneous breathing process and cardiac function is conceivable and harrowing. In addition, a more avid receptor-binding domain is postulated to allow SARS-CoV-2 to attach more securely to the human ACE2 receptor and enable it to better infect cells and spread than SARS-CoV-1. 141 The above literature and clinical observations merit urgent investigation by healthcare professionals and the scientific community into the extent of neuroinvasive potential with SARS-CoV-2, which if overlooked, could result in significantly higher morbidity and mortality for patients with COVID-19.
To fight this virus, we need transparency. We need access to all of the available autopsy and pathology data worldwide. The CNS, brainstem, and peripheral nerves of the eyes, nose, and mouth should be further examined in any existing autopsy specimens. Frontline clinicians also need appropriate testing of CSF with national and global testing guidelines.
Regardless of current specialty in surgery or medicine, the reality is that SARS-CoV-2 and COVID-19 will affect us all. The subspecialization of medicine has siloed health care professionals, preventing us from seeing the true scope and complexity of this pathogen. The scientific and medical communities must collectively unite and form a multidisciplinary approach to understanding the effects this virus has on all of the various organ systems in the human body and we must act now.

CONFLICT OF INTERESTS
The authors declare no potential conflict of interests.