Atypical Neurological Manifestations of COVID-19

The novel coronavirus (SARS-CoV-2), belonging to a group of RNA-enveloped viruses and believed to be transmitted by aerosol route, is a worldwide pandemic. Many studies have described typical clinical manifestations such as fever, cough, fatigue, diarrhea, and nasal congestion. However, to our knowledge, there are minimal studies on the neurological manifestations in SARS-CoV-2 positive patients. Our review aims to identify the various neurological manifestations in SARS-CoV-2 positive patients, which could be an added advantage in the early diagnosis and prevention of further complications of the nervous system.

This study did not require ethical approval as data was obtained from already available databases, and patients were not directly involved.

Results/analysis
A total of 20 eligible studies were screened and found eligible for data extraction (see Table 1).

FIGURE 3: Bar graph showing the various neurological symptoms
The six-week preterm infant had a witnessed episode of sustained upward gaze associated with bilateral leg stiffening and decreased responsiveness lasting ten seconds with subsequent return to baseline and no hypoxia or vital signs change [20].
Our results show that there is a wide range of symptoms that a COVID-19 patient can present with. Hence, physicians must suspect COVID-19 in those presenting with neurological symptoms as well.

Discussion
Coronaviruses are a group of viruses that can involve and affect multiple organ systems. They can affect both humans and animals [26]. The novel coronavirus SARS-CoV-2 is the causative agent of COVID-19. Coronaviruses are a group of enveloped viruses [26]. The alphacoronavirus and betacoronavirus infect mammals [26,27]. Coronaviruses are spread mainly by the aerosol route. They can also be spread by feco-oral transmission and through fomites. Human coronaviruses primarily target the epithelial cells of the respiratory epithelium, whereas the animal coronaviruses have their main affinity towards the epithelial cells of the digestive tract [28].
Three human coronaviruses produce symptoms that are severe:
Coronaviruses are primarily attracted to the respiratory epithelium [3]. Some studies provide evidence of neuronal involvement of SARS-CoV-2. The nervous tissue expresses the ACE-2 (angiotensin-converting enzyme-2) receptor, which has been detected over the glial and the neural tissues. SARS-CoV-2 has an affinity for the ACE-2 receptors, thus making the nervous system a probable target of SARS-CoV-2 [3].

Route of the Spread of SARS-CoV-2 into the Nervous System
SARS-CoV-2 being a new emergent virus, little is known about its mechanism of action. Because of its genomic similarity with severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV), it is considered to mimic them [29]. In the Mediterranean SARS-CoV infection, the autopsy findings showed evidence of neural tissue involvement [30]. The spread of SARS-CoV-2 through the cribriform plate, which is in close proximity to the olfactory region, has been demonstrated in patients affected with SARS-CoV-2. SARS-CoV-2 can spread through two different pathways [30]. The virus may enter the systemic circulation and enter the cerebral arteries through which it gains access to the brain. The endothelium of the capillaries also contains the ACE-2 receptors [30]. Thus, the virus may get attracted to the ACE-2 receptors and destroy the capillary endothelium, thus breaking the blood-brain barrier and entering the brain. The virus starts multiplying in the brain and can spread along the neural tissue due to the presence of ACE-2 receptors and can cause neural damage without significant inflammation [30]. The accessory pathway through which the SARS-CoV-2 can gain entry to the CNS is through the cribriform plate as it is in close proximity to the olfactory bulb [25].

Manifestation of SARS-CoV-2
After a comprehensive screening of the available literature, a total of 20 eligible studies, which included mostly case series and case reports, were selected, and the patient data was assessed.
The study reports a total of 1034 COVID-positive patients, of which 468 were males (45.26%) and 566 were females (54.74%) as seen in Figure 1. The age range of the patients was six weeks to 74 years, with an average age of 44 years as seen in Table 2. The majority of patients in our study (734) were European in origin [7,10,17]. A wide variety of comorbidities such as asthma, hypertension, hypothyroidism, and diabetes mellitus were present. Ground glass opacities were the most common radiological findings. The patients presented with a wide range of neurological and non-neurological symptoms, as summarized below.

Neurological Manifestations of SARS-CoV-2
Both CNS and PNS symptoms were analyzed, and it was found that more patients had peripheral symptoms. The presentation of olfactory symptoms in SARS-CoV-2-affected patients is due to the fact that the illness spreads through the cribriform plate, which is in close proximity to the olfactory region [30].
GBS was diagnosed in four cases, but the outcomes were not specified [13,18,19,24]. One patient also presented with neurosensory hearing loss [15]. This patient was cared for with standard respiratory care and recovery. There was no observation of a change of hearing loss in this case. Auditory complication due to coronavirus is little mentioned in the literature [15]. A 75-year-old male patient was found to be encephalopathic, nonverbal, and unable to follow any commands [6]. Considering the possibility of subclinical seizures due to an area of encephalomalacia and epileptiform discharges in the right temporal region, anti-epileptic medications were given prophylactically. The patient was treated empirically with vancomycin, meropenem, and acyclovir [6]. A lumbar puncture did not indicate any evidence of central nervous system infection. Due to his progression in symptomatology, he was then tested for COVID-19 and found to be positive [6]. The patient developed respiratory failure, required intubation, and was transferred to the ICU. The patient was started on hydroxychloroquine and lopinavir/ritonavir and was continued on broad-spectrum antibiotics. The patient is critically ill with poor prognosis and currently remains in the ICU [6].
The six-week preterm infant had a witnessed episode of sustained upward gaze associated with bilateral leg stiffening and decreased responsiveness lasting ten seconds, with a subsequent return to baseline, and no hypoxia or vital signs change [20].
A 64-year-old male patient from France with no significant comorbidities who was infected with SARS-CoV-2 presented with paresthesia in feet and hands, had a fever and cough for two days, and developed severe flaccid tetraparesis within three days [18]. Electrodiagnostic tests five days after neurological symptom onset showed a demyelinating pattern in accordance with GBS criteria. On needle examination, no rest-activity was observed [18]. During muscle contraction, only one single motor unit was recorded with a firing rate up to 25 Hz in the right tibialis anterior, the right vastus lateralis, the left first interosseous, and the left deltoideus muscles. On cerebrospinal fluid (CSF) analysis, the protein level was 1.66 g per liter, and the cell count was normal [18]. Anti-gangliosides antibodies were absent in the serum.

Conclusions
Our results show that there is a wide range of symptoms that can be presented by COVID-19 patients. Hence, physicians must suspect COVID-19 in those presenting with neurological symptoms as well. This systematic review of the current literature on COVID-19 provides insight into some of the atypical manifestations of the disease. With the pandemic continuing to unfold, research is the need of the hour. Even with massive numbers of publications, gaps remain in the understanding of the natural history of the disease. Further studies need to be undertaken in this regard.

Conflicts of interest:
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