Cranial Nerve Impairment Associated With COVID-19 Infections: A Systematic Review

The COVID-19 pandemic has created huge economic and healthcare burdens. In most cases, the virus affects the lungs and causes respiratory symptoms. Additionally, its impact on the cranial nerves remains unclear. We thus aimed to investigate cranial nerve dysfunction in patients with COVID-19 infection. We conducted a systematic literature search of relevant and eligible literature in five databases: PubMed, Web of Science, Medline, EBSCO, and Google Scholar. Our sample included 21 case reports, one case series with 29 patients, and one analytical study with 135 cases. Participant ages ranged from 23 months to 72 years (mean age of 47.5 ± 19.02). The mean time from respiratory symptoms to the onset of neurological signs was (9.6 ± 7.4) days, and the mean recovery time was (16.3 ± 15.3) days. Cranial nerve impairment associated with COVID-19 infection has affected a large population, from infants to the elderly. Facial and abducent nerves were the most commonly affected cranial nerves with reported good prognosis or complete recovery within a few days to weeks. Olfactory dysfunctions were widely detected among COVID-19 patients.


Introduction And Background
Coronaviruses are typically considered respiratory pathogens. However, neurologic complications such as confusion, stroke, seizure, and neuromuscular disorders have been associated with these viruses, particularly in those with severe infections [1][2][3][4].
In 2002, an outbreak of SARS-CoV-1, a member of the coronavirus family of viruses, induced a series of neurological disorders, including encephalopathy, stroke, seizures, cranial nerve dysfunction, peripheral neuropathy, and myopathy. The death rate of around 10% helped limit the spread of the disease [5,6]. However, in 2012, another coronavirus, Middle East Respiratory Syndrome coronavirus (MERS), spread across the Middle East [5]. MERS causes multiple organ disorders affecting the brain, nerves, and muscles [7].
In 2019, the COVID-19 pandemic was caused by a coronavirus with high SARS-CoV-1 and MERS homology that affects both the central and peripheral nervous systems [4,8,9]. COVID-19 caused a global health and economic crisis, and around 50 million people worldwide have been infected [10,11].
The pathophysiology of nerve injury is neuronal swelling and edema of the brain inducing neurological damage, peripheral vasodilatation, hypercarbia, hypoxia, and anaerobic metabolism [12]. An investigation in China has reported a higher incidence of neurological symptoms in severe cases of COVID-19 [3]. Further investigation is needed to detect the impact of the COVID-19 virus on neurological manifestations, particularly cranial nerve involvement such as facial nerve palsy and loss of taste and smell.
This systematic review, conducted between August and September 2021, aimed to summarize the published literature regarding COVID-19 patients with cranial nerve impairment.
Using five essential databases (PubMed, Web of Science, Medline, Google Scholar, and EBSCO), we conducted a systematic literature search. We limited our search to papers written in English and used keywords compliant with PubMed's Medical Subject Headings (MeSH) terms, including "COVID-19," "SARS-CoV-2," "Coronavirus Disease-2019", "2019-novel coronavirus", "severe acute respiratory syndrome coronavirus 2", "Cranial nerve," "neurological manifestations," and "CNS." Keywords were combined with Boolean operators such as "OR" and "AND." We then selected studies that met the following selection criteria: case reports, case series, and analytical studies of COVID-19 associated with cranial nerve involvement or neurological manifestations involving patients of any age. We excluded papers not written in English language or with limited access (e.g., paywalls). We then used Rayyan for Systematic Reviews (Rayyan Systems Inc., Cambridge, USA) to identify and remove duplicate records [13].
After screening abstracts according to the inclusion and exclusion criteria, the whole texts of eligible publications were evaluated by the reviewers. Any disagreements were resolved via debate and discussion. A data extraction form was used to record information from the qualifying articles. This information included the study topic, authors, year, design, and population, as well as the number of participants, their ages, genders, diagnoses, medical histories, presentation at admission, and treatments. Neurological signs (cranial nerve involvement, number of days from early respiratory symptoms to neurological symptoms, and time to recovery) also were recorded.
We evaluated the quality of the included case reports and the risk of bias using Joanna Briggs Institute software (JBI, Adelaide, Australia), discussing any discrepancies that arose. We then organized all results in tables, including research characteristics and data outcomes. After completing the data extraction, a qualitative analysis of the collected data was conducted.

Review
The first systematic search yielded 580 studies, from which Rayyan identified 87 duplicate records. Another 390 were removed due to irrelevant findings or incorrect research type or design. The whole-text assessment step eliminated 75 more papers due to improper outcome, wrong population, or unavailable data on cranial nerve involvement. The final set thus comprised 23 eligible articles. Figure 1 illustrates the selection and identification process.

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
These 23 eligible articles included 21 case reports, one series comprising six cases, and one analytical study with 135 cases. Participant ages ranged from 23 months to 72 years, with a mean age of 47.5 ± 19.02. Six were done in the U.S, Three in Italy, two in Spain, seven in Brazil, two in India, two in France, one in England, one in Portugal, one in Japan, one in Bangladesh, one in Kuwait, one in Qatar, one in Turkey, and one in Morocco . Most cases presented with general symptoms, such as hyperthermia, shortness of breath, cough, fatigue, anosmia, loss of sense of taste, nausea, vomiting, and diarrhea.
The most frequently affected cranial nerves among COVID-19 patients were the facial nerve (26%) and the abducens nerve (12%). [15][16][17][18]22,23,25,26,28,29,[34][35][36]. The mean time from respiratory symptoms to the onset of neurological signs was 9.6 ± 7.4 days, and the mean recovery time was 16.3 ± 15.3 days. The most frequent neurological manifestations in facial nerve paralysis were the inability to close one eye, drooping on one side of the mouth, loss of forehead wrinkling on the affected side, and deviation of angle of the mouth towards the opposite side along with drooling of saliva on the right side [19,23 ]. Regarding sixthnerve palsy, diplopia was the most common sign [25,26,28,29,34].
Generally, children were less symptomatic than adults, but neurological manifestations were observed in children with extrapulmonary symptoms. A study of 27 children with COVID-19 pediatric multisystem inflammatory syndrome (MIS-C) showed that 14.8% had acute onset of central nervous system (CNS) symptoms, including brain parenchyma causing encephalopathy, weakness, headaches, loss of reflexes, and cerebellar dysfunction [39].
Furthermore, one study reported a higher incidence of facial paralysis during the COVID-19 pandemic than in the same period in 2020, indicating a possible link between COVID-19 and peripheral facial nerve paralysis [40]. Facial nerve paralysis has also been associated with infections, most commonly herpes simplex virus, varicella-zoster, human immunodeficiency viruses, Lyme disease, and mycobacterium tuberculosis [41]. Also, vagus and hypoglossal nerve impairment were reported which can lead to swallowing difficulty [42]. However, the reported dysphagia was mostly associated with prolonged endotracheal intubation [43].
Olfactory nerve dysfunction leading to an impaired sense of smell and taste which was common among patients with COVID-19 infection and was seen to persist after the resolution of other symptoms in 63% of patients. [44]. However, most patients with olfactory dysfunctions experience the onset of olfactory impairment at the same time as COVID-19 infection [45]. Other studies have reported that taste dysfunction in COVID-19 occurs more often than olfactory impairment, and 10.2-22.5% of patients have impaired taste without olfactory dysfunction [44,46,47].

Conclusions
Our systematic review showed that the sixth and seventh cranial nerves were most affected among COVID-19 patients, and most symptoms involved isolated facial paralysis with mild to moderate impairment and no other neurological signs. Supportive care and oral steroids are the mainstays of reported treatment. Patients had complete recovery or noticeable improvement in a few days to weeks after starting the treatment, suggesting a favorable prognosis for peripheral facial palsy associated with COVID-19. Treatment for cases involving sixth-nerve palsy target management of COVID-19 and its complications. Also, olfactory nerve impairment with loss of smell and taste sensations was widely detected among COVID-19 patients.
Vagus and hypoglossal nerve impairment were reported in this review, along with the absence of the gag reflex, less effective voluntary and reflex cough, oropharyngeal dysphagia, altered sense of taste, tongue deviation, and paralysis of vocal cords. The vagus nerve and its branches supply multiple muscles in the head and neck in addition to their sensitive, sensory, and vegetative parts.
Ophthalmological manifestations due to third-nerve palsy affecting the optic nerve also were reported in this review. Symptoms included ptosis, double vision, and blurred vision. Supportive treatment and eye care were the most effective management strategies.
It is possible that some of the neurological manifestations reported in this review may not be associated with COVID-19 infection and are instead coincidental co-morbidities in the patient. Moreover, the associated sepsis and organ failure in patients with serious COVID-19 infection led to various neurological presentations that typically present in any critical condition. More research on neurological manifestations associated with COVID-19 infection is needed to determine if these observed symptoms are due to possible side effects from medication used to treat COVID-19.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.