A Systematic Review of Neurological Manifestations of COVID-19

The coronavirus can infect the upper respiratory tract, sinuses, and nose, and its severity manifests in its respiratory symptoms and neurological and psychological consequences. The majority of people who have COVID-19 present with moderate flu-like illness, and patients who are elderly with comorbid conditions, such as hypertension and diabetes, are more prone to experience severe illness and death. However, in the ongoing COVID-19 pandemic, neurological consequences have become a substantial source of morbidity and mortality. COVID-19 poses a global hazard to the nervous system because of its widespread dispersion and multiple pathogenic pathways. This review offers a critical assessment of the acute and long-term neurological effects of the COVID-19 virus. Some neurological problems include headache, dizziness, myalgia/fatigue, meningitis, ischemic/hemorrhagic stroke, and myelitis. Other people who have contracted COVID-19 also exhibit neurological features such as loss of taste and smell, reduced consciousness, and Guillain-Barré syndrome. This study seeks to help neurologists comprehend the wide range of neurologic aspects of COVID-19, as understanding neurological symptoms may help with the management and enhance the patient's outcomes.

Understanding neurological symptoms may help physicians with early diagnosis and management of COVID-19 and improve the patient's outcomes.

Review Methods
The study used the following methodological framework in conjunction with the extended Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for scoping reviews ( Figure  1).

Search Strategy and Selection Criteria
The systematic review includes observational retrospective case studies and research articles about individuals with proven COVID-19 infection and its neurologic symptoms from Google Scholar, PubMed, Cureus, and the World Health Organization database to establish an extensive pool of helpful information regarding the neurological effects of COVID-19. It includes some gray material and literature for the same purpose. We deliberately placed a search limit after December 2019, as that is when the first COVID-19 case surfaced. Some straightforward terms used for the search were "Coronavirus," "COVID-19," and "SARS-CoV-2" alone or in combination with "neurology," "neuroinvasion," "CNS," "PNS," "meningoencephalitis," "stroke," "Guillain-Barre syndrome (GBS)," "neuromuscular disorder," and "Cerebrovascular Disease-Related Symptoms."

Inclusion and Exclusion Criteria
We used cross-referencing to find any missing pertinent articles and identified neurological symptoms of COVID-19 and its underlying mechanisms as the main themes. The study included a population of all ages and sexes and articles from various parts of the world. If the papers dealt with COVID-19-positive humans, we had the full texts in English. The study omitted thematically unrelated research, animal studies, editorials, commentaries, case reports, and preprints. Instead, it focused on peer-reviewed case-control, population-based cohort studies or human clinical trials.

Data Extraction and Quality Assessment
We checked all titles and abstracts and included entire texts after discussion and 100% agreement over the papers. Variables that aided in data extraction were information about the research (name of author(s), year of publication, title), methodology (study design or type), and intervention (duration and setting). The Joanna Briggs Institute (JBI) tool was also utilized, as it offers thorough criteria for the assessment and evaluation of the majority of study types and offers thorough checklists for the evaluation and assessment of the majority of study types. Therefore, by using JBI's checklist methodology for cohort studies, case series, and case reports, we can solidify the analysis and understanding of this systematic review's findings.

Results
In total, 100 articles were reviewed, and after quality assessment, 58 were excluded. Forty-two articles were included in this review: retrospective case series, case reports, prospective case series, multicohort and multicenter studies, and systematic review articles about individuals with proven COVID-19 infection and its neurological symptoms. The sample sizes ranged from a single patient to 3,055 patients [9][10][11][12]. Several neurological signs were found, with the most prevalent neurological complaints overall being fatigue (32%), myalgia (20%), taste impairment (21%), headache (19%), and impairment of smell (21%) [13]. The study also found that stroke is the most common diagnosis of COVID-19, and we included five other sample studies to support this [2,8,[14][15][16]. Two other studies supported dizziness as a neurological symptom [13,16], while six other articles supported headaches as a common symptom. We did not base our study in one area, and the articles were from all over the world. We even included studies from China [17] and the US [18]. Two of the articles were specific studies, with one focusing on a 24-year-old [11], while the other focused on a 41-year-old [12]. Hence, it is expected that their results mirror those of other case reports and study series. One of the articles summarized and pooled information on neurological signs and symptoms from 350 studies [13] ( Table 1).  The pooled prevalence of neurological symptoms (Misra et al. [13]).

Discussion
The sharp rise in COVID-19 verified cases and deaths is evidence of person-to-person transmission by the virus. According to the Centers for Disease Control and Prevention, the virus transmits by person-to-person contact (within six feet) via respiratory droplets [9]. Due to the neurotropic properties of the virus, COVID-19 affects the central and peripheral nervous systems (CNS and PNS), either directly or indirectly. These include thrombosis complications, inflammatory side effects, hypoxia, metabolic anomalies, and labile blood pressure. Neurological signs and symptoms involving the central or peripheral nervous systems are either self-reported symptoms (such as headache and ageusia) or neurological signs or diagnoses obtained through clinical evaluation [10]. Generally, viral pathogens can enter the central nervous system (CNS) through various routes, including the hematogenous route, which involves endothelial infection, and peripheral nerve or olfactory neuron paths [22,23]. Epithelial cells in the digestive and respiratory tracts are the primary target cells for SARS-CoV-2 [24].
The SARS-CoV-2 virus may harm these cells by attaching them to angiotensin-converting enzyme-2 (ACE-2), reducing mitochondrial function and endothelial nitric oxide synthetase activity, which can indirectly affect the heart and brain. The angiotensin-converting enzyme employs angiotensin-converting enzyme-2 (ACE-2) receptors in these cells to allow a virus to enter the cells. SARS-CoV-2 can invade and harm angiotensinconverting enzyme-2 (ACE-2) receptors, leading to neurological consequences. One neurological manifestation is harm to the brain through a cytokine storm brought on by the immune system's response to the virus. It moves throughout the body and crosses the blood-brain barrier, causing infections in the brain and surrounding neurons and glial cells [25].
The blood-brain barrier and the blood-cerebrospinal fluid barrier normally protect the brain from the unrestricted passage of unwanted chemicals, viruses, and cells [24]. Brain damage may also result from cytokine release due to microglial activation and a generalized inflammatory response [14]. For example, proinflammatory cytokines with high levels in the bloodstream cause altered mental status [26,27]. Since the angiotensin-converting enzyme-2 (ACE-2) receptor controls the renin-angiotensin-aldosterone system (RAS), disrupting it can cause labile blood pressure [28].
The neurological consequences also manifest through hypoxia and lack of oxygen reaching the brain. Ischemic strokes can also result from thrombosis problems. Given that SARS-CoV-2 may affect the central nervous system (CNS) directly or indirectly, acute cerebrovascular illness, stroke, and intracranial infectionrelated symptoms are among the CNS-related manifestations linked to COVID-19 that this review explains. In 13 cases of unexplained encephalopathy, MRI brain scans showed bilateral frontotemporal hypoperfusion in 84% of the cases, leptomeningeal enhancement in 62% of the cases, and ischemic stroke in 23% of the cases [16,29].

Nonspecific neurological signs and symptoms
Patients with COVID-19 most frequently reported nonspecific symptoms, including headaches, fatigue, dizziness, and nausea.

Dizziness
In 46 case studies, dizziness had a prevalence of 7% (95% CI: 5% to 8%), and in nine other studies, headache and dizziness occurred together with a prevalence of 12% (95% CI: 8% to 17%) [13]. It is a generic symptom of many illnesses and is one of the most prevalent neurological characteristics of COVID-19, especially in patients receiving intensive care due to serious illness [16].

Headache
The most prevalent CNS symptom is headache, with prevalence rates ranging from 6.5% to 23% and a mean of 8% in several studies [7]. In a Wuhan study, 8% of patients reported headaches as a symptom [17], whereas a study from Zhejiang found that 34% of patients had headaches [19]. In another French study, 82% of the COVID-19 cases had a headache as a symptom [12]. A recent study of 130 hospitalized COVID-19 patients found that 35% had severe headaches with a frontal predominance and an oppressive nature. The study revealed that 62% of those patients suffered headaches within 24 hours of contracting the disease. Nearly half of the individuals exhibited tension-type headaches [11]. Typically, migraines, tensiontype headaches, and acute headaches brought by flu-like sickness predominate in the first few days of illness. Headaches brought on by hypoxia and systemic inflammation due to a cytokine storm may develop later. In venous sinus thrombosis and meningitis associated with COVID-19, headaches may potentially be sentinel signs [2].

Altered Mentation
Approximately 9% of people who have contracted COVID-19, especially those who are severely ill, may have impairments in their degree of consciousness [30]. Older people, particularly those with preexisting chronic medical conditions, are more likely to experience delirium or impaired consciousness. Almost onethird of patients may experience dysfunction after discharge, and more than two-thirds of critically ill patients exhibit agitation and disorientation [18]. These patients may present with encephalopathy and confusion. Furthermore, cerebral hemorrhages may cause altered mental status. Toxic-metabolic encephalopathy brought by systemic hyperinflammation, cerebrovascular events, seizures, and a potential SARS-CoV-2 CNS infection causes altered mentation in COVID-19 [29,30].

Seizures
Patients with COVID-19 have experienced recurrent transient generalized seizures and epilepsy. Most instances, if not all, had a history of seizure disorders or epileptic seizures. In a group of 32 COVID-19 patients who experienced seizures, 40% had no prior diagnosis of epilepsy or other disorders affecting the central nervous system [14].
A systematic examination of case series and reports found that 47 patients with COVID-19 experienced epilepsy. Most individuals did not have a history of previous seizures and had previous respiratory problems. COVID-19 severely affects the central nervous system because of a cytokine storm brought on by proinflammatory cytokines entering the CNS from the periphery or produced by activated microglia. Tumor necrotizing factor, granulocyte colony-stimulating factor, and the release of inflammatory cytokines are among the hypotheses to explain COVID-19-associated epilepsy. These factors can cause neuronal hyperexcitability by activating glutamate receptors, resulting in episodic seizures. Secondary seizures may develop in COVID-19 patients from strokes, electrolyte abnormalities, and elevated oxidative stress [30]. On the other hand, some scientists think that encephalitis and virus invasion of the brain may be to blame for seizures. In COVID-19 patients, a lower seizure threshold may develop even without overt inflammatory signs, leading to new-onset seizures or the recurrence of previously well-controlled seizures. However, in some circumstances, an adverse pharmacological reaction from antiviral medications such as ribavirin may cause epilepsy [14].

Anosmia and Ageusia
Scent problems and taste disorders are common in some people who have contracted the coronavirus. Over 80% of patients without nasal blockage or discharge report acute intermittent impairment in odor. The precise mechanisms underlying SARS-CoV-2 anosmia and ageusia are still unclear. Although olfactory dysfunction manifests concurrently with or after the clinical beginning of COVID-19 in 88% of cases, it could be the sentinel sign in 12% of cases [2].
The majority of the time, anosmia and ageusia are present in asymptomatic people or when the disease first manifests itself without any other symptoms. As individuals recover from SARS-COV-2 infection, most patients progressively regain their sense of taste and smell. Although other people's recovery from smell and taste impairment may take longer, 25% to 80% of instances have shown near complete resolution in under two weeks [20,32].

Guillain-Barré Syndrome
After COVID-19 infection, people around the world documented a few isolated cases of Guillain-Barré syndrome (GBS). At least 73 instances of GBS and its variations associated with COVID-19 have been documented thus far [21]. The most common clinical manifestation (70%) was flaccid-areflexic weakness with or without sensory complaints, while 10% of cases had characteristics indicative of Miller-Fisher syndrome (MFS). There have also been reports of polyneuritis cranialis (2.7%), facial diplegia (6.8%), and pharyngeal-cervical-brachial variation (1.3%) [33]. There are two reports of isolated right abducens-related ophthalmoplegia and pupillary-sparing oculomotor nerve palsy [34]. Interestingly, one-fourth of the patients had early and severe respiratory impairment, probably caused by the brainstem respiratory center's involvement [35]. Most of these individuals showed progressing limb weakness that worsened over one to four days [36]. Similar to other viral infections linked to GBS, there is a five-to 16-day lag between the onset of viral illness and the emergence of muscle weakness [33].
While neurological symptoms typically started to arise during the first week of illness and were indicative of an immune-mediated postinfectious pathology, one case had a neurological beginning indicative of autoimmune para-infectious pathology. However, it is unclear whether COVID-19 is more likely to cause GBS. Although numerous studies have discovered a connection between SARS-CoV-2 infection and GBS, further information is required to validate the association and pinpoint the precise mechanism. Researchers should assess epidemiological data about the alleged infectious agent and GBS to validate the link between COVID-19 and GBS. Direct viral invasion may not be as important in developing COVID-19-related GBS as indirect immune-mediated mechanisms such as neuroinflammation and molecular mimicry. Additionally, additional molecular analysis is required to pinpoint the precise process that results in GBS following SARS-CoV-2 infection [37].

Muscle Involvement
Since angiotensin-converting enzyme-2 (ACE-2) is present in skeletal muscle, SARS-CoV-2 may associate with it and infect the muscle. SARS-CoV-2 can directly target the nervous system by binding to angiotensinconverting enzyme-2 (ACE-2) and inflicting skeletal muscle injury, or it can enter the central nervous system via peripheral nerves. Skeletal muscle damage is a sign of nervous system dysfunction. Myalgia may result from injury to the skeletal muscles. Myalgia shows muscular pain and discomfort from local or systemic infection. Patients with COVID-19 who complained of muscle problems had higher levels of creatine kinase (CK) and lactate dehydrogenase (LDH). This prevalent symptom of COVID-19 manifests in 10%-74% of cases [2].
In one study, 11% of hospitalized COVID-19 cases had skeletal muscle injury with elevated blood creatinine kinase levels > 200 U/L, particularly in patients with hepatic and renal failure [38]. COVID-19 cases document that rhabdomyolysis causes weakness, discomfort, and tenderness in the lower limbs. Some patients experienced weariness, discomfort in their muscles, and higher levels of muscle enzymes, which may indicate virus-induced muscle damage and inflammation [39][40][41].

Conclusions
This is the first time in a long time that a virus (the coronavirus) has spread over the globe, and it has caused a significant change in how people do things. The health industry was under a lot of strain trying to limit its spread. Several worldwide health organizations collaborated to battle this disaster. For those in the medical field, the COVID-19 epidemic poses some difficulties that present in various neurological ways, and in many cases, neurological symptoms may appear before normal respiratory symptoms. This review proves that numerous neurological symptoms of COVID-19 are possible. It is essential to have a comprehensive understanding of the range of COVID-19's neurological effects if we want to stop the virus's spread. As the outbreak gradually subsides, the number of postinfectious neurological problems, including GBS, will also decrease. Although neurological symptoms are frequently present in severe cases, neurologists and other medical personnel should diagnose patients with a solely neurological presentation with extreme caution.
Generally, clinicians need to be mindful of potential neurological and cognitive issues following COVID-19, particularly in elderly patients, patients with cognitive impairment, or patients with psychiatric comorbidities. When treating and managing patients with neurological comorbidities, especially those who are using immunosuppressants, medical personnel must take the appropriate caution. The overview of COVID-19's neurological manifestations provided above will aid the neurologist in making the necessary preparations, which are crucial for avoiding infections. People should have a neuropsychological evaluation or cognitive screening if there are cognitive concerns following COVID-19 and consult a psychiatrist or psychologist in cases of complex cognitive or emotional issues following 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.