Received 2022-08-05

Revised 2022-08-21

Accepted 2022-08-31

Introduction

The coronavirus disease 2019
(COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recognized as a worldwide pandemic and mostly affects the respiratory system [1-3]. Within two weeks of exposure to COVID-19, mild symptoms such as shortness of breath, cough, chills, fever, exhaustion, vomiting, nausea, congestion, sore throat, loss of smell and/or taste, headache, and body aches could appear [4-7]. Many people who survive an acute illness develop chronic and debilitating neurological problems, especially in the central nervous system (CNS), with severe personal and socioeconomic ramifications [8]. During the acute state of COVID-19, one-third of patients reveal neurological involvement, including stroke, altered mental status, seizures, and headache, placing SARS-CoV-2 as a new neuropathogen [9-11]. A post-infectious viral syndrome has been reported in one-third of COVID-19-infected people with several neuropsychiatric symptoms [12]. Neurological problems can appear during viral infections in various ways, such as direct infection of endothelial cells in the nervous system, glia, and neurons in the CNS, which results in acute cellular damage [13, 14]. In this review, we explore the potential paths through which SARS-CoV-2 could infect the nervous systems, as well as the role and effects of
COVID-19 in neurological illnesses.

SARS-CoV-2

The human coronavirus SARS-CoV-2 is a enveloped positive-sense single-stranded RNA (ssRNA) [15, 16]. The respiratory system can be infected by coronaviruses, including the Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV,
HCoV-HKU1, HCoV-NL63, HCoV-OC43, and HCoV-22E [17]. Many human coronaviruses lead to mild diseases; however, some of them, including SARS-CoV-2, MERS-CoV, and SARS-CoV can be extremely lethal [18]. Furthermore, while MERS-CoV and SARS-CoV typically infect the lower respiratory tract, SARS-CoV-2 infects both the lower and upper respiratory tracts [19-21]. SARS-CoV-2 has been shown to infect human cells by interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor [22-24]. The respiratory epithelial cells and the pulmonary type II alveolar cells express high levels of ACE2, which demonstrates that COVID-19 is largely a respiratory disease. On the other hand, this receptor expression is not restricted to the respiratory tract. Bladder urothelial cells, renal proximal tubule cells, esophageal epithelial cells, ileal cells, brain, and myocardial cells have all been discovered to have significant ACE2 expression [25]. As a result, the function and overactivity of ACE2 receptors may increase infection susceptibility and affect such tissues [25, 26].

Mechanism of CNS Invasion

SARS-CoV-2 can enter the CNS by one of two main routes. The virus could first pass via the cribriform plate by retrograde axonal transport. Motor proteins can act as a bridge for SARS-CoV-2, which can help the virus reach the brain via sensory and olfactory
nerves [27]. Loss of smell is one sign of this pathway [28]. SARS-CoV-2 can enter the circulation after the involvement of the respiratory tract as an alternate route to the CNS [29]. With cerebral blood flow, the virus could infect other organs and tissues. Due to the particular physiology of the blood-brain barrier (BBB), the virus cannot easily travel from capillaries to the CNS via endothelial cells. Paracellular migration, transcellular migration, and the trojan horse method are the three main ways a virus might cross the blood-brain barrier [30].

Mechanisms of CNS Damages

SARS-CoV-2 causes neurological injury through a combination of mechanisms, including hypoxic brain injury and immune-mediated CNS damage.

Hypoxic Brain Injury

Systemic hypoxia resulting from severe pneumonia can cause CNS damage. Peripheral vasodilation, hypercarbia, hypoxia, and anaerobic metabolism with hazardous chemical buildup are all contributing causes. These conditions can cause brain edema, leading to nervous system impairment [31].

Immune-Mediated Damage

Activation of endothelial cells, macrophages, and T lymphocytes and elevation of inflammatory mediators are the main causes of immune-mediated damage. Vascular leakage, coagulation cascades, complement activation disseminated intravascular coagulation, and end-organ destruction result from the continued release of Interleukins 6
(IL-6) [32, 33].

CNS-Associated Signs and Complications

COVID-19 has been linked to several CNS symptoms, such as ataxia, epilepsy, acute cerebrovascular illness, altered consciousness, dizziness, and headache [34]. Headache is the most frequent symptom in various studies, with a mean prevalence of 8% [34]. Wang et al. demonstrated that thirteen individuals suffered from dizziness among 138 patients with COVID-19, and nine patients seemed to have a headache [35]. Dizziness was also more common in patients in the intensive care unit (ICU) [35]. In acute infections, older adults were at an increased risk of confusion and encephalopathy [36, 37]. In addition, cerebral hemorrhages can cause confusion or reduced awareness. Intracerebral hemorrhage is also reported in some cases [38]. Cerebrovascular disease is among the most common comorbidities in people with severe epilepsy [39].

Furthermore, viral infections like COVID-19 have been linked to the development of cerebrovascular disorders such as acute ischemic stroke [40]. Some COVID-19-positive critically sick individuals have a high risk of clot formation [41]. In COVID-19 individuals, just a few incidences of ataxia and acute disseminated encephalomyelitis (ADEM) have been reported [29, 42].

Peripheral Nervous System (PNS)-Associated Signs and Complications

Guillain-Barre syndrome (GBS), muscle soreness, hypogeusia/ageusia, and hyposmia/anosmia are far less severe PNS signs and symptoms of COVID-19. Common PNS signs of COVID-19 infection are anosmia and ageusia, which have previously been documented in prior coronaviruses [43]. These symptoms appear rapidly and are frequently accompanied by fewer nasal symptoms [43]. Ageusia and anosmia were the most commonly found in individuals without any symptoms [44]. As a result, some researchers believe that people who exhibit these symptoms could be carriers and should avoid contact with others [45]. The sense of taste and smell are recovered after individuals recover from COVID-19 infection [45]. The exact mechanism of SARS-COV-2 anosmia is unknown. Coronavirus can cause transneuronal spread into the CNS through ACE2 and Transmembrane Serine Protease 2 in olfactory cells [46, 47]. As a result of the disruption of the olfactory neuroepithelium, anosmia develops. However, some researchers suggest that inflammatory reactions are the main culprit of anosmia [48].

Neurological Manifestations

Following SARS-CoV-2 infection, CNS symptoms, including epileptic seizures, encephalopathy, encephalitis, and ischemic stroke may be seen. COVID-19 has been linked to inflammatory-mediated neurological disorders and neurodegenerative diseases. In the following, we provide a brief overview of several neurological illnesses as well as current case studies.

Epilepsy

Unprovoked and recurrent seizures characterize epilepsy caused by an imbalance of excitatory and inhibitory neural
activity [49-51]. Seizures are observed in COVID-19 infection; however, not in large numbers [52-54]. In an observational study [55], a young adult with myalgia, lethargy, and fever was reported. Briefly, following a generalized tonic-clonic seizure, the patient was taken to the hospital, and a cerebrospinal fluid investigation indicated lymphocytic pleocytosis. Except for the sphenoid sinus, where modest mucosal thickening was seen, the rest of the imaging was unremarkable. The presence of SARS-CoV-2 was initially disputed by polymerase chain reaction (PCR) analysis, but a second test proved the patient's infection. However, the patient did not have COVID-19-related respiratory symptoms, the overall clinical course was moderate, and SARS-CoV-2 was not found in the patient's CSF fluid [55]. Another adult guy exhibited numbness of the left hand and face, loss of smell, and bulging of the scalp flap in a recent investigation [55]. The patient experienced a focal conscious seizure. The right temporal lobe was swollen on imaging, but there was no evidence of a cerebral infarction or new vascular obstruction. SARS-CoV-2 infection was verified by PCR analysis [55]. According to Kadono et al., presence of severe cerebral edema was most likely related to COVID-19 neuroinvasion [56].

Furthermore, another study discovered that 0.7 percent of 1043 COVID-19 patients had a seizure [57]. Four of the seven individuals studied had new-onset seizures. Another epileptic patient had significant leukoencephalopathy with gyriform restricted diffusion imaging, most likely owing to the patient's state or viral encephalitis [57]. Seizures may be caused by SARS-CoV-2 infection through a variety of methods. These symptoms could arise from therapeutic interventions, organ failure, metabolic disturbances, hypoxia, brain injury, and SARS-CoV-2 neuroinvasion [58]. COVID-19-related epilepsy has been linked to the release of granulocyte colony-stimulating factor, tumor necrosis factor (TNF), and inflammatory cytokines [59, 60]. In some circumstances, epilepsy may be linked to antiviral drugs or adverse drug reactions [61].

Ischemic Stroke

Ischemic stroke is described as an episode of neurological impairment induced by focal cerebral, spinal, and/or retinal infarction [62]. It is caused by a reduced brain blood flow and the resulting hypoxia. Thrombosis or embolism can cause blood vessel obstruction and hypoxia [63]. SARS-CoV-2 and stroke have been linked in multiple case
reports [64-68]. For example, an elderly man presented with confusion, weakening of the left upper limb, and dysarthria [69]. Apart from shortness of breath, patients had no symptoms associated with SARS-CoV-2 infection before the onset of neurological signs. Ischemic stroke, atrial fibrillation, and obstructive pulmonary disease were all present in the patient's medical history. Acute anterior cerebral artery infarction was discovered on imaging. SARS-CoV-2 was later validated by PCR analysis [69]. Ischemic stroke was also described in four individuals with different stages of COVID-19 infection in a retrospective analysis [70]. One of the patients arrived with altered mental status, while the other patients acquired stroke symptoms after hospitalization. Bilateral multifocal subcortical infarctions were suggested by the imaging results. Another patient was admitted to the hospital with acute respiratory distress syndrome, septic shock, and organ failure, and imaging revealed a right posterior cerebral artery infarction [70].

Multiple Sclerosis (MS)

MS is an autoimmune disease characterized by gliosis, demyelination, inflammation, and CNS cell damage [71]. Patients with MS are known to have a higher infection risk, which can result in neurological signs due to BBB failure. Since MS patients receive immunosuppressive drugs, they might be more prone to COVID-19 [72, 73]. A previous study discovered that in MS patients, the prevalence of COVID-19 was 2.5 times higher (1%) than in healthy individuals (0.4%) [74]. Another study indicated that people with MS have not an elevated incidence of COVID-19 independent of their disease-modifying medication regimen [75]. Some other studies have reported that there are no relationship between COVID-19 susceptibility and MS [76]. Based on these contradictory reports, the relationship between COVID-19 susceptibility and MS is now debatable [77].

Moreover, previous research has indicated that viral infection might cause MS exacerbations by inducing autoimmunity [78-80]. A young adult, for example, had visual neuritis after contracting SARS-CoV-2 [81]. Hence, more research is required to fully comprehend the intricate link between MS and COVID-19.

Alzheimer’s Disease (AD)

AD is a devastating neurodegenerative disorder caused by neuron damage. Cognitive and behavioral defects are all symptoms of AD [82]. Patients with dementia had a higher mortality rate (62.2%) than patients without dementia in COVID-19-infected individuals, according to recent retrospective research (26.2%) [83]. Patients with AD may be at a higher risk for developing COVID-19. Patients who live alone and do not have access to a caretaker may be unable to follow COVID-19 prevention suggestions such as hand washing, wearing a mask, covering mouth and nose when coughing or sneezing, physical distancing, and/or staying at home [84]. Amyloid fibrils can trigger an inflammatory response and cytokine production [83]. Interferon type 1 could induced genes that be upregulated in AD patients. According to these findings, amyloid fibrils may catch viruses, stimulate glial cells, and initiate interferon production [83, 85, 86]. However, the probable association between AD and COVID-19 remains unknown.

Parkinson’s Disease

Another neurodegenerative disorder is Parkinson's disease, which causes rigidity, resting tremors, and bradykinesia [87]. COVID-19 was discovered to be 0.9 % of people with Parkinson's disease, according to a recent cohort survey [88]. This number is higher than the 0.25 % regional frequency in Tuscany, the study's locale, and the multi-centered survey done [88]. In addition, a cohort research found that patients with Parkinson's disease had a greater COVID-19 death rate than those over 70 years old [89]. Another study [90] found that COVID-19 prevalence in the general population was similar to prevalence among individuals with Parkinson's disease. No difference was found between the two populations regarding mortality and morbidity [90].

Furthermore, pro-inflammatory cytokines such as IL-6, IL-1, and TNF-α are found in increased concentrations in the elderly [85]. These inflammatory markers are crucial participants in the elevated immune response associated with acute illness. As a result, more studies are needed to determine that the reported rise in COVID-19 among people with Parkinson's disease is due to neurodegenerative disease or other factors such as age.

GBS

To our knowledge, the first report of COVID-19-associated GBS was inconclusive [91]. Further research has found significant evidence of a link between COVID-19 and GBS. Five GBS occurrences were recorded among 1000–1200 SARS-CoV-2 infected patients admitted to a hospital in Italy [92]. Finsterer et al. [93] also looked at 24 cases of GBS that could be linked to COVID-19. Male and older patients were the most commonly afflicted, and the bulk of the instances came after the beginning of COVID-19 signs [93]. Acute, inflammatory, and demyelinating polyradiculoneuropathy was the most common disease subtype, accounting for 58% of cases [93]. Viruses were not found in the CSF, which was notable. In general, patients responded well to intravenous (IV) immunoglobulin
therapy [93]. In addition, autonomic dysfunction linked to COVID-19-related GBS was seen in diagnosed patients [94]. The patient had no fever or lung symptoms, which was unusual. The patient proved positive for SARS-CoV-2 infection after undergoing a variety of tests. An X-ray of the chest revealed mild bibasilar atelectasis with scattered consolidations [94]. He was transferred to the ICU three days after his admission due to a deteriorating respiratory state. GBS was diagnosed, and the patient was given IV immunoglobulin to treat it. He had autonomic dysfunction the next day. He developed quadriplegia after six days due to considerable weakness. He had symptoms of inadequate antidiuretic hormone secretion two days later [94]. GBS can have unusual symptoms as well [95]. Two examples of atypical GBS were recorded by
Assini et al. [95]. A 55-year-old man got GBS/Miller-Fisher overlap syndrome in the first case. After being taken to the hospital for COVID-19, the patient had dysphonia, dysphagia, and acute bilateral eyelid ptosis 12 days later. The results of a motor nerve conduction examination confirmed that he had GBS. Following IV immunoglobulin treatment, the patient's condition significantly improved [95].

Subarachnoid Hemorrhage (SAH)

SAH is a serious disorder characterized by subarachnoid space bleeding [96]. In a study, the authors described SAH in a 66-year-old woman with a history of hyperlipidemia, hypertension, and diabetes [97]. The patient had general malaise, shortness of breath, and dry cough for one week. After arriving at the emergency department, the patient was intubated, and a chest X-ray showed bilateral infiltration. SARS-CoV-2 testing revealed that the patient was positive. The computed tomography (CT) scan of the brain discovered a SAH spreading into the suprasellar cistern, Sylvian and interhemispheric fissures, effacement of the fourth ventricle, and extensive cerebral edema. The patient was unresponsive, with fixed dilated pupils that were not sensitive to light, no corneal or gag reflexes, and no oculocephalic or vestibulocephalic movements. Once more experiencing cardiac arrest, the patient was pronounced dead [97]. Al
Saiegh et al. described another instance of SAH in a male 31-year-old patient with arthralgia, cough, malaise, moderate fever, and infection in the upper respiratory tract [98]. The patient experienced a strong headache and lost consciousness all of a sudden. A SAH was discovered during a head CT scan. SARS-CoV-2 test was done because of his respiratory symptoms and was confirmed positive. After being intubated the following day, the patient was extubated, his symptoms progressively improved, and he was sent home for rehabilitation [98].

Conclusion

SARS-CoV-2 is largely a respiratory virus; however, some patients may experience brain problems, particularly in advanced disease. Although the underlying processes of illness etiology are unknown, neuroinvasion, neuroinflammation, and BBB disruption have all been implicated in the appearance of various CNS symptoms in investigations. Several inflammatory-mediated neurological disorders may also increase the susceptibility to COVID-19 infection. The majority of the research were case reports. As a result, more research is needed to fully understand the mechanism of COVID-19, which leads to neurological problems. Although vaccine advances offer hope for containing the pandemic, more research and understanding of COVID-19's clinical symptoms and processes are required.

Acknowledgment

This study was financially supported by Shiraz University of Medical Sciences
(grant no: 26718).

Conflict of Interest

The authors declare that there are no conflicts of interest.

 Correspondence to: Morteza Jafarinia, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Telephone Number: +987136257497 Email Address: jafarinia@sums.ac.ir

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